EA040614B1 - COMPOSITIONS - Google Patents

Description

Technical field

The present invention relates to a formulation containing a pharmaceutically active ingredient and a coating. The present invention also relates to the use of the composition for the treatment and prevention of disorders of the gastrointestinal tract. Methods for preparing the compositions are also disclosed.

BACKGROUND OF THE INVENTION

Formulating pharmaceutically active ingredients into a form suitable for administration to a patient is an advanced field of science. It is also a key factor in the effectiveness of the drug. There are many examples of methods for formulating drugs and other active ingredients. The purposes of these formulations are varied and can range from increasing systemic absorption, which allows for new routes of administration, to improving bioavailability, which reduces the metabolism of the active ingredient or avoids unwanted routes of administration.

International application WO 2008/122965 discloses oral compositions of cyclosporine microcapsules with modified release properties that release cyclosporine at least in the colon. WO 2010/133609 discloses compositions containing a water-soluble polymer matrix in which oil droplets are dispersed, the compositions comprising a modified release coating. The disclosed compositions also contain an active ingredient.

Brief summary of the present invention

Surprisingly, pharmaceutical formulations having a coating that is or contains a water-soluble cellulose ether have been found to have a higher overall release of the active ingredient from the formulation and/or a faster release rate of the active ingredient compared to an uncoated formulation. This coating constitutes the first coating. The first coating may also be referred to as the inner coating. The greater degree and/or rate of release of the active ingredient provides a formulation that has a new in vitro release profile (and hence a new in vivo pharmacokinetic profile) compared to the same uncoated formulations. In vitro dissolution testing has also shown that the formulations of the present invention reduce batch to batch variability in the in vitro release profile. Therefore, formulations are expected to exhibit reduced patient and/or interpatient variability compared to uncoated formulations.

The composition may contain a second coating to control or modulate the release from the composition of the active ingredient, such as cyclosporine A, mesalazine and hydralazine. Preferably, the coating is a polymeric coating to provide delayed and/or sustained release from the formulation of the active ingredient, for example, cyclosporine A, mesalazine and hydralazine. Such acceptable coatings are described in more detail below and include a coating that is or comprises a coating selected from a controlled release polymer, a sustained release polymer, an enteric soluble polymer, a pH independent polymer, a pH dependent polymer, and a polymer, especially susceptible to degradation by bacterial enzymes in the gastrointestinal tract, or a combination of two or more of these polymers. In a specific embodiment, the second coating is or contains a pH independent polymer, such as a coating that is or contains ethyl cellulose. In a further specific embodiment, the second coating is or contains a pH-independent polymer, such as ethyl cellulose, and a water-soluble polysaccharide, such as pectin or chitosan, or a combination thereof, such as pectin. The respective polymers of the first coating and the second coating are different. Often, the second coating does not contain any of the polymer found in the first coating, for example, if the first coating contains (eg is) hydroxypropyl methylcellulose, then the second coating will also not contain hydroxypropyl methylcellulose. In addition, it is contemplated that if the first coating is or contains a water-soluble ester or ester of cellulose ester, then the main component(s) (for example, more than 50%) of the second coating is (are) or contains (at ) polymer other than the polymer in the first coating. Therefore, the first and second coatings suitably provide two layers of substance as part of the composition. It should also be understood that if the second coating contains a mixture of components, then the minor components of the outer second coating may be the same as the substance of the inner coating. By way of example, if the first coating is or contains HPMC and the second coating contains ethyl cellulose, then the ethyl cellulose may optionally additionally contain a minor amount (e.g., less than 50%, 40%, 30%, or 20%) of the first coating material, in this example HPMC. According to such embodiments, the first coating and the second coating are considered different.

According to an embodiment of the present invention, the active ingredient optionally is or contains cyclosporin A, hydralazine, or mesalazine, said coating, which is or contains a water-soluble cellulose ether, is the first coating, and the composition further comprises a second coating on the outside of the first coating, and wherein the second coating is or comprises a coating, preferably a polymeric coating, to control or modulate the release of the active ingredient from the formulation. The polymeric coating may be a coating, described later in other parts of this description.

In accordance with the present invention, the first coating is preferably or contains a water-soluble cellulose ether. The water-soluble cellulose ether can be any cellulose ether or cellulose ether derivative, for example a cellulose ether ester, which is water-soluble. Thus, the water-soluble cellulose ether can be selected from alkylcellulose, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, and carboxyalkylcellulose. Preferably, the first coating is or contains one or more water-soluble cellulose ethers selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, as well as combinations thereof. In specific embodiments, the first coating is or contains water-soluble hydroxypropyl methylcellulose. The water-soluble cellulose ether and its water-soluble derivatives (e.g. water-soluble cellulose ether esters) comprise in the first coat (inner coat) preferably at least 20%, 40%, 50%, 60%, 70%, 80%, 85% or 90% by weight based on the dry weight of the first coating.

The composition of the present invention may comprise a core, a first coating on the outside of the core, where the first coating is the water-soluble cellulose ether described above and elsewhere herein, and a second coating on the outside of the first coating, where the core contains a hydrogel-forming polymer matrix and a pharmaceutically active ingredient, optionally a hydrophobic or hydrophilic active ingredient, such as cyclosporine A, hydralazine or mesalazine.

The present invention relates to a pharmaceutical composition comprising a core and a coating, wherein the core comprises a hydrogel-forming polymeric matrix and a pharmaceutically active ingredient, and the coating comprises or is a water-soluble cellulose ether, and the coating is present in an amount corresponding to the increase in weight due to the coating by 0 .5-20% of the mass of the nucleus.

The coating according to the present invention modifies the release of the active ingredient from the formulation. The coating on the formulation is expected to slow down the rate of release of the active ingredient in the formulation. It is reasonable to expect that coating the composition with an additional material will provide an additional barrier to the dissolution medium coming into contact with the active ingredient in the composition. Contrary to this expected result, the present invention unexpectedly provides a coated formulation containing or being a water-soluble cellulose ether which increases the rate of release of the active ingredient compared to an uncoated formulation. In addition, the coating of the present invention has the beneficial effect of keeping the active ingredient in solution, while a comparable uncoated formulation of the present invention provides less active ingredient in solution over time. Without wishing to be bound by theory, it is believed that the coating prevents precipitation of the active ingredient from solution, thereby maintaining a higher amount of active ingredient in solution.

Throughout this application, the terms active ingredient, active ingredient and pharmaceutically active ingredient are used interchangeably and they all refer to the same object of the invention.

The composition according to the present invention may take any form known to the person skilled in the art. Preferably the formulation is an oral formulation. The composition may be in the form of a single mini-granule or a plurality of mini-granules.

The composition may contain a coating present in an amount corresponding to the increase in weight due to the coating, selected from the ranges from 0.5 to 15%, from 1 to 15%, from 1 to 12%, from 1 to 10%, from 1 to 8% , 1 to 6%, 1 to 4%, 2 to 10%, 2 to 8%, 2 to 6%, 2 to 7%, 2 to 4%, 4 to 8%, from 4 to 7%, 4 to 6%, 5 to 7%, 7 to 20%, 7 to 16%, 9 to 20%, 9 to 16%, 10 to 15% and 12 to 16%.

The composition according to the present invention may contain a coating with a thickness of 1 µm to 1 mm. Thus, the percentage weight gain due to the coating as defined above may correspond to a thickness of 1 µm to 1 mm.

The present invention also relates to a pharmaceutical composition comprising a core and a coating, wherein the core contains a hydrogel-forming polymeric matrix and a pharmaceutically active ingredient, wherein the coating contains or is a water-soluble cellulose ether and the coating has a thickness of 1 µm to 1 mm.

The coating may have a thickness selected from the ranges from 1 to 500 µm, from 10 to 250 µm, from 10 to 100 µm, from 10 to 50 µm, from 10 to 20 µm, from 50 to 100 µm, from 100 to 250 µm, 100 to 500 µm, 50 to 500 µm, 50 to 250 µm, 100 to 1 mm, 500 to 1 mm. The coating with the thickness disclosed in this paragraph may be any of the coatings according to this application. In particular, the coating referred to in this paragraph may be a coating of water-soluble cellulose ether.

- 2 040614

Any of the pharmaceutical compositions of the present invention may contain an additional or second coating. The second coating may be on the outside of the first coating. The second coating may be or contain a delayed release polymer. If the compositions according to the present invention contain a second coating, then the aforementioned coating may be referred to as the first coating. Any disclosure below in relation to the second coating also applies to the second coating referred to in this paragraph. According to any embodiment and any aspect of the present invention, the first and second coatings may be different.

The present invention thus encompasses a pharmaceutical formulation comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core contains a pharmaceutically active ingredient, the first coating comprises or is a water soluble cellulose ether and the second coating comprises or is a delayed polymer release, wherein the first coating is present in an amount corresponding to the increase in mass due to the coating from 0.5 to 20% of the mass of the core. The core may optionally further comprise a hydrogel-forming polymer.

In addition, the present invention relates to a pharmaceutical composition comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core contains a pharmaceutically active ingredient, the first coating contains or is a water-soluble cellulose ether, the second coating contains or is a delayed polymer release and the first coating has a thickness of 1 µm to 1 mm. The core may optionally further comprise a hydrogel-forming polymer.

The present invention relates to a pharmaceutical composition comprising a core and a coating, wherein the core contains a pharmaceutically active ingredient and the coating contains or is a water-soluble cellulose ether. The coating is present in an amount that provides a higher percentage in solution of the pharmaceutical active ingredient from the formulation than from the uncoated formulation 0.5 hour after the start of the dissolution test to measure the percentage in solution of the pharmaceutical active ingredient in a dissolution medium consisting of water, at The dissolution test is then performed according to USP <711> Dissolution using Apparatus II (paddle apparatus) operated at 75 rpm paddle speed and with dissolution medium at 37±0.5°C. Alternatively, a higher percentage in solution of the active ingredient from the formulation may be observed 20, 40 minutes, 1 or 1.5 hours after the start of the dissolution test, rather than 0.5 hours. In addition, a higher percentage in solution of the active ingredient from the composition can be observed at time points selected from 20 and 40 minutes, 0.5 and 1 h, 1 and 1.5 or 0.5 h, 1 and 1.5 h. The percentage in solution of the active ingredient from the composition may be more high for a period selected from one of 0 to 0.5 hours, 0 to 1 hours, 0 to 1.5 hours, or 0.5 to 1.5 hours. of the composition according to the present invention is higher than from the composition without coating, for a period of up to 1.5 hours after the start of the dissolution test.

In embodiments, a higher percentage in solution of the pharmaceutically active ingredient is observed after 0.5 hours and at a time selected from 20, 40 minutes, 1, 1.5 hours, and any combination thereof. In embodiments, a higher percentage in solution of the pharmaceutically active ingredient can be observed for up to 1.5 hours after the start of the dissolution test.

The percentage in solution of the active ingredient of the coated formulation of the present invention may be higher than that of the uncoated formulation at a particular time by 10 or more, 15 or more, 20 or more, 30 or more, 40 or more, or 45 or more after 0 .5 h; 10 or more, 15 or more, or 20 or more after 1 hour; and/or 3 or more, 5 or more, 8 or more, or 10 or more after 1.5 hours. point in time, or if a period is specified.

For example, the coated composition of the present invention may give a percentage in solution of 10 or more after 0.5 hours, and 10 or more after 1 hour, and 5 or more after 1.5 hours.

According to an aspect of the present invention, it is contemplated that the coating may furthermore be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 1 to 15%, from 1 to 12%, from 2 to 15%, from 2 to 12%, from 1 up to 9%, 2 to 8%, 2 to 3%, 2 to 5%, 5 to 7%, 4 to 6.5%, 6 to 7% or 2 to 7%. Preferably, the coating may be present in an amount corresponding to a weight gain of 1 to 9%, 2 to 8%, 4 to 6.5%, 2 to 5%, or 2 to 7%, optionally 4 to 6.5%. , 2 to 5% or 2 to 7%. The percentage increase in weight of the coating relative to the core can be combined with any of the defined higher percentages in solution and at any point in time.

For example, the coating may be present in an amount corresponding to a higher percentage in the pharmaceutically active ingredient solution after 0.5 hour, while the percentage in the active ingredient solution may be 30, optionally 35 higher, and the coating may be present in an amount corresponding to the percentage increase mass relative to the mass of the core from 2 to 7%, optionally from 2 to 4%. Alternatively, the coating may be present in an amount corresponding to a higher percentage in the solution of the pharmaceutically active ingredient after 0.5 hours, whereby the percentage in the solution of the active ingredient may be 40, optionally 45 higher, and the coating may be present in an amount corresponding to the percentage an increase in mass relative to the mass of the core from 4 to 7%, optionally from 5 to 7%.

The present invention also encompasses a composition comprising a core and a coating, wherein the core contains a pharmaceutically active ingredient and the coating contains or is a water-soluble cellulose ether. The coating is present in an amount that provides a percentage in solution of more than 60% of the pharmaceutical active ingredient 1 hour after the start of a dissolution test to measure the percentage in a solution of the pharmaceutical active ingredient in a dissolution medium consisting of water, the dissolution test being performed according to USP <711> Dissolution using Apparatus II (apparatus with a paddle) operating at a paddle speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C. Alternatively, the percentage in solution of the active ingredient may be more than 65%, 70%, 75%. The percentage in solution can also be selected from the range of 60 to 90%, 65 to 85%, 68 to 83%, 68 to 73%, 72 to 78%, 75 to 85%, or 77 to 83% , from 68 to 78%, preferably from 68 to 83%.

In combination with or alternatively to any of the amounts corresponding to the percent in solution disclosed in the previous paragraph, the coating may be present in an amount, additionally or alternatively, providing a percent in solution greater than 35, 38, 48, 50, 60, 65, 70 or 75% after 0.5 hours from the start of the dissolution test and/or more than 75% after 1.5 hours.

According to an aspect of the present invention, it is contemplated that the coating may furthermore be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 1 to 15%, from 1 to 12%, from 2 to 15%, from 2 to 12%, from 1 up to 9%, 2 to 8%, 2 to 3%, 2 to 5%, 5 to 7%, 4 to 6.5%, 6 to 7% or 2 to 7%. Preferably, the coating may be present in an amount corresponding to a weight gain of 1 to 9%, 2 to 8%, 4 to 6.5%, 2 to 5%, or 2 to 7%, optionally 4 to 6.5%. , 2 to 5% or 2 to 7%. The percentage increase in weight of the coating relative to the core can be combined with any of the defined percentage values in solution and at any point in time.

For example, the coating may be present in an amount to provide a percentage in solution of greater than 70%, optionally greater than 75%, or 70 to 90%, or 75 to 85% of the pharmaceutically active ingredient after 1 hour, and the coating may be present in an amount corresponding to the percentage increase in weight relative to the weight of the core from 2 to 7%, optionally from 2 to 4% or 5 to 6%. Alternatively, the coating may be present in an amount to provide a percentage in solution of greater than 65%, optionally greater than 68%, or 65 to 90%, or 68 to 78% of the pharmaceutically active ingredient after 1 hour, and the coating may be present in an amount corresponding to percentage increase in mass relative to the mass of the core from 9 to 20%, optionally from 9 to 16% or 10 to 15%.

The present invention also relates to a pharmaceutical composition comprising a core and a coating, wherein the core contains a pharmaceutically active ingredient, optionally a hydrophobic active ingredient, and the coating contains or is a water-soluble cellulose ether. The coating is present in an amount to provide a percentage in solution of the pharmaceutically active ingredient greater than 75%, optionally 80%, 12 hours after the start of the dissolution test in a dissolution medium consisting of water, the dissolution test being performed according to USP <711> Dissolution using apparatus II (apparatus with a blade) operating at a blade speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C. Alternatively or in addition to a coating present in an amount to provide a percentage in solution of the pharmaceutically active ingredient greater than 75% after 12 hours, the coating may be present in an amount to provide a percentage in solution of the pharmaceutical active ingredient greater than 70% (e.g., greater than 75% or 80% ) after 14 hours, more than 60% (for example, more than 65, 70, or 75%) after 16 hours, more than 50% (for example, more than 55, 60, 65, or 70%) after 18 hours, more than 40% (for example, more 45, 50, 55, 60, 65, or 70%) after 20 hours, more than 40% (for example, more than 45, 50, 55, 60, 65, or 70%) after 22 hours, or 35% (for example, more than 40, 45 , 50, 55, 60, or 65%) after 24 hours. In an embodiment, the coating is present in an amount providing the percent in solution defined in this paragraph at one or more of the time points defined in this paragraph.

For example, in an embodiment, the percentage in solution is greater than 75% after 12 hours and greater than 35%, optionally greater than 50% after 24 hours. Alternatively, the percentage in solution is greater than 80% after 12 hours and greater than 50% after 24 hours. The percentage in solution can be over 75% after 12 hours and over 70% after 14 hours. The percentage in solution can be over 75% after 12 hours and over 60% after 16 hours. The percentage in solution can be over 75% after 12 hours and more than 50% after 18 hours. The percentage in solution can be more than 75% after 12 hours and more than 40% after 20 hours. The percentage in solution can be more than 75% after 12 hours and more than 40% after 22 hours. The percentage in solution can be more than 75% after 12 hours, more than 60% after 16 hours and more than 35% after 24 hours. The percentage in solution can be more than 75% after 12 hours,

- 4 040614 more than 70% after 14 hours, more than 60% after 16 hours, more than 50% after 18 hours, more than 40% after 20 hours, more than 40% after 1 hour and more than 35% after 24 hours.

According to an aspect of the present invention, it is contemplated that the coating may furthermore be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 7 to 20%, from 8 to 20%, from 9 to 20%, from 8 to 17%, from 8 up to 16%, from 9 to 16%, from 10 to 15%, from 12 to 17%, from 8 to 12% or from 9 to 12%. Preferably, the coating may be present in an amount corresponding to a weight gain of 9 to 16%, 10 to 15%, 12 to 17%, 8 to 12% or 9 to 12%, optionally 9 to 16% or 10 to 15%. The percentage increase in weight of the coating relative to the core can be combined with any of the defined percentage values in solution and at any point in time.

For example, the coating may be present in an amount to provide a percentage in solution of greater than 70%, optionally greater than 75% or 80% of the pharmaceutically active ingredient after 12 hours, and the coating may be present in an amount corresponding to a percentage weight increase relative to the core weight of 9 to 16%, from 10 to 15%, 12 to 17%, 8 to 12% or 9 to 12%, optionally 9 to 16% or 10 to 15%. Alternatively, the coating may be present in an amount to provide a percentage in solution of greater than 70%, optionally greater than 75% or 80% of the pharmaceutically active ingredient after 12 hours and greater than 50%, optionally greater than 50%, 55%, 65%, 70% or 75% after 16 hours, and the coating may be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 9 to 16%, from 10 to 15%, from 12 to 17%, from 8 to 12% or from 9 to 12%, optionally from 9 to 16% or 10 to 15%. The following such combinations of features are contemplated by the present invention.

The present invention also relates to a pharmaceutical composition comprising a core and a coating, wherein the core contains a pharmaceutically active ingredient, optionally a hydrophobic active ingredient, and the coating contains or is a water-soluble cellulose ether. The coating is present in an amount to provide a higher percentage in solution of the pharmaceutically active ingredient of the formulation than the corresponding uncoated formulation 12 hours after the start of the dissolution test in a dissolution medium consisting of water, the dissolution test being performed according to USP <711> Dissolution using Apparatus II (apparatus with a paddle) operating at a paddle speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C. As an alternative or in addition to the coating present in an amount that provides a higher percentage in solution of the pharmaceutically active ingredient after 12 hours, a higher percentage in solution of the active ingredient from the formulation can be observed after 10, 11, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24 hours, or any combination of one or more of these, from the start of the dissolution test.

A hydrophobic active ingredient is any active ingredient that is substantially insoluble in water. The active ingredient may have some water solubility. Thus, a hydrophobic active ingredient is an active ingredient that is more readily soluble in the non-aqueous phase than in water. In addition, the hydrophobic active ingredient may be an active ingredient that falls into class II or class IV of the biopharmaceutical classification system, which classes include high permeability, low solubility drugs and low permeability, low solubility drugs, respectively.

The solubility of the components according to the present invention, for example, active compounds, functional components, and the like. in a solvent (eg water) can be determined as follows (solubility is measured at 25° C. and parts are by weight).

descriptive group parts solvent to 1 part solute Very well soluble less than 1 Highly soluble 1 to 10 Soluble from 10 to 30 Moderately soluble from 30 to 100 Poorly soluble from 100 to 1000 Very poorly soluble from 1000 to 10000 Practically insoluble over 10000

In embodiments, the coating is present in an amount that provides a higher percentage in solution of the pharmaceutically active ingredient from the formulation than from the corresponding uncoated formulation, at time points selected from the following combinations: 10 and 12 hours; 12 and 14 h; 12, 14 and 16 hours; 12, 14, 16 and 18 hours; as well as 12, 14, 16, 18 and 20 hours.

In embodiments, the coating is present in an amount that provides a higher percentage in solution of the pharmaceutically active ingredient from the formulation than from the corresponding uncoated formulation for a period selected from one of 8 to 16 hours, from

- 5 040614 to 16h, 10h to 18h, 10h to 24h, 12h to 18h, 12h to 22h, 12h to 24h, 4h to 24h and 0h to 24h, preferably from 12 to 24 h.

In addition, the percentage in solution of a coated formulation may be higher than that of a corresponding uncoated formulation at a particular time by more than 5 or 10 in 12 hours, 5, 10 or 15 in 14 hours, 5, 10, 15 , 20 or 25 after 16 hours, 5, 10, 15, 20, 25 or 30 after 18 hours, 5, 10, 15, 20, 25, 30 or 35 after 20 hours, 5, 10, 15, 20, 25, 30 or 35 after 22 hours and/or 5, 10, 15, 20, 25, 30, 35 or 40 after 24 hours. more than one point in time is defined, or if a period is defined.

For example, the percent in solution of a coated formulation may be higher than that of a corresponding uncoated formulation by more than (optionally 10) after 12 hours; or (optionally 10) after 12 hours and 10 (optionally 15) after 14 hours; or (optionally 10) after 12 hours, 10 (optionally 15) after 14 hours and 15 (optionally 20) after 16 hours; or (optionally 10) after 12 hours, 10 (optionally 15) after 14 hours, 15 (optionally 20) after 16 hours, and 20 (optionally 25) after 18 hours; or (optionally 10) after 12 hours, 10 (optionally 15) after 14 hours, 15 (optionally 20) after 16 hours, 20 (optionally 25) after 18 hours, and 25 (optionally 30) after 20 hours; or (optionally 10) after 12 hours, 10 (optionally 15) after 14 hours, 15 (optionally 20) after 16 hours, 20 (optionally 25) after 18 hours, 25 (optionally 30) after 20 hours and 20 (optionally 25) after 22 hours; or (optionally 10) after 12 hours, 10 (optionally 15) after 14 hours, 15 (optionally 20) after 16 hours, 20 (optionally 25) after 18 hours, 25 (optionally 30) after 20 hours, 20 (optionally 25) after 22 hours and 20 (optionally 30) after 24 hours.

By way of illustration, the percentage in solution achieved by the formulation of the present invention may be 50% after 12 hours, and the percentage in solution achieved by the corresponding uncoated formulation may be 40% after 12 hours, in which case the percentage in solution for the coated formulation higher than for the uncoated composition by 10.

According to an aspect of the present invention, it is contemplated that the coating may furthermore be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 5 to 20%, from 7 to 20%, from 8 to 20%, from 9 to 20%, from 8 up to 17%, from 8 to 16%, from 5 to 16%, from 9 to 16%, from 10 to 15%, from 12 to 17%, from 8 to 12% or from 9 to 12%. Preferably, the coating may be present in an amount corresponding to a weight gain of 9 to 16%, 10 to 15%, 12 to 17%, 8 to 12% or 9 to 12%, optionally 9 to 16% or 10 to 15%. The percentage increase in weight of the coating relative to the core can be combined with any of the defined percentage values in solution and at any point in time.

For example, the coating may be present in an amount that provides a higher percentage in solution of the pharmaceutically active ingredient after 12 hours (i.e., a higher percentage in solution than that achieved by the corresponding uncoated formulation), while the percentage in solution of the active ingredient may be higher by 5, optionally 10, and the coating may be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 9 to 16%, from 10 to 15%, from 12 to 17%, from 8 to 12%, or from 9 to 12%, optionally 9 to 16% or 10 to 15%. Alternatively, the coating may be present in an amount that provides a higher percentage in solution of the pharmaceutically active ingredient after 12 hours, while the percentage in solution of the active ingredient may be 5, optionally 10, and 5, optionally 10, 15, 20, or 25 higher. , after 16 hours, and the coating may be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 9 to 16%, from 10 to 15%, from 12 to 17%, from 8 to 12% or from 9 to 12%, optionally 9 to 16% or 10 to 15%.

The present invention relates to a pharmaceutical composition comprising a core and a coating, wherein the core contains a pharmaceutically active ingredient and the coating contains or is a water-soluble cellulose ether. The coating is present in an amount that reduces (compared with the corresponding uncoated formulation) the percentage in solution of the pharmaceutical active ingredient by 15 or less over a period of 10 to 16 hours after the start of the dissolution test in a dissolution medium consisting of water, while the test for dissolution is performed according to USP <711> Dissolution using apparatus II (paddle apparatus) operating at a paddle speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C.

Alternatively, the period may be selected from 8 am to 4 pm, 6 am to 4 pm, 4 am to 4 pm, 8 am to 2 pm, 6 am to 2 pm, 4 am to 2 pm, 8 am to 6 pm , 6 to 18 hours, or 4 to 16 hours. The percent reduction in solution can be 10 or less, 8 or less, 5 or less, or 3 or less. The decrease in percentage in the solution can be any amount selected from 15 or less, 10 or less, or 5 or less, at any given point in time.

For example, the decrease in percentage in solution may be 10 or less over a period of

- 6 040614 to 16 hours The decrease in the percentage in solution may be 15 or less over a period of 4 to 18 hours The decrease in the percentage in solution may be 10 or less over a period of 4 to 18 hours The decrease in the percentage in solution may be 8 or less over a period of 4 to 18 hours. The percentage decrease in solution may be 10 or less over a period of 4 to 16 hours. The percentage decrease in solution may be 8 or less over a period of 4 to 16 hours. percentage reduction in solution may be 3 or less over a period of 6 to 12 hours. Percentage reduction in solution may be 15 or less over a period of 6 to 16 hours. Percentage reduction in solution may be 10 or less over a period of 6 to 16 hours. The decrease in percentage in solution can be 5 or less over a period of 6 to 16 hours.

According to an aspect of the present invention, it is contemplated that the coating may furthermore be present in an amount corresponding to a percentage increase in mass relative to the mass of the core from 5 to 20%, from 7 to 20%, from 8 to 20%, from 9 to 20%, from 8 up to 17%, from 8 to 16%, from 9 to 16%, from 5 to 16%, from 10 to 15%, from 12 to 17%, from 8 to 12% or from 9 to 12%. Preferably, the coating may be present in an amount corresponding to a weight gain of 9 to 16%, 10 to 15%, 12 to 17%, 8 to 12% or 9 to 12%, optionally 9 to 16% or 10 to 15%. The percentage increase in weight of the coating relative to the core can be combined with any of the defined percentage values in solution and at any point in time.

Throughout the disclosure of this application, any change in the percentage in solution, for example, if it is indicated that the percentage in solution is higher by a certain value or the percentage in solution is lower by a certain value, the value of the change has been given in the form of a number. This figure indicates the absolute amount by which the percentage in solution has changed, for example, if it is indicated that the percentage in solution of the active ingredient of the composition according to the present invention with a coating is higher than that of the uncoated composition, this means that if the percentage in solution of the composition uncoated is 50%, then the percentage in solution of the composition according to the present invention will be more than 60%.

The present invention also relates to a pharmaceutical composition comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core contains a pharmaceutically active ingredient, the first coating contains or is a water-soluble cellulose ether, in addition, the second coating contains or is a polymer delayed release, wherein the first coating is present in an amount that provides a higher percentage of release of the pharmaceutically active ingredient from the pharmaceutical composition than from the corresponding pharmaceutical composition without the first coating 12 hours after the start of the dissolution test.

Unless otherwise indicated, the dissolution medium used in a dissolution test according to any aspect of the present invention may be a dissolution medium, which is a typical in vivo medium in which the composition is intended to be used, in particular in aspects of the present invention in which the first coating and second coating. In such embodiments, the dissolution test can be any dissolution test known to one of skill in the art and representing the gastrointestinal tract. Preferably, the dissolution test is performed according to USP <711> Dissolution using Apparatus II (paddle apparatus) operating at 75 rpm paddle speed and with appropriate dissolution medium at 37°C.

According to embodiments of the present invention, the dissolution test may be a two-stage dissolution test, and this two-stage dissolution test may consist of a first stage, providing a dissolution medium of 750 ml of 0.1 N HCl, into which the composition is placed, and a second stage, starting after 2 h, while 250 ml of 0.2 M trisubstituted sodium phosphate containing 2% sodium dodecyl sulfate (SDS) are added to the dissolution medium and the pH is adjusted to 6.8. This dissolution test may be particularly useful for measuring the release from a formulation of hydrophobic active ingredients such as cyclosporine.

In other embodiments, the dissolution test may include a dissolution medium consisting of 1000 ml of 0.05 M pH 7.5 phosphate buffer prepared by dissolving potassium dihydrogen phosphate and sodium hydroxide in water. This dissolution test may be particularly useful for measuring the release from a formulation of hydrophilic active ingredients such as hydralazine and mesalamine. Specifically, the dissolution test may be the dissolution test described below: 0.05 M at pH 7.5 of a phosphate buffer prepared by dissolving 6.8 g of potassium dihydrogen phosphate and 1 g of sodium hydroxide in water to obtain 1000 ml of a solution and adjusting the pH with 10 N sodium hydroxide to 7.5±0.05, 900 ml are used in USP apparatus 2 with a blade speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C.

In particular, a two-stage dissolution test is performed according to USP <711> Dissolution using apparatus II (paddle apparatus) operating at a paddle speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C. In the first stage of the test, the dissolution medium is 750 ml of 0.1 N HCl, which mimics the intragastric environment. After the start of the test (t=0), the sample is placed in

- 7 040614 dissolution medium. After 2 hours, start the second stage of the dissolution test. In the second step, 250 ml of 0.2M tribasic sodium phosphate containing 2% sodium dodecyl sulfate (SDS) is added to the dissolution medium and the pH is adjusted to 6.8±0.05 with 2N NaOH or 2N HCl if necessary.

In any of the formulations containing the first coating and the second coating, the first coating may be present in an amount that provides a higher percentage of release of the pharmaceutically active ingredient at any time after 3 hours after the start of the dissolution test. For example, a higher percentage of release can be observed after 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. A higher percentage of release can be observed at one or more time points, preferably at one or more consecutive time points.

For example, a higher percentage of release can be observed after 3 and 4 hours; 3, 4 and 5 hours; 3, 4, 5, 11, 12 and 13 hours; 11, 12 and 13 hours; or 11, 12, 13, 14, 20, 21, 22 and 24 hours.

A higher percentage of release can be observed during a period selected from one or a combination of periods from 11 to 12 hours, from 11 to 13 hours, from 12 to 13 hours, from 11 to 14 hours, from 10 to 14 hours, from 18 to 22 h, 20 to 24 h, 4 to 8 h, 3 to 8 h, 3 to 12 h, 3 to 6 h, 8 to 14 h, 8 to 18 h, 8 to 22 h, 6 to 22 hrs, 8 to 24 hrs, 4 to 14 hrs, 4 to 18 hrs, 4 to 22 hrs, 4 to 24 hrs, 3 to 20 hrs, 3 to 22 hrs, or 3 up to 24 hours

A higher percentage of release can be observed after 16, 17 and 18 hours, or after 14, 15, 16, 17 and 18 hours. A higher percentage of release can be observed during the period from 18 to 22 hours or from 20 to 24 hours. Optional dissolution medium is deionized water.

In addition, the percent in solution of the coated formulation may be higher than that of the corresponding uncoated formulation at a particular time by more than 5, 10, 15, 20, or 25 after 12 hours; 5, 10, 15 or 20 after 14 hours; 5, 10, 15 or 20 after 16 hours; 5, 10, 15 or 20 after 18 hours; 5, 10 or 15 after 20 hours; 5 or 10 after 22 hours; 5 or 10 after 24 hours; 5, 10, 15, 20 or 25 after 10 hours; 5, 10, 15 or 20 after 8 hours; 5, 10, 15 or 20 after 6 hours; 5 or 10 after 4 hours. Higher percent in solution values disclosed herein can be achieved if one time point is specified, more than one time point is specified, or if a period is specified.

For example, the percent in solution of a coated formulation may be higher than that of a corresponding uncoated formulation by more than (optionally 10, 15, 20, or 25) after 12 hours; or (optionally 10, 15, 20 or 25) after 12 hours and 5 (optionally 10, 15 or 20) after 14 hours; or (optionally 10, 15, 20 or 25) after 10 hours and 5 (optionally 10, 15, 20 or 25) after 12 hours; or (optionally 10, 15 or 20) after 8 hours, 5 (optionally 10, 15, 20 or 25) after 10 hours and 5 (optionally 10, 15, 20 or 25) after 12 hours; or (optionally 10, 15, or 20) after 6 hours, 5 (optionally 10, 15, or 20) after 8 hours, or 5 (optionally 10, 15, 20, or 25) after 10 hours, and 5 (optionally 10, 15, 20, or 25) after 12 hours; or (optionally 10, 15, 20 or 25) after 12 hours, 5 (optionally 10, 15 or 20) after 14 hours and 5 (optionally 10, 15 or 20) after 16 hours; or (optionally 10, 15, 20 or 25) after 10 hours, 5 (optionally 10, 15, 20 or 25) after 12 hours and 5 (optionally 10, 15 or 20) after 14 hours; or (optionally 10, 15, 20, or 25) after 10 hours, 5 (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15, or 20) after 14 hours, and 5 (optionally 10, 15, or 20) after 16 hours; or (optionally 10, 15, 20 or 25) after 12 hours, 5 (optionally 10, 15 or 20) after 14 hours, 5 (optionally 10, 15 or 20) after 16 hours and 5 (optionally 10, 15 or 20) after 18 hours; or (optionally 10, 15, 20, or 25) after 10 hours, 5 (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15, or 20) after 14 hours, 5 (optionally 10, 15, or 20) after 16 hours and 5 (optionally 10, 15 or 20) after 18 hours; or (optionally 10, 15 or 20) after 8 hours or 5 (optionally 10, 15, 20 or 25) after 10 hours, 5 (optionally 10, 15, 20 or 25) after 12 hours, 5 (optionally 10, 15 or 20) after 14 hours, 5 (optionally 10, 15 or 20) after 16 hours and 5 (optionally 10, 15 or 20) after 18 hours; or (optionally 10, 15, or 20) after 6 hours, 5 (optionally 10, 15, or 20) after 8 hours, 5 (optionally 10, 15, 20, or 25) after 10 hours, 5 (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15 or 20) after 14 hours, 5 (optionally 10, 15 or 20) after 16 hours and 5 (optionally 10, 15 or 20) after 18 hours; or (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15, or 20) after 14 hours, 5 (optionally 10, 15, or 20) after 16 hours, and 5 (optionally 10, 15, or 20) after 18 hours and 5 (optionally 10 or 15) after 20 hours; or (optionally 10, 15, 20, or 25) after 10 hours, 5 (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15, or 20) after 14 hours, 5 (optionally 10, 15, or 20) after 16 hours and 5 (optionally 10, 15 or 20) after 18 hours and 5 (optionally 10 or 15) after 20 hours; or (optionally 10, 15, or 20) after 8 hours, 5 (optionally 10, 15, 20, or 25) after 10 hours, 5 (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15, or 20) after 14 hours, 5 (optionally 10, 15

- 8 040614 or 20) after 16 hours, 5 (optionally 10, 15 or 20) after 18 hours and 5 (optionally 10 or 15) after 20 hours;

or (optionally 10, 15, or 20) after 6 hours, 5 (optionally 10, 15, or 20) after 8 hours, 5 (optionally 10, 15, 20, or 25) after 10 hours, 5 (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15 or 20) after 14 hours, 5 (optionally 10, 15 or 20) after 16 hours, 5 (optionally 10, 15 or 20) after 18 hours and 5 (optionally 10 or 15) after 20 hours; or (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15, or 20) after 14 hours, 5 (optionally 10, 15, or 20) after 16 hours, 5 (optionally 10, 15, or 20) after 18 hours, 5 (optionally 10 or 15) after 20 hours and 5 (optionally 10) after 22 hours; or (optionally 10, 15, 20, or 25) after 12 hours, 5 (optionally 10, 15, or 20) after 14 hours, 5 (optionally 10, 15, or 20) after 16 hours, 5 (optionally 10, 15, or 20 ) after 18 hours, 5 (optionally 10 or 15) after 20 hours, 5 (optionally 10) after 22 hours and 5 (optionally 10) after 24 hours; or (optionally 10) after 12 hours, 10 (optionally 15) after 14 hours, 15 (optionally 20) after 16 hours, 20 (optionally 25) after 18 hours, 25 (optionally 30) after 20 hours and 20 (optionally 25) after 22 hours; or (optionally 10) after 12 hours, 10 (optionally 15) after 14 hours, 15 (optionally 20) after 16 hours, 20 (optionally 25) after 18 hours, 25 (optionally 30) after 20 hours, 20 (optionally 25) after 22 hours and 20 (optionally 30) after 24 hours.

The present invention also relates to a pharmaceutical composition comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core contains a pharmaceutically active ingredient, the first coating contains or is a water-soluble cellulose ether, in addition, the second coating contains or is a polymer delayed release, wherein the first coating is present in an amount that provides a percentage release of the pharmaceutically active ingredient of more than 50%, optionally more than 55 and 60% (for example, more than 65, 70, 75, 80, 85 or 90%) 12 hours after the start of the test for dissolution, with the dissolution test described above.

The first coating may be present in an amount to provide a percentage release of the pharmaceutically active ingredient after 12 hours from 70 to 95%, from 75 to 95%, from 70 to 90%, from 75 to 90%, from 70 to 85%, from 70 to 80 % or 75 to 85%, preferably 75 to 95%, 80 to 95% or 85 to 95%.

The first coating may be present in an amount to provide a percentage release of the pharmaceutically active ingredient after 12 hours from 55 to 80%.

The first coating may furthermore be present in an amount to provide a percentage release of the pharmaceutically active ingredient of greater than 40% (optionally greater than 45% or greater than 50%) 6 or 4 hours after the start of the dissolution test. The percentage release of the pharmaceutically active ingredient may be 40 to 65% (optionally 45 to 65%) 6 or 4 hours after the start of the dissolution test. Optionally, the first coating may provide a weight gain of 1 to 20% and the second coating may provide a weight gain of 4 to 25%, optionally 4 to 15%, 4 to 12%, 15 to 25%, 4 to 6%, or from 8 to 13%. If the release percentage is 20% or more (optionally 45% or more) after 4 hours, then the second coating preferably provides a weight gain of at least 4%, preferably no more than 25% and optionally 4 to 6%. If the release percentage is 40% or more (optionally 45% or more) after 6 hours, then the second coating preferably provides a weight gain of at least 4%, preferably no more than 25% and optionally 8 to 13%.

The first coating, additionally or alternatively, may be present in an amount to provide a percentage release of the pharmaceutically active ingredient in an amount of more than 15% (for example, more than 20%, 25%, 28% or 30%), optionally from 25% to 40% or from 25% to 35%. %, 4 hours after the start of the dissolution test. Optionally, the first coating may provide a weight gain of 1 to 20%, and the second coating may provide a weight gain of 4 to 15%, optionally 4 to 6%, or 8 to 13%.

The first coating may be present in an amount to provide a percentage release of the pharmaceutically active ingredient greater than 25%, optionally 25 to 40% or 25 to 35% after 6 hours. Optionally, the first coating may provide a weight gain of 1 to 20% and a second the coating may provide a weight gain of 4 to 15%, optionally 4 to 6% or 8 to 13%. If the percent release of the active ingredient is more than 25%, optionally 25 to 40% or 25 to 35%, after 6 hours, then the active ingredient may be a hydrophilic active ingredient, such as mesalamine, optionally suspended in the discontinuous phase. The dispersed phase is described in more detail below.

In embodiments, the percentage release after 12 hours may be greater than 80%, wherein the first coating may provide a weight gain of 1 to 20% and the second coating may provide a weight gain of 4 to 15%, optionally 4 to 6% or 8 up to 13%.

In embodiments, the active ingredient is a hydrophobic active ingredient, such as cyclosporine A. In embodiments, the active ingredient is a hydrophobic active ingredient, such as cyclosporine A, and the percentage of release is greater than 70% (optionally 75 or 80%) after 12 hours. Optionally, the first coating may be present in an amount corresponding to the increase in weight due to coating from 0.5 to 20% of the weight of the core (optionally from 1 to 16%, from 4 to 16%, from 4 to 12% or from 3 to 6%) and /or the second coating is present in an amount corresponding to the increase in weight due to the second coating from 2 to 20% by weight (optionally from 4 to 20%, from 4 to 15%, from 8 to 18% or from 8 to 12%).

The first coating may be present in an amount providing a percentage release of the pharmaceutically active ingredient after 12 hours from 55 to 80%, a percentage release of the pharmaceutically active ingredient after 6 hours from 25 to 40% and a percentage release of the pharmaceutically active ingredient after 4 hours more than 15%.

According to any aspect of the present invention and any embodiment, the core may comprise a hydrogel-forming polymer matrix. The hydrogel-forming polymer matrix may be as described below.

The core of the pharmaceutical composition according to any aspect or embodiment of the present invention may be in the form of a solid colloid. The colloid contains a continuous phase and a dispersed phase. Acceptable continuous phases and dispersed phases that can be used to make up the core are defined in more detail below and in the detailed description of the present invention. The continuous phase may comprise or be a hydrogel-forming polymer matrix. Therefore, if the continuous phase is a hydrogel-forming polymer matrix, then the composition of the present invention may take the form of a solid unit of hydrogel-forming polymer containing a discontinuous phase. The dispersed phase may be droplets dispersed in the continuous phase or a hydrogel-forming polymer matrix. The dispersed phase may contain or be a hydrophobic phase.

The continuous phase of the solid colloidal core is or contains a hydrogel-forming polymer matrix. In embodiments, the hydrogel-forming polymer matrix is or contains a non-hydrocolloid resin or chitosan. In a specific embodiment, the hydrogel-forming polymer matrix is or contains gelatin, agar, polyethylene glycol, starch, casein, chitosan, soy protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, phthalated gelatin, succinated gelatin, cellulose acetate phthalate, oleoresin , polyvinyl acetate, polymers of acrylic or methacrylic esters and polyvinyl acetate phthalate, as well as any derivative of any of the above or a mixture of two or more of these polymers. In a further embodiment, the hydrogel-forming polymer matrix is or contains a hydrocolloid selected from carrageenan, gelatin, agar and pectin, or a combination thereof, optionally selected from gelatin and agar, or a combination thereof. In particular, the polymer of the hydrogel-forming polymer matrix is or contains gelatin. In an embodiment, the hydrogel-forming polymer does not contain cellulose or a cellulose derivative, eg does not contain cellulose ether.

According to this aspect of the present invention, the core may be in the form of a solid colloid, wherein the colloid contains a continuous phase and a discontinuous phase, and the pharmaceutically active ingredient may be in solution or may be suspended in the discontinuous phase. For example, the active ingredient may be a hydrophobic active ingredient in solution in the discontinuous phase, or a hydrophilic active ingredient suspended in the discontinuous phase.

According to embodiments of this aspect of the present invention, the active ingredient may be a hydrophobic active ingredient, such as cyclosporine, and the active ingredient may be in solution in the discontinuous phase. The first coating may provide a weight gain of 0.5 to 20% and the second coating may provide a weight gain of 8 to 12%, with the first coating present in an amount to provide a release percentage of 80% or more. Optionally, the water-soluble cellulose ether may be hydroxypropylmethylcellulose.

According to a further aspect, the present invention relates to a pharmaceutical composition comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core contains a pharmaceutically active ingredient, the first coating comprises or is a water-soluble cellulose ether, furthermore, the second coating comprises or is a delayed release polymer, wherein the first coating is present in an amount that provides a percentage release of the pharmaceutically active ingredient of more than 70% (for example, more than 75 or 80%) 6 hours after the start of the dissolution test, while the dissolution test is described above.

In embodiments, the first coating is present in an amount to provide a percentage release of 75 to 95% or 80 to 90% of the pharmaceutically active ingredient after 6 hours.

The second coating may be present in an amount to provide a weight gain of 2 to 20%, 5 to 15%, 8 to 12%, 2 to 8%, 3 to 7%, or 4 to 6%.

The active ingredient may be a hydrophobic active ingredient such as cyclosporine A. The active ingredient may be in solution in the discontinuous phase.

- 10 040614

The present invention also covers a pharmaceutical composition comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core contains a pharmaceutically active ingredient, optionally a hydrophilic active ingredient, the first coating contains or is a water-soluble cellulose ether, in addition, while the second the coating contains or is a delayed release polymer, wherein the first coating is present in an amount that provides a percentage release of the pharmaceutically active ingredient of more than 30% (for example, more than 35, 40, 45, 50, 55 or 60%) 12 hours after the start of the test for solubility, with the solubility test described above.

The first coating may be present in an amount to release 30 to 80%, optionally 30 to 70%, 35 to 70%, 40 to 70%, 40 to 50% or 60 to 70% of the active ingredient after 12 hours. .

The first coating may provide a weight gain selected from the range of 1% to 20%, 4% to 7%, 5% to 7%, 4% to 15%, 4% to 12%, and 8% to 12%. The second coating may provide a weight gain selected from the range of 8 to 12%.

The active ingredient may be in solution in the continuous phase of the formulation, wherein the formulation is in the form of a solid colloid containing a continuous phase and a dispersed phase. The active ingredient may be a hydrophilic active ingredient, such as mesalazine or hydralazine, which is in solution in the continuous phase. In embodiments, the active ingredient is a hydrophilic active ingredient in solution in the continuous phase, the first coating is present in an amount to provide a percentage release of 35 to 50% and a weight gain of 4 to 7%, and a second coating to provide a weight gain of 8 to 12%. In alternative embodiments, the active ingredient is a hydrophilic active ingredient in solution in the continuous phase, the first coating is present in an amount to provide 55 to 75% percent release and 8 to 12% weight gain, and the second coating provides 8 to 12% weight gain. .

It should also be understood that the individual embodiments described above may be combined with one or more of the other described embodiments to provide additional embodiments of the present invention defined, for example, by a combination of one or more embodiments for time points, time periods, percent per solution, percentage release, increase values for a higher percentage in solution, increase values for a higher percentage release.

The first coating may be in contact with the core. The second coating may be on the first coating. In embodiments, the first coating is in contact with the core and the second coating is on the first coating.

The second coating may be or may comprise a delayed release polymer, and the delayed release polymer may be selected from an enteric soluble polymer, a pH independent polymer, a pH dependent polymer, and a polymer specifically susceptible to degradation by bacterial enzymes in the gastrointestinal tract, or combinations of two or more of these polymers. Therefore, the second coating may be any of the above-mentioned delayed release polymers or any having the characteristics mentioned in relation to the delayed release polymer mentioned below.

In embodiments, the delayed release polymer may be water-soluble or water-permeable in an aqueous environment with a pH greater than 6.5. The delayed release polymer may be or contain a pH independent polymer such as ethyl cellulose.

According to any aspect and any embodiment of the present invention, the water-soluble cellulose ether may be selected from any one or combination of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. The water-soluble cellulose ether may preferably be hydroxypropylmethylcellulose.

In embodiments, the first coating may be or contain hydroxypropylmethylcellulose and the second coating may be or contain ethylcellulose.

According to any aspect or embodiment providing for a first coating and a second coating, the first coating may provide a percentage increase in mass relative to the core from 0.5 to 20%. In addition, the first coating may be present in an amount corresponding to the increase in weight due to the coating, selected from the ranges from 0.5 to 15%, from 1 to 15%, from 1 to 12%, from 1 to 10%, from 1 to 8 %, 1 to 6%, 1 to 4%, 2 to 10%, 2 to 8%, 2 to 6%, 2 to 7%, 2 to 4%, 4 to 8%, 4 to 7%, 4 to 6%, 5 to 7%, 7 to 20%, 7 to 16%, 9 to 20%, 9 to 16%, 10 to 15% and 12 up to 16%.

In any aspect or embodiment involving a first coating and a second coating, the second coating may provide a weight gain percentage of 2 to 40%. In addition, the second coating may be present in an amount corresponding to the increase in weight due to the coating, selected from the ranges from 4 to 30%, from 4 to 7%, from 7 to 40%, from 7 to 30%, from 8 to 25%, from

- 11 040614 up to 20%, from 2 to 25%, from 2 to 20%, from 4 to 25%, from 4 to 20%, from 4 to 15%, from 4 to 13%, from 7 to 15%, from up to 13%, from 8 to 12%, from 9 to 12% and from 20 to 25%.

Throughout this disclosure, the weight gain of the first coat is given as a percentage of the weight of the core, and the weight gain of the second coat is given as a percentage of the weight of the composition that is coated with the second coat, eg core and first coat.

According to any aspect and embodiment of the present invention, the first coating may provide a percentage weight increase relative to the core from 0.5 to 20%, preferably from 1 to 16% or from 4 to 16%, and the second coating can provide a percentage weight increase from 4 to 24 %, 7 to 24%, 22 to 24%, 7 to 15% or 8 to 12%, preferably 22 to 24%, 7 to 15% or 8 to 12%.

The hydrogel-forming polymer may be or contain a hydrocolloid other than a hydrocolloid resin or chitosan. The hydrogel-forming polymer may be a reversible hydrocolloid, such as a thermoreversible hydrocolloid or a thermoreversible hydrogel-forming polymer. Alternatively, the hydrogel-forming polymer may be or contain an irreversible hydrocolloid. The hydrogel-forming polymer matrix may be or contain gelatin, agar, polyethylene glycol, starch, casein, chitosan, soy protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, phthalated gelatin, succinated gelatin, cellulose acetate phthalate, oleoresin, polyvinyl acetate, polymers of acrylic or methacrylic esters and polyvinyl acetate phthalate; and any derivative of any of the foregoing, or a mixture of one or more of such hydrogel-forming polymers. The hydrogel-forming polymer matrix may be or contain a hydrocolloid selected from carrageenan, gelatin, agar and pectin or a combination thereof, optionally selected from gelatin and agar or a combination thereof, optionally the hydrogel-forming polymer matrix polymer is or contains gelatin. The hydrogel-forming polymer matrix is or contains a non-hydrocolloid resin, optionally selected from a cross-linked alginic acid salt. In preferred embodiments, the hydrogel-forming polymer is or contains gelatin.

In embodiments, the hydrogel-forming polymer further comprises a plasticizer, optionally a plasticizer selected from glycerol, a polyhydric alcohol, such as sorbitol, polyethylene glycol, and triethyl citrate, or a mixture thereof, such as sorbitol.

The hydrogel-forming polymer matrix can encapsulate the active ingredient. The active ingredient may be encapsulated as a suspension in a hydrogel-forming polymer matrix or in solution. The active ingredient may be in solution, or may be suspended in another component, such as the hydrophobic phase or discontinuous phase discussed elsewhere, of the composition, which is also encapsulated in a hydrogel-forming polymeric matrix.

The core of the pharmaceutical composition according to the present invention may be in the form of a solid colloid containing a continuous phase and a dispersed phase, while the continuous phase optionally contains a hydrogel-forming polymer matrix. Therefore, the pharmaceutical composition according to all aspects of the present invention may contain at least the following features: the core and the first coating, while the core contains the active ingredient and is in the form of a solid colloid containing a continuous phase and a dispersed phase, and the coating contains or is a soluble cellulose ether in water. The continuous phase may be in the form of a hydrogel-forming polymer matrix.

In embodiments, the active ingredient is or is present in the dispersed core phase.

In embodiments, the active ingredient is contained in the continuous phase of the core. In embodiments, the first active ingredient is or is contained in the dispersed core phase, and the second active ingredient is contained in the continuous core phase.

The dispersed phase may be solid, semi-solid or liquid. In particular, the dispersed phase may be liquid. In other specific cases, the dispersed phase may be semi-solid, for example, it may be waxy.

The dispersed phase may be a hydrophobic phase, such as a hydrophobic phase that is solid, semi-solid or liquid. Preferably the discontinuous phase is or contains a liquid lipid and optionally a solvent miscible therewith.

The active ingredient may be dissolved in the discontinuous phase. The active ingredient may be suspended in the discontinuous phase. The dispersed phase may be as described elsewhere herein, for example, it may be described in the immediately preceding two paragraphs.

According to a specific embodiment, the dispersed phase is or contains a liquid lipid and a solvent, the solvent being miscible with the liquid lipid and water, optionally the solvent being selected from 2-(2-ethoxyethoxy)ethanol and polyethylene glycol, in particular the solvent being 2 -(2-ethoxyethoxy)ethanol. According to the following option

- 12 040614 implementation of the dispersed phase is or contains an oil phase containing mono-, di - or triglyceride with medium chain length (in particular triglyceride with medium chain length), polyethoxylated castor oil and 2-(ethoxyethoxy)ethanol. The dispersed phase described in this paragraph may contain a hydrophobic active ingredient, such as cyclosporine A, or a hydrophobic active ingredient, such as mesalazine.

In embodiments, the formulation further comprises one or more surfactants, with suitable surfactants being described in more detail in the Detailed Description of the present invention. In those embodiments in which the formulation comprises a core in the form of a solid colloid comprising a continuous phase and a dispersed phase, wherein the continuous phase comprises a hydrogel-forming polymer matrix, the surfactant may be in the continuous phase, the dispersed phase, or both the continuous phase and in the dispersed phase. Therefore, in one embodiment, the core further comprises a surfactant present at least in the continuous phase, wherein the surfactant has an HLB value greater than 10, such as greater than 20. In a further embodiment, the discontinuous phase further comprises a surfactant an active substance with an HLB value in the range of 1 to 10, such as 1 to 5.

The core may have the characteristics of a core composed by mixing a dispersed phase with a continuous phase to form a colloid, wherein the continuous phase is an aqueous phase containing a hydrogel-forming polymer and the dispersed phase is a hydrophobic phase, wherein the pharmaceutically active ingredient is in the continuous phase or dispersed phase , while the colloid is thickened to form a nucleus.

The active ingredient may be a hydrophobic active ingredient or a hydrophilic active ingredient. The active ingredient may be present in the core in solution or in suspension, and this is the case when the dispersed phase or the continuous phase contains the active ingredient. In embodiments where the active ingredient is a hydrophobic active ingredient, it may be in solution in the discontinuous phase, for example, if the discontinuous phase is or contains a hydrophobic phase, a liquid lipid, an oil, a polyunsaturated fatty acid, or a solvent, or may be suspended in continuous phase. In embodiments where the active ingredient is a hydrophilic active ingredient, it may be suspended in the discontinuous phase, for example if the discontinuous phase is or contains a hydrophobic phase, liquid lipid, oil, polyunsaturated fatty acid, or solvent, or in solution in the continuous phase .

The core composition may contain a hydrogel-forming polymer matrix and a pharmaceutically active ingredient and may have the characteristics of a core obtained by a process comprising (i) dissolving the hydrogel-forming polymer in an aqueous liquid to form an aqueous solution;

(ii) dissolving or dispersing the active ingredient in a liquid to form a solution or dispersion (in particular a solution) of the active ingredient in the liquid (oil phase);

(iii) mixing the aqueous solution (i) and the solution or dispersion (ii) to form a colloid;

(iv) pushing the colloid through the nozzle to form droplets;

(v) inducing or causing the hydrogel-forming polymer to thicken or solidify to form a hydrogel-forming polymer matrix; and (vi) drying the solid.

Solution or dispersion (ii) (oil phase) can be prepared by dissolving or dispersing cyclosporin A in a suitable hydrophobic liquid. The hydrophobic liquid may be, for example, any of the oils or liquid lipids disclosed herein. By way of example, the hydrophobic liquid may be or contain saturated or unsaturated fatty acids, or a triglyceride, or an ester thereof, or an ester with polyethylene glycols. In particular, the oil for the oil phase is or contains a triglyceride, for example an oil containing a medium chain triglyceride, optionally, the oil contains a triglyceride of at least one fatty acid selected from fatty acids with 6, 7, 8, 9, 10 , 11 or 12 carbon atoms, for example C ₈ -C ₁₀ fatty acids.

In an embodiment, the composition core may comprise a hydrogel-forming polymer matrix and a pharmaceutically active ingredient, and may have the characteristics of a core prepared by a process comprising (i) dissolving the hydrogel-forming polymer and active ingredient in an aqueous liquid to form an aqueous solution;

(ii) mixing the aqueous solution of (i) and the second liquid (oil phase) to form a colloid;

(iii) pushing the colloid through the nozzle to form droplets;

(iv) inducing or causing the hydrogel-forming polymer to thicken or solidify to form a hydrogel-forming polymer matrix; And

- 13 040614 (v) drying the solid.

The active ingredient used in all of the methods described herein may be the active ingredient disclosed herein, for example, it may be hydrophilic or it may be hydrophobic. It may be selected from the hydrophilic active ingredients disclosed herein. It may be selected from the hydrophobic active ingredients disclosed herein.

Preferably, the aqueous phase premix (i) further comprises an anionic surfactant, eg as described elsewhere herein, eg sodium dodecyl sulfate (SDS).

In one embodiment, the core having the characteristics of the core obtained by the above method is a core comprising a hydrogel-forming polymer matrix and a non-aqueous phase dispersed in a hydrogel-forming polymer matrix, wherein the core is or contains gelatin, SDS, sorbitol, polyethoxylated castor oil, caprylic/capric acid triglyceride, 2-(ethoxyethoxy)ethanol, wherein the aqueous solution of (i) is or contains gelatin, sorbitol and SDS, and the solution or dispersion;

(ii) is or contains polyethoxylated castor oil, caprylic/capric acid triglyceride, 2-(ethoxyethoxy)ethanol and an active ingredient.

The composition core may alternatively comprise a hydrogel-forming polymer matrix and a pharmaceutically active ingredient, and may have the characteristics of a core prepared by a process comprising (a) dissolving the hydrogel-forming polymer in an aqueous liquid to form an aqueous solution;

(b) before, during or after the dissolution of the hydrogel-forming polymer in the aqueous liquid, mixing the active ingredient in the aqueous liquid;

(c) then pushing the aqueous liquid containing the hydrogel-forming polymer and the active ingredient through the nozzle to form droplets;

(d) inducing or causing the hydrogel-forming polymer to thicken or solidify to form a hydrogel-forming polymer matrix; and (e) drying the solid.

In the method according to the immediately preceding paragraph, the active ingredient may be dissolved in an aqueous liquid or, for example, it may be dispersed in an aqueous liquid in the form of particles.

Cores having the characteristics of cores obtained by the methods described above, for example cores obtained by the methods, are coated to provide a coating that contains or is a water-soluble cellulose ether, optionally with a second coating to control or modify release, preferably with a polymer coating as described above and in this document. The coated composition can be obtained by coating the core, for example by applying the first and second coatings to the core, as described. Prior to coating, the core can be obtained by a method comprising steps (i)-(vi), (i)-(v) or (a)-(e) described above. Suitable methods for applying the coating(s) are described below and include coating by spray coating of the coating composition on the core. Methods comprising steps (i)-(vi), (i)-(v) or (a)-(e) themselves form aspects of the present invention.

It has been found that the use of certain surfactants during the preparation of compositions is particularly effective in stabilizing a colloid (e.g. emulsion) obtained by mixing an aqueous solution (i) and an oil phase (ii) containing a hydrophobic active ingredient, for example cyclosporine A. When the colloid contained an oil-in-water emulsion, it has been found that the presence of a surfactant with an HLB of up to 10 (especially up to 8) in the oil phase is particularly effective in stabilizing the emulsion in the formulation. It has been found that the presence of such surfactants inhibits the formation of crystals of the hydrophobic active ingredient, for example cyclosporin A, after the formation of a colloid (oil-in-water emulsion). The presence of a surfactant with an HLB of up to 10 maintains a hydrophobic active ingredient, e.g., cyclosporin A, in solution in the oil phase during manufacture, and may also provide a beneficial release of the hydrophobic active ingredient, e.g., cyclosporin A, in soluble form from the composition after oral administration of the composition to a subject . Compositions containing a surfactant with an HLB of up to 10, at least in the oil phase, may exhibit high release rates and/or extent of release of a hydrophobic active ingredient, such as cyclosporin A, from the composition compared to using surfactants with more high HLB value in the oil phase. The presence of a surfactant with an HLB of up to 10 in at least the oil phase in the composition can inhibit the precipitation of a hydrophobic active ingredient, such as cyclosporin A, after the release of a hydrophobic active ingredient, such as cyclosporin A, from the composition, thereby maintaining higher levels of hydrophobic active ingredient in soluble form in the gastrointestinal tract, for example in the colon. The compositions disclosed herein, when the composition contains an oil phase and a surfactant with an HLB of up to 10, represent a further independent aspect of the present invention.

Therefore, a pharmaceutical composition is provided comprising a core and a coating, wherein the core contains a pharmaceutically active ingredient and is in the form of a solid colloid containing a continuous phase and a dispersed phase, wherein the continuous phase contains a hydrogel-forming polymer matrix, and the dispersed phase contains a surfactant with an HLB value in the range of 1 to 10, such as 1 to 5, and the coating contains or is a water-soluble cellulose ether, and the coating is present in an amount corresponding to the increase in weight due to coating from 0.5 to 20% by weight of the core.

Similarly, a pharmaceutical composition is provided comprising a core and a coating, wherein the core contains a pharmaceutically active ingredient and is in the form of a solid colloid containing a continuous phase and a dispersed phase, wherein the continuous phase contains a hydrogel-forming polymer matrix and the dispersed phase contains a surfactant. with an HLB value in the range of 1 to 10, such as 1 to 5, and the coating contains or is a water-soluble cellulose ether, and the coating has a thickness of 1 µm to 1 mm.

The dispersed phase may contain an oil phase. In an embodiment, the oil phase contains an oil and a surfactant (preferably a non-ionic surfactant), with both the oil and the surfactant having an HLB in the range of 0 to 10. Therefore, the core of the present invention may contain a pharmaceutically active ingredient and may be in the form of a solid colloid containing a continuous phase and a dispersed phase, wherein the continuous phase contains a hydrogel-forming polymer matrix, and the dispersed phase contains an oil phase containing an oil and a surfactant (preferably a non-ionic surfactant), while both the oil and surfactant have an HLB ranging from 0 to 10. For example, an oil has an HLB of 1 to 5, such as 1 to 4 or 1 to 2, and a surfactant has an HLB of 2 to 8, such as 3 -7, 2-6 or 3-4.

The surfactant present in the oil phase may be any of the surfactants disclosed herein with an HLB value up to 10 The surfactant present in the oil phase may be an HLB value selected from a maximum of 8, a maximum 7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2-4, 3-4, 5-8, 6-8 and 6-7. Preferably, the surfactant present in the oil phase is a non-ionic surfactant with the aforementioned HLB value.

The oil may be any of the oils disclosed herein. Preferably, the oil itself is not a surfactant. However, some oils, especially those derived from natural sources, will contain components that may have surfactant properties. For example, many triglyceride oils also contain mono- and diglyceride components and thus may exhibit some properties similar to those of surfactants. Therefore, the oil preferably has an HLB value of 0-10, however more preferably the oil has an HLB close to 0, such as an HLB of 0 to 3, optionally about 0, about 1, or about 2.

Both the oil and the surfactant present in the oil phase can independently have an HLB value of 0 to 10. The oil can have an HLB of 1-5 and the surfactant can have an HLB of 2-8, optionally 3-7, 2-6 or 3-4. Preferably the oil and surfactant are different.

The active ingredient may be a hydrophobic active ingredient such as cyclosporine A and may be oil soluble. The hydrophobic active ingredient, for example cyclosporin A, may be soluble in the surfactant used in the oil phase. Preferably the hydrophobic active ingredient, for example cyclosporin A, is soluble in both oil and surfactant. Preferably, substantially all of the cyclosporin A may be dissolved in the oil phase.

The oil phase may additionally contain a solvent, wherein the solvent is miscible with the dispersed phase and water, optionally the solvent is selected from 2-(2-ethoxyethoxy)ethanol and polyethylene glycol, in particular, the solvent is 2-(2-ethoxyethoxy) ethanol.

The hydrogel-forming core polymer can be any of the hydrogel-forming polymers disclosed herein.

The composition may furthermore contain additional surfactants in addition to the surfactant discussed above, ie. surfactant present in the dispersed phase or oil phase. In particular, the continuous phase containing the hydrogel-forming polymer may additionally contain one or more surfactants. Surfactants that may be present in the continuous phase are any of the surfactants disclosed herein as being acceptable for inclusion in the aqueous (continuous) phase of the composition. Preferably the continuous phase contains one or more anionic surfactants, for example at least one surfactant selected from fatty acid salts, alkyl sulfates and bile acids, in particular the surfactant in the continuous phase is or contains an alkyl sulfate, for example sodium dodecyl sulfate.

The active ingredient may be an immunosuppressant, a hydroxylase inhibitor or an anti-inflammatory agent, optionally the active ingredient is cyclosporine A, hydralazine or mesalazine. Cyclosporine or mesalamine can conveniently be used, for example, in the method comprising steps (i)-(vi) described above. Hydralazine can conveniently be used, for example, in a method comprising steps (i)-(vi), (i)-(v) or (a)-(e) described above, in particular in a method comprising steps (i)- (v) described above.

The core may further comprise a surfactant, optionally the surfactant being an anionic surfactant, optionally selected from alkyl sulfates, carboxylates, or phospholipids, or a non-ionic surfactant, optionally selected from sorbitan surfactants, PEG- fatty acids or glyceryl fatty acids or poloxamers, or combinations thereof. Therefore, a pharmaceutical composition according to all aspects of the present invention may be characterized by at least the following features: the presence of a core and a first coating, wherein the core contains the active ingredient and a surfactant, and the coating contains or is a water-soluble cellulose ether.

In embodiments where the core is in the form of a solid colloid, the surfactant may be in a dispersed phase or in a continuous phase. The surfactant in the continuous phase may be an anionic surfactant, for example at least one surfactant selected from fatty acid and bile salts, in particular an alkyl sulfate, for example sodium dodecyl sulfate. The surfactant in the discontinuous phase may be a non-ionic surfactant.

In embodiments, the core contains both a nonionic surfactant and an anionic surfactant. An anionic surfactant, such as sodium dodecyl sulfate, may be in the dispersed phase, and a nonionic surfactant, such as polyethoxylated castor oil, may be in the dispersed phase. Alternatively, an anionic surfactant, such as sodium dodecyl sulfate, may be in the continuous phase, and a nonionic surfactant, such as polyethoxylated castor oil, may be in the discontinuous phase.

In embodiments, the core further comprises a combination of adjuvants selected from a non-ionic surfactant and a solvent;

an anionic surfactant and solvent;

an anionic surfactant, a nonionic surfactant and a solvent;

non-ionic surfactant and oil;

an anionic surfactant and oil;

nonionic surfactant, anionic surfactant and oil; as well as a non-ionic surfactant, an anionic surfactant, a solvent, and an oil.

Preferably, the anionic surfactant is an alkyl sulfate, e.g., sodium dodecyl sulfate, the nonionic surfactant is polyethoxylated castor oil, the oil is a medium chain mono-, di-, and/or triglyceride, e.g., caprylic/capric acid triglyceride, and the solvent is 2 -(ethoxyethoxy)ethanol.

The pharmaceutical formulation may further comprise an adjuvant selected from a surfactant, a solubilizer, a penetration enhancer, a disintegrant, a crystallization inhibitor, a pH modifier, a stabilizer, or a combination thereof.

The core of the pharmaceutical composition according to the present invention may contain a discontinuous phase representing or containing a pharmaceutically active ingredient, such as cyclosporine, hydralazine or mesalamine;

mono-, di - and/or medium chain triglyceride, for example caprylic/capric acid triglyceride;

non-ionic surfactant, such as polyethoxylated castor oil; and a solvent, for example, 2-(ethoxyethoxy)ethanol, and may further contain a continuous phase, which is or contains an anionic surfactant, for example, at least one surfactant selected from salts of fatty acids and bile acids, in particular from alkyl sulfate, for example sodium dodecyl sulfate;

a hydrogel-forming polymer matrix that is or contains a hydrocolloid selected from carrageenan, gelatin, agar, and pectin, or a combination thereof, optionally selected from gelatin and agar, or a combination thereof, wherein the hydrogel-forming polymer matrix optionally is or contains gelatin; and optionally a plasticizer, such as a plasticizer selected from glycerol, a polyhydric alcohol, such as sorbitol, polyethylene glycol and triethyl citrate, or mixtures thereof, such as sorbitol.

According to an embodiment of the formulation described in the immediately preceding paragraph, the discontinuous phase contains no or substantially no active ingredient, the active ingredient being dissolved in the continuous phase.

According to one embodiment, the composition comprises a core and a coating on the outside of the core, wherein the core is in the form of a solid colloid containing a continuous phase and a dispersed phase, wherein the dispersed phase is or contains a hydrophobic active ingredient, for example, cyclosporin A;

mono-, di - and/or medium chain triglyceride, for example caprylic/capric acid triglyceride;

polyethoxylated castor oil and a co-solvent, for example, 2-(ethoxyethoxy)ethanol, wherein the continuous phase is or contains a hydrogel-forming polymer matrix, which is or contains a hydrocolloid selected from carrageenan, gelatin, agar and pectin, or a combination thereof, optionally selected from gelatin and agar, or a combination thereof, optionally the water-soluble polymer matrix polymer is or contains gelatin;

optionally a plasticizer, optionally a plasticizer selected from glycerol, a polyhydric alcohol such as sorbitol, polyethylene glycol and triethyl citrate, or mixtures thereof, such as sorbitol; and an anionic surfactant, such as at least one surfactant selected from fatty acid and bile salts, in particular an alkyl sulfate, such as sodium dodecyl sulfate, wherein the coating on the core is any of the coatings disclosed herein.

Preferably, the coating comprises a first coating and a second coating on the outside of the first coating, wherein the first coating is a coating that is or contains the water-soluble cellulose ether described above; and the second coating is or contains a coating, preferably a polymeric coating as defined above, to control or modulate the release of cyclosporin A from the formulation.

In embodiments involving a first coating and a second coating, for example as mentioned in the immediately preceding paragraph, the particular first coating is or contains hydroxypropylmethylcellulose and the particular second coating on the outside of the first coating is or contains a pH-independent polymer, such as ethylcellulose;

more specifically, the second coating is or contains ethyl cellulose and optionally a polysaccharide selected from water-soluble and naturally occurring polysaccharides, such as pectin or other water-soluble naturally occurring polysaccharide.

The second coating may thus contain pectin or the other polysaccharide mentioned, or it may be essentially free of pectin and the other polysaccharides mentioned.

Thus, second coatings are disclosed that contain ethyl cellulose as a controlled release polymer and which additionally contain pectin or another specified polysaccharide, as well as second coatings that contain ethyl cellulose as a controlled release polymer and which additionally do not contain pectin or another specified polysaccharide.

The core may contain a hydrogel-forming polymer containing gelatin, optionally in an amount of from 300 to 700 mg/g, while the core additionally contains mono-, di - and/or medium chain triglyceride, optionally in an amount of from 20 to 200 mg/g , while the pharmaceutical composition additionally contains the following components:

a solvent, for example 2-(ethoxyethoxy)ethanol, optionally in an amount of 150 to 250 mg/g;

a non-ionic surfactant, such as polyethoxylated castor oil, optionally in an amount of 80 to 200 mg/g; and an anionic surfactant, for example sodium dodecyl sulfate, in an amount of 15 to 50 mg/g.

If the core is a colloid, then the active ingredient may be dissolved in the continuous phase of the colloid.

In accordance with the present invention, it may be necessary for the core to contain a dispersed phase, wherein the core may have a single phase, which is, for example, a hydrogel-forming polymer matrix, the matrix having the active ingredient dissolved therein. For example, the active ingredient may be hydralazine.

The scope of the present invention covers compositions in which the core is a colloid having a dispersed phase and a continuous phase (matrix phase), while the colloid further includes dispersed particles of the pharmaceutically active ingredient, such as microparticles or nanoparticles. Elsewhere in the present description, the dispersed phase and the continuous phase may be described differently.

The pharmaceutical composition of the present invention and/or the core may be in the form of a mini-granule. The core may be a mini-bead and the first coating and, where applicable, the second coating, when combined with the core, form a mini-bead. However, it may be possible that the core is a mini-bead and the composition is not a mini-bead. The composition may further comprise a plurality of minigranules.

Therefore, the present invention encompasses a mini-granule with the features of the pharmaceutical compositions disclosed herein.

The composition or minigranule may have a largest core cross-sectional dimension of about 0.01 mm to about 5 mm, such as 1 to 5 mm, as in the case of 1 to 3 mm or 1 to 2 mm. The minigranule may be spheroidal. The spheroidal mini-granules may have an aspect ratio of not more than 1.5, for example from 1.1 to 1.5.

In embodiments, the pharmaceutical composition does not contain an antigen selected from inactivated and attenuated microorganisms.

The pharmaceutical composition according to the present invention may be intended for oral administration. The formulation may be formulated into a unit dosage form for oral administration containing 0.1 to 1000 mg, optionally 1 to 500 mg, such as 10 to 300 mg or 25 to 250 mg, preferably about 25 mg, 35 mg, about 75 mg, about 180 mg, about 210 mg or about 250 mg of pharmaceutically active ingredient. Preferably, the formulation is formulated into a multiple minigranule unit dosage form selected from soft or hard gel capsules, gelatin capsules, HPMC capsules, compressed tablets, or sachets. The minigranules may be as described elsewhere herein.

Another aspect of the present invention relates to the composition described herein, intended for use as a medicine. The active ingredient may be an immunosuppressant such as cyclosporine A; the composition may contain at least one additional active ingredient, for example at least one additional immunosuppressant. In particular, this document provides a composition in which the active ingredient is an immunosuppressant intended for the treatment, for example prevention, of a condition of the gastrointestinal tract. The composition can be used to treat inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, celiac disease, graft versus host disease, graft versus host disease of the gastrointestinal tract, gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis , colitis, pseudomembranous colitis, diverticulosis, diverticulitis, inflammation of the ileoanal pocket, endometriosis, colorectal carcinoma and adenocarcinoma.

In embodiments where the pharmaceutical composition does not contain a second coating, said composition may be for the treatment of conditions that affect the small intestine. Such formulations may be useful in the treatment of conditions selected from celiac disease, GVHD, or Crohn's disease.

In addition, the present invention relates to a method of administering a pharmaceutically active ingredient to a subject, including oral administration to the subject of the composition described herein. The method can be carried out for the treatment, such as prevention, of a disease. The subject may be a mammal, in particular a human. Also provided is a method of treating a gastrointestinal condition in a subject, preferably a human in need thereof, comprising orally administering to a mammal a therapeutically effective amount of a composition described herein, wherein the pharmaceutically active ingredient is a potentially effective ingredient in said method. For example, the condition may be inflammation and the active ingredient is an immunosuppressant such as cyclosporine A. Gastrointestinal conditions that may be treated or prevented include those disclosed herein.

Another aspect of the present invention relates to the use of the composition described herein for use in the manufacture of a medicament for the treatment, eg prevention, of a gastrointestinal condition. Conditions of the gastrointestinal tract include those disclosed herein.

The present invention also provides a method for treating a condition selected from inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, celiac disease, graft versus host disease, graft versus host disease.

- 18 040614 of the gastrointestinal tract, gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, pseudomembranous colitis, diverticulosis, diverticulitis, endometriosis, colorectal carcinoma and adenocarcinoma, and the method includes the introduction of a pharmaceutical composition according to the present invention.

In another aspect, the present invention relates to a method for treating conditions that affect the small intestine, the method comprising administering a pharmaceutical formulation of the present invention that does not contain a second coating. Conditions that affect the small intestine can be selected from celiac disease, GVHD, or Crohn's disease.

An aspect of the present invention relates to a process for preparing a pharmaceutical formulation, the method comprising the step of coating the core with a coating containing HPMC, wherein the weight gain due to the coating is between 0.5 and 20% by weight of the pharmaceutical formulation. The core may contain a pharmaceutically active ingredient and may be the core described in the present description.

The method according to the immediately preceding paragraph may further comprise obtaining a core, wherein obtaining the core comprises the steps of mixing a non-aqueous phase with an aqueous phase to form a solid colloid, wherein at least one of the aqueous phase or non-aqueous phase contains a pharmaceutically active ingredient, wherein (a) the non-aqueous phase contains a surfactant; and (b) the aqueous phase contains a hydrogel-forming polymer;

and then inducing or allowing the emulsion to solidify.

The present invention relates to a process for preparing more than one batch of a plurality of solid unit dosage forms comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core contains the active ingredient and a hydrogel-forming polymer matrix, the first coating contains or is a water-soluble ester cellulose, and the second coating contains or is a delayed release polymer, in addition, while the first coating is present in an amount that provides each of more than one batch with a graph of the percent release of the active ingredient versus time with a difference of less than 5 units of percent release at any time time on the graph, the method involves compiling a batch of cores, coating the cores with the first coating in an amount that provides an increase in mass due to coating from 0.5 to 20%, and coating the core with a second coating providing one or more batches.

In embodiments, the coating is present in an amount to provide an 8 to 12% weight gain, or any other weight gain referred to herein.

A method for minimizing batch-to-batch variability in the dissolution profile of a plurality of solid unit dosage forms from two or more batches involves formulating two or more batches of the multiple solid unit dosage forms and coating each batch of solid unit dosage forms with a coating containing hydroxypropyl methylcellulose, wherein the weight gain due to the coating is from 0.5 to 20%.

If multiple batches are referred to herein, such as two or more batches, then the number of batches may be at least 100, optionally at least 1000.

Another aspect of the present invention relates to a method for preventing systemic side effects of cyclosporine, the method comprising providing a composition containing cyclosporine and a coating present in an amount corresponding to a weight gain of 0.5 to 20% due to hydroxypropyl methylcellulose. The method can be used in the treatment of a condition selected from inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, celiac disease, graft versus host disease, gastrointestinal graft versus host disease, gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, pseudomembranous colitis, diverticulosis, diverticulitis, endometriosis, colorectal carcinoma and adenocarcinoma.

The coating according to the present invention improves the rate and/or degree of release of the active ingredient from the formulation compared to the corresponding uncoated formulation. It is contemplated that the formulations of the present invention thus provide high concentrations of the active ingredient in vivo after oral administration, which may improve the oral bioavailability of the active ingredient, thereby enhancing the therapeutic benefit of the active ingredient. Improved bioavailability can also provide a lower dose of the active ingredient to be administered and thereby reduce the size of the unit dosage form or reduce the number of unit dosage forms administered to the patient (eg, by reducing the number and/or size of capsules required). Therefore, the present invention relates to the use of the composition according to the present invention to increase the bioavailability of the active ingredient. The present invention further relates to a method for increasing the oral bioavailability of an active agent, the method comprising administering to a patient a formulation of the present invention.

Formulations of the present invention that release the active ingredient in the stomach and/or upper gastrointestinal tract (eg, small intestine) may be particularly useful in improving bioavailability. Therefore, formulations of the present invention are preferred which release high amounts of the active ingredient during the first 2-4 hours of the dissolution test disclosed herein. Preferably, such formulations may be those disclosed herein containing a first coating (eg, water-soluble cellulose ether) but without a second coating.

For some active ingredients, it may be desirable to limit or delay the release of the active ingredient from the formulation until the formulation has passed through the stomach and upper gastrointestinal tract. Compositions of the present invention containing a second coating may be particularly suitable for such applications. The second coating acts with a delayed release from the formulation, while the presence of the coating of the present invention (eg, HPMC) increases the amount of active ingredient released when the formulation releases the active ingredient in the lower gastrointestinal tract. The delay in release of the active ingredient resulting from the presence of the second coating can be optimized by appropriate selection of the nature or amount of the second coating used. For a given second coating material, a higher increase in coating weight will generally increase the period of time between formulation administration and active ingredient release. The compositions of the present invention can thus be used to provide high levels of release of the active agent through very specific parts of the gastrointestinal tract to provide, for example, local treatment of diseased tissue in the gastrointestinal tract. Such delayed release formulations may be particularly useful if the active ingredient has undesirable side effects that may occur upon systemic absorption in the upper gastrointestinal tract.

The subject matter of the appended claims is incorporated herein by reference. Thus, the present description should be read in conjunction with the claims and the features mentioned in the claims are applicable to the objects of the present description. For example, the feature described in the claimed method is also applicable to the products mentioned in the present description, if the feature is embodied in the product. For example, the feature mentioned in relation to the claimed product also applies to the corresponding methods that are the objects provided in the present description. Likewise, a feature mentioned herein in the context of a method also applies to products mentioned herein if the feature is embodied in the product. In addition, the feature mentioned in the present description in the context of the product is also applicable to the corresponding methods that are the objects provided in the present description.

Brief description of graphic materials

Embodiments of the present invention are further disclosed with reference to the accompanying drawings.

In FIG. 1 is a graphical representation of the percentage of cyclosporine in solution versus time over 4 hours and presents the release profiles of the minigranules of Example 1 and Examples 2a-2c with various levels of coating containing hydroxypropyl methylcellulose, compared to the release profile for the core of example 1, which does not have hydroxypropyl methylcellulose. coatings.

In FIG. 2 is a graphical representation of the percentage of cyclosporine in solution versus time over 24 hours and presents the release profiles of the minigranules of Example 1 and Examples 2a-2c with different levels of coating containing hydroxypropyl methylcellulose, compared to the release profile for the core of example 1, which does not have hydroxypropyl methylcellulose. coatings.

In FIG. 3 is a graphical representation of the percent release of cyclosporine versus time over 24 hours and shows the release profiles of the minigranules of Examples 5b-5d with different levels of coating containing hydroxypropyl methylcellulose compared to the release profile for the core of Example 5a, which was not coated with hydroxypropyl methylcellulose.

In FIG. 4 is a graphical representation of the percent release of cyclosporine versus time over 24 hours and shows the release profiles of the minigranules of example 1 and examples 5f and 5g with different levels of coating containing hydroxypropyl methylcellulose, compared to the release profile for the core of example 5e, which did not have hydroxypropyl methylcellulose coating.

In FIG. 5 is a graphical representation of the percent release of cyclosporine versus time over 24 hours and shows the release profiles of the minigranules of Examples 5i and 5j with different levels of coating containing hydroxypropyl methylcellulose, compared to the release profile for the core of Example 5h, which was not coated with hydroxypropyl methylcellulose.

In FIG. 6 is a graphical representation of the percent release of cyclosporine versus time over 24 hours and shows the release profiles of the minigranules of Examples 9b and 9c with different levels of coating containing hydroxypropyl methylcellulose compared to the profile

- 20 040614 release for the core of example 9a, which does not have a hydroxypropyl methylcellulose coating.

In FIG. 7 is a graph representing the release profiles of FIG. 3 and 6 in one graph.

In FIG. 8 is a graphical representation of the percentage release of mesalazine versus time over 24 hours and shows the release profiles of the minigranules of examples 12b and 12c with various levels of coating containing hydroxypropyl methylcellulose, compared to the release profile for the core of example 12a, which has no hydroxypropyl methylcellulose coating.

In FIG. 9 is a graphical representation of the percentage release of hydralazine versus time over 24 hours and shows the release profiles of the minibeads of Examples 14b, 14c and 14e, 14f with different levels of coating containing hydroxypropyl methylcellulose and different levels of Surelease/pectin coating compared to the release profiles of the minibeads of Examples. 14a and 14d, which do not have a hydroxypropyl methylcellulose coating.

In FIG. 10 is a graphical representation of the percent release of celecoxib versus time over 18 hours and shows the release profiles of the hydroxypropyl methyl cellulose coated and Surelease coated minibeads of Example 16 compared to the release profile of the minibeads that were not coated with hydroxypropyl methyl cellulose.

In FIG. 11 is a graphical representation of percent ciclosporin release versus time over 24 hours and shows the reduction in variability in release profiles across batches of hydroxypropyl methylcellulose coated minigranules with a second Surelease/pectin coating.

In FIG. 12 is a scanning electron microscope image of a cross section of a minibead according to the present invention.

In FIG. 13 is an enlarged view of a portion of the image in FIG. 12 showing individual layers of coatings.

Detailed description of the present invention

The terms treatment and methods of treatment covered by the present invention include the following and combinations thereof:

(1) risk reduction or inhibition, such as delaying, initiation and/or progression of a condition, disorder or disease;

(2) prevention, such as reducing the risk of or delaying the onset of a clinical symptom, condition, disorder, or disease developing in a patient (e.g., human or animal) that may be suffering from or predisposed to the condition, disorder, or disease, but not yet experiencing or does not demonstrate clinical or subclinical symptoms of the condition, disorder, or disease;

(3) inhibition of the condition, disorder, or disease (eg, stopping, reducing, or delaying the development of the disease, or its recurrence in the case of maintenance treatment, or at least one clinical or subclinical symptom thereof); and/or (4) alleviating the condition (eg, causing regression of the condition, disorder, or disease, or at least one of its clinical or subclinical symptoms).

If the composition of the present invention is used to treat a patient, then the treatment includes any or more of the following:

maintaining the health of the patient;

restoring or improving the patient's health; and delaying the progression of the disorder.

The benefit to the patient being treated can be both statistically significant and at least tangible to the patient or to the attending physician. It is to be understood that a drug does not necessarily produce a clinical effect in every patient to which it is administered and this paragraph is to be understood accordingly. The compositions and methods described herein find use in the treatment and/or prevention of a disease.

Treatments may include supportive care for patients who suffer from a disorder and whose condition subsequently improves, for example, as a result of treatment. Such patients may or may not have a symptomatic disorder. Maintenance therapy aims to stop, reduce or delay the (re)occurrence or progression of the disorder.

The term "effective amount" means an amount sufficient to achieve the desired treatment, such as causing the desired therapeutic or prophylactic response. A therapeutic or prophylactic response may be any response that the recipient (eg, clinician) recognizes as an effective response to treatment. It is also within the skill of the art to determine the appropriate duration of treatment, appropriate doses, and any potential combinations of treatments based on an assessment of the therapeutic or prophylactic response.

Each of the terms dry and dried as applied to a formulation according to the present disclosure may refer to formulations containing less than 5% free water by weight, for example

- 21 040614 less than 1% free water by weight. In general, however, the terms dry and dried as applied to formulations in accordance with the present disclosure mean that the hydrogel present in the original cured formulation has dried sufficiently to form a rigid formulation.

When a solid colloid is mentioned, this also refers to a dried colloid as defined herein.

The ingredients and adjuvants of the formulations described are acceptable for the intended use. For example, pharmaceutical formulations contain pharmaceutically acceptable ingredients.

Unless otherwise indicated, ingredients, components, excipients, etc. formulations of the present invention are suitable for one or more of the intended uses discussed elsewhere herein.

For the avoidance of doubt, it is hereby stated that the information disclosed earlier in the present description under the heading Background of the present invention is in accordance with the present invention and should be considered as part of the disclosure of the present invention.

Throughout the description and claims of this disclosure, the words contain and include, as well as variations thereof, mean including without limitation and they are not intended to exclude (and do not exclude) other fragments, additives, components, integers or steps. Throughout the description and claims of the present disclosure, the singular form provides for the plural, unless the context requires otherwise. In particular, when the singular form is used, the present description is intended to be construed as embracing both the singular and the plural unless the context otherwise requires.

Features, integers, characteristics, compounds, chemical moieties, or groups described in connection with a particular aspect, embodiment, or example of the present invention should be understood to apply to any other aspect, embodiment, or example described herein, unless they are are incompatible with them. All of the features disclosed in this specification (including any of the appended claims, abstract and drawings) and/or all steps of any disclosed method or process may thus be combined in any combination except for combinations in which, at least some of such features and/or steps are mutually exclusive. The present invention is not limited to the details of any of the above embodiments. The present invention extends to any new feature or any new combination of features disclosed in the present specification (including any of the appended claims, abstract and drawings), or to any new step or any new combination of steps of any disclosed method or process.

The reader's attention is directed to all articles and documents that are filed concurrently with or prior to this disclosure with respect to this application and that are open to public review with this disclosure, and the contents of all such articles and documents are incorporated herein by reference.

Solubility profile.

Mention of a two-stage dissolution test using apparatus II with a blade speed of 75 rpm and with a dissolution medium at a temperature of 37°C; while during the first 2 hours of the dissolution test, the dissolution medium is 750 ml of 0.1 N HCl, and for the rest of the dissolution test, 250 ml of 0.2 M trisodium phosphate containing 2% SDS is added to the dissolution medium, pH which is then adjusted to 6.8 refers to an in vitro test performed according to USP <711> Dissolution using apparatus II (paddle apparatus) operated at a paddle speed of 75 rpm and with an appropriate dissolution medium at a temperature of 37±5°C . At the start of the test (t=0), the sample is placed in the dissolution medium. After 2 hours, an aliquot of the medium is taken for subsequent analysis and the second stage of the dissolution test is started immediately (preferably within 5 minutes). In the second step, 250 ml of 0.2 M trisodium phosphate containing 2% sodium dodecyl sulfate (SDS) is added to the dissolution medium and the pH is adjusted to 6.8±0.05 using 2N NaOH or 2N HCl as needed. Samples of the dissolution medium are taken at time points during the second stage of the test, for example, 4, 6, 12 and 24 hours after the start of the test (ie from t=0 at the beginning of the first stage). Samples are analyzed for the active ingredient dissolved in the medium. The term % released is the amount of active ingredient (eg, cyclosporine) in solution in an appropriate dissolution medium at a particular point in time relative to the amount of active ingredient in the composition at the start of the test. The concentration of the active ingredient in a sample can be measured using standard methods such as reverse phase HPLC as shown in the examples. Reference to a two-stage dissolution test refers to this testing method.

Compound.

The composition contains a matrix and a pharmaceutically active ingredient. The matrix may be formulated with a hydrogel-forming polymer and may contain additional adjuvant(s) in the polymer. The active ingredient is contained in a matrix. The active ingredient may be in solution or suspension or a combination of the two, however, the present invention is not limited to formulations comprising a solution or suspension of the active ingredient, and provides, for example, active ingredients encapsulated in liposomes or cyclodextrin. The matrix may contain inclusions in which the active ingredient is contained, for example the inclusions may contain a hydrophobic medium in which the active ingredient is dissolved or suspended. The active ingredient may therefore be directly dissolved or suspended in the matrix, or it may be dissolved or suspended indirectly in the matrix by inclusions in which the active ingredient is dissolved or suspended.

The composition therefore contains a matrix-forming polymer, in particular a hydrogel-forming polymer. The composition matrix may be or may comprise a polymer matrix including a polymer selected from a water-permeable polymer, a water-swellable polymer, and a biodegradable polymer. In particular, the matrix is or contains a hydrogel-forming polymer, described in more detail below.

Modified release of the active ingredient from the formulation can be achieved due to the properties of the matrix material. For example, the matrix may be a permeable or degradable polymer that contains the active ingredient, eg dissolves or suspends, and after oral administration, the matrix gradually dissolves or breaks down, thereby releasing the active ingredient from the matrix. Destruction can be achieved by biodegrading the biodegradable polymer matrix. If the matrix is permeable, then water will enter the matrix allowing the drug to diffuse out of the matrix. The matrix formed by the hydrogel-forming polymer may therefore include a modified release polymer. As such modified release polymers there may be mentioned cellulose derivatives, for example hydroxypropylmethylcellulose, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymers, polyethylene glycol block copolymers, polyorthoesters, polyanhydrides, polyanhydride esters, polyanhydride imides, polyamides and polyphosphazines.

Water-soluble cellulose ether coating.

The present invention relates to pharmaceutical compositions that have a coating that is or contains a water-soluble cellulose ether. The present invention relates to pharmaceutical compositions that have a polymer coating, in which the polymer is or contains a water-soluble cellulose ether. The water-soluble cellulose ether may, for example, be selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.

Preferably, the material of the first coating (ie the inner coating) is different from that of the second coating of the composition. For example, if the first coating is or contains a water-soluble cellulose ester, then the main component(s) (for example, more than 50%) of the second coating is (are) or contains (s) a polymer other than that first coverage. Therefore, the first and second coatings preferably provide two layers of material as part of the composition. It should be understood that if the second coating contains a mixture of components, the minor components of the outer second coating may be the same as the material of the first coating. By way of example, if the first coating is or contains HPMC and the second coating contains ethyl cellulose, then the ethyl cellulose may optionally additionally contain a minor amount (e.g., less than 50%, 40%, 30%, or 20%) of the first coating material, HPMC in this example. According to such embodiments, the inner coating and the second coating are considered different.

The water-soluble cellulose ether may be a water-soluble cellulose ether selected from alkylcellulose, eg methylcellulose, ethylmethylcellulose;

hydroxyalkylcellulose, such as hydroxyethylcellulose (available as Cellosize™ and Natrosol™), hydroxypropylcellulose (available as Klucel™) or hydroxymethylcellulose;

hydroxyalkylalkyl cellulose, such as hydroxyethyl methyl cellulose (HEMC), hydroxypropyl methyl cellulose (available as Methocel™, Pharmacoat™, Benecel™) or ethyl hydroxyethyl cellulose (HEC); and carboxyalkyl cellulose, such as carboxymethyl cellulose (CMC).

Preferably, the water-soluble cellulose ether may, for example, be selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.

The water-soluble cellulose ether may be a low viscosity polymer that is suitable for use as a film or coating for a formulation. The viscosity of the polymer may be from about 2 mPa-s to about 60 mPa-s, for example from about 2 mPa-s to about

- 23 040614 up to about 20 mPa-s, from about 2 mPa-s to about 8 mPa-s, more preferably from about 4 mPa-s to about 10 mPa-s, for example from about 4 mPa-s to about 6 mPa-s With. Alternatively, the viscosity of the polymer may be outside any or all of the above ranges, for example may be above 20 mPa-s. Alternatively, the viscosity of the polymer may be outside any or all of the above ranges, for example may be above 20 mPa-s. The viscosity of a polymer can be determined by measuring the viscosity of a 2% solution of polymer in water at 20° C. using an Ubbelode viscometer using standard ASTM methods (D1347 and D2363).

The water-soluble cellulose ether may be water-soluble hydroxypropyl methylcellulose (HPMC or hypromellose). HPMC is obtained by modifying cellulose with the replacement of hydroxy groups with methoxy and hydroxypropyl groups. Each anhydroglucose unit in the cellulose chain has three hydroxyl groups. The number of substituent groups in the anhydroglucose units can be expressed as the degree of substitution. If all three hydroxyl groups in each unit are substituted, then the degree of substitution is 3. The number of substituent groups on the ring determines the properties of the HPMC. The degree of substitution can also be expressed as wt % of the methoxy and hydroxypropyl groups present. Preferably, HPMC has from about 19% to about 30% methoxy substitution and from about 7% to about 12% hydroxypropyl substitution. In particular, HPMC has 25 to 30% methoxy substitution and 7 to 12% hydroxypropyl substitution. Preferably, the HPMC is a low viscosity HPMC that is suitable for use as a film or coating for a formulation. The viscosity of the HPMC is preferably from about 2 to 60 mPa-s, for example from about 2 mPa-s to about 20 mPa-s, more preferably the viscosity is from about 4 mPa-s to about 10 mPa-s. The viscosity of HPMC is determined by measuring the viscosity of a 2% solution of HPMC in water at 20° C. using an Ubbelode viscometer using standard ASTM methods (D1347 and D2363). Such HPMC is available, for example, as Methocel™, such as Methocel™ E, including Methocel™ E5.

If the first coating is or contains a water-soluble cellulose ether derivative, then the derivative may be, for example, a water-soluble cellulose ester ester. Water-soluble cellulose esters are well known and may include cellulose esters formed with one or more suitable acylating agents. The acylation agents can be, for example, suitable acids or acid anhydrides or acyl halides. Therefore, a cellulose ester ester may contain one ester moiety or two or more ester moieties to form a mixed ester. Examples of water-soluble cellulose esters can be water-soluble phthalate, acetate, succinate, propionate or butyrate of cellulose esters (eg HPMC). Preferably the water-soluble cellulose ester is a water-soluble cellulose ester phthalate, acetate succinate, propionate, propionate acetate or acetate butyrate (eg HPMC).

In one embodiment, the water-soluble cellulose ester may be or may contain a water-soluble ester of any of the water-soluble cellulose esters described above with respect to the inner coating.

Particular water-soluble esters of cellulose ethers are water-soluble esters of HPMC. Esters of HPMC which are soluble in water above pH 5.5 may be or may contain hydroxypropyl methylcellulose phthalate (HPMCP); or hydroxypropyl methyl cellulose acetate succinate (HPMCAS), in which the presence of ionizable carboxyl groups ensures polymer solubility at high pH (>5.5 for grade LF and >6.8 for grade HF). These polymers are commercially available from Shin-Etsu Chemical Co. Ltd.

The cellulose ether-containing coating may or may not contain hypromellose, for example, it may be made from a mixture of hypromellose, titanium dioxide and polyethylene glycol; the coating may contain at least 20 wt.% hypromellose and optionally at least 50 wt.% or at least 75 wt.% hypromellose, for example at least 80 wt.% or at least 85 or 90 wt.% hypromellose. The coating material used to form the coating may therefore contain the dry weight percentage of hypromellose mentioned in the previous sentence.

If a mixture of hypromellose, titanium dioxide and polyethylene glycol is desired for coating, products corresponding to such mixtures are commercially available, including Opadry White, a product sold by Colorcon. In a broader sense, various products sold under the trademark Opadry and Opadry II may be mentioned. The following non-limiting examples include Opadry YS-1-7706-G White, Opadry Yellow 03B92357, Opadry Blue 03B90842. These formulations are available as dry film coating formulations that can be dissolved in water immediately prior to use. Opadry and Opadry II formulations contain a cellulose former

- 24 040614 polymer film (for example, HPMC and / or HPC) and may contain polydextrose, maltodextrin, plasticizer (for example, triacetin, polyethylene glycol), polysorbate 80, dye (for example, titanium dioxide, one or more of paints or varnishes) and /or other suitable film-forming polymers (eg copolymers of acrylate and methacrylate). Acceptable OPADRY or OPADRY II formulations may contain a plasticizer and one or more of maltodextrin and polydextrose (including without limitation a) triacetin and polydextrose or maltodextrin or lactose, or b) polyethylene glycol and polydextrose or maltodextrin). Particularly preferred commercial products are Opadry White (based on HPMC/HPC) and Opadry II White (based on PVA/PEG).

The cellulose ether-containing coating can also be applied as a simple solution comprising water and the first coating polymer. For example, if the polymer is HPMC, such as Methocel, then the first coating may be applied to the core as an aqueous solution or dispersion of HPMC. Optionally, the coating solution may include other solvents such as alcohol. Alternatively, the coating may be applied as a solution or dispersion with a volatile organic solvent.

Preferably, the coating, which contains the water-soluble cellulose ether, is present in an amount corresponding to the weight gain of the composition due to the coating from 0.5 to 40% (for example, from 0.5 to 30%, from 0.5 to 20%, from 1 up to 25%, 1 to 15%, 1 to 6%, 1 to 4%, 4 to 6%, 6 to 10%, 9 to 15% or 12 to 15%) by weight based on weight of the composition before coating.

According to another embodiment, the first coating, which contains a water-soluble cellulose ether, is present in an amount corresponding to the increase in weight due to the first coating in the range selected from 9-30%, preferably 9-20%, or particularly preferably from 10 to 15% by weight. weight based on the weight of the formulation prior to coating.

Preferably, the coating, which contains a water-soluble cellulose ether, provides a coating thickness on the composition from about 10 µm to about 1 mm, for example, from about 10 µm to about 500 µm, from about 50 µm to about 1 mm, or from about 50 µm to about 500 µm. The thickness may therefore be from about 100 µm to about 1 mm, for example from 100 µm to about 750 µm, or from about 100 µm to about 500 µm. The thickness may be from about 250 µm to about 1 mm, for example from about 250 µm to about 750 µm, or from 250 µm to about 500 µm. The thickness may be from about 500 µm to about 1 mm, for example from about 750 µm to about 1 mm, or from about 500 µm to about 750 µm. The thickness may therefore be from about 10 µm to about 100 µm, for example from about 10 µm to about 50 µm, or from about 50 µm to about 100 µm.

If the first coating contains a water-soluble cellulose ether, then the cellulose ether(s) preferably comprise(s) at least 40%, 50%, 60%, 70%, 80%, 85% or 90% by dry weight of the first coating. Alternatively, water-soluble cellulose ether is the first coating.

It is preferable to dry the composition according to the present invention before applying the first coating, which contains a water-soluble cellulose ether, as described in more detail below in relation to the coating process.

It has been found that coating a core comprising the pharmaceutically active ingredient of an inner coating, referred to elsewhere in this application as an undercoat (therefore undercoat and first coat are equivalents), which contains a water-soluble cellulose ether, prior to applying a delayed release coating provides unexpected benefits. . The presence of such an inner coating has been found to enhance the solubility properties of the delayed release formulations of the present invention. In particular, the presence of such an internal coating has been found to increase the rate of release of the active ingredient from the formulation as well as increase the amount of active ingredient released in a given period of time compared to formulations made without the use of such an internal coating. These results are surprising as one would surmise that the presence of an inner coating in addition to the outer delayed release coating would act to delay or inhibit the release of drug from the formulation and there would be less drug released at a given time as the thicker coating is present. However, as shown in the examples, contrary to these expectations, both the degree and the rate of release of the active ingredient are increased compared to formulations without such an internal coating. Therefore, the delayed release formulations of the present invention comprising an inner coating that contains or is a water soluble cellulose ether and a delayed release coating on the outside of the inner coating provide a unique dissolution profile. Also found that the presence of such an internal coating reduces the variability between batches, especially when the core is in the form of a mini-bead. An inner coating that contains or is a water-soluble cellulose ether can therefore also reduce patient and inter-patient variability as a result of a more consistent dissolution profile. The unique properties of the internally coated formulations of the present invention (especially the dissolution profile) are believed to contribute to the favorable pharmacokinetic properties of the formulations of the present invention.

Therefore, in an embodiment, a formulation is provided comprising a pharmaceutically active ingredient, wherein the formulation further comprises a first coating, and wherein the first coating is or comprises a water-soluble cellulose ether.

The formulation may have a second coating comprising or being a delayed release polymer.

Therefore, according to an embodiment, a formulation is provided comprising a pharmaceutically active ingredient, wherein the formulation further comprises a first coating and a second coating on the outside of the first coating, wherein the first coating is or contains a water-soluble cellulose ether and the second coating is or contains the delayed release coating, for example, is or contains a delayed release polymer.

An aspect of the present invention relates to a composition of a plurality of minigranules comprising at least two groups of minigranules containing the active ingredient, wherein members of at least one group of minigranules are the minigranules described herein (i.e., formulations of the present invention in the form of minigranules ). It should be understood that the two groups are different. Such a composition of several groups of minigranules may contain the following two groups or may consist of the following:

the first group having a coating that is or contains a water-soluble cellulose ether, but not having an external coating, for example, as described herein; and a second group having a first coating that is or contains a water-soluble cellulose ether and a second coating that is or contains a delayed release coating, for example as described herein, for example a coating that is or contains a delayed release polymer release.

The respective minigranules of each composition group of the plurality of minigranules may contain the same active ingredient(s) as the minigranules of any or all of the other groups, or they may contain a different active ingredient(s). (s), such as a different combination. Thus, all minigranules of a group of multiple minigranules may contain the same active ingredient(s), for example, they may all contain an active ingredient selected from immunosuppressants (for example, cyclosporine), hydroxylase inhibitors (for example, hydralazine) and anti-inflammatory means (for example, mesalazine). In a broader sense, all minigranules of a group of multiple minigranules may contain any identical active ingredient, for example, selected from those described herein.

The composition of multiple groups can be used in the treatment of disorders of the gastrointestinal tract, for example, as described herein. Such a formulation may be used in the treatment of a disorder affecting multiple sites in the gastrointestinal tract, such as the upper intestine and lower intestine, and may contain an active ingredient selected from immunosuppressants (eg, cyclosporine), hydroxylase inhibitors (eg, hydralazine), and anti-inflammatory agents. (eg mesalazine).

Minigranules of the composition of multiple groups as a primer may be contained in a gel capsule or in a sachet.

An example of an active ingredient of a formulation according to the present disclosure is cyclosporin A. Preferably, according to the embodiment of the previous paragraph, the first coating (inner coating) is applied to the core including cyclosporin A. In a specific embodiment, the core is or contains a pharmaceutically active ingredient, for example, cyclosporine A, in a polymer matrix, in particular a water-soluble polymer matrix. Even more specifically, the core contains a matrix of hydrogel-forming polymer and cyclosporin A. Such cores are described in more detail below. Cyclosporin A can be replaced in this example with hydralazine or mesalazine.

The second coating is outside the first coating and may be any of the delayed release coatings described herein. In particular, the second coating is or comprises the pH independent modified release polymer coating described above. For example, the second coating may be or may comprise an enteric coating or a pH independent coating. The second coating may contain a mixture of polymers, including a polymer degradable by bacterial or other enzymes. According to a particular embodiment, the second coating comprises ethyl cellulose and optionally a water-soluble polysaccharide, in particular susceptible to degradation by intestinal bacteria, preferably pectin. Therefore, the second coating may contain the mixture of Surelease and pectin described above. The second coating may be or may contain ethyl cellulose (for example,

- 26 040614

Surelease™) and a blowing agent, wherein the blowing agent is a water-soluble adjuvant that acts to increase the permeability of the coating when placed in an aqueous environment, such as that found in the lower gastrointestinal tract. Suitable blowing agents include those described above. In embodiments, the second coating does not contain a blowing agent; thus, the second coating may not contain pectin.

Therefore, according to one embodiment of the present invention, there is provided a composition comprising a core, a first coating and a second coating on the outside of the first coating, wherein the core comprises a polymer matrix, in particular a hydrogel-forming polymer matrix and a pharmaceutically active ingredient;

wherein the first coating is or contains a water-soluble cellulose ether, in particular hydroxypropyl methylcellulose;

wherein the second coating is or comprises a modified release coating or a delayed release coating, in particular a modified release pH independent coating;

wherein the first coating is present in an amount corresponding to the increase in weight due to the first coating in the range selected from (i) from 8 to 12%, for example approximately 10%;

(ii) 4 to 6%, such as about 5%; or (iii) about 6% to about 10%, such as about 7%, about 7.5%, about 8%, about 8.5%, about 9%, or about 9.5%, by weight based on the weight of the composition before applying the first coating, while the second coating is present in an amount corresponding to the increase in the mass of the composition due to the second coating, selected from (a) from 10 to 12%, for example about 11% or about 11.5%;

(b) from 16 to 18%, for example about 17%; or (c) about 8% to about 12%, such as about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, or about 11%, by weight based on the weight of the composition before applying the second coat.

The first and second coatings according to the embodiment in the immediately preceding paragraph are preferably any of the first and second coatings described above or below. Therefore, it is contemplated that the coatings described in this section may, if desired, be applied to any of the formulations described herein to provide delayed release coverage. Coatings are particularly useful for providing modified release coatings for cores comprising a polymeric matrix and a pharmaceutically active ingredient as described herein.

The presence of the internal coating described herein, among other things, increases the amount of active ingredient released from the formulation upon dissolution compared to formulations without such an internal coating. Therefore, a delayed release formulation is provided comprising a pharmaceutically active ingredient, wherein the formulation comprises a first coating (inner coating) and a second coating as described herein; wherein the first coating is present in an amount that provides a percentage release of the active ingredient that is higher than the percentage release of the active ingredient from the corresponding formulation without the first coating over a period of time from 8 to 18 hours, as measured by the dissolution test described herein. For example, an internally coated formulation provides a higher percentage release over a period of 10 to 16 hours, preferably 10 to 14 hours, and more specifically, about 10 hours, about 12 hours, about 14 hours, or about 16 hours in a dissolution test. An internally coated formulation of the present invention, for example, can provide an active ingredient release of greater than 2% or more, 5% or more, or 10% or more at a given time in a dissolution test compared to the same formulation without an internal coating. eg 2-15% more active ingredient; what is stated in this paragraph applies in particular to cyclosporine A.

Core with polymer matrix.

The composition according to the present invention contains a core, while the core contains a pharmaceutically active ingredient and a continuous phase or matrix phase to provide mechanical strength. In embodiments, the active ingredient phase is or contains a discontinuous phase in a continuous phase or matrix. The continuous phase or matrix phase preferably contains a water-soluble polymer matrix, and in particular contains a matrix of hydrogel-forming polymer. The core may comprise a polymeric matrix, wherein the matrix-forming polymer is a hydrogel-forming polymer, or a combination thereof.

The active ingredient may be present as a discontinuous phase in a matrix of hydrogel-forming polymer (in continuous phase or aqueous phase) core. The dispersed phase may be hydrophobic, wherein the active ingredient of the present invention may be hydrophobic, and may alternatively be hydrophilic. For example, the dispersed phase may contain a lipid and cyclosporine A or other hydrophobic active ingredient. Cores can be prepared by dispersing the active ingredient phase in an aqueous phase to form a colloid and then allowing the formulation to solidify (gelling), thereby immobilizing the active ingredient in a hydrogel-forming polymer matrix.

The core may be in the form of a solid colloid, wherein the colloid includes a continuous phase and a discontinuous phase, wherein the continuous phase is or contains a hydrogel-forming polymer, and the discontinuous phase is or contains a pharmaceutically active ingredient, e.g., several pharmaceutically active ingredients. The dispersed phase may contain a medium containing the active ingredient, for example containing it in the form of a solution or suspension. The medium may be hydrophobic and may contain or may be a solution of a hydrophobic active ingredient or a suspension of a hydrophilic active ingredient. The dispersed phase as a primer may be liquid, semi-solid or solid.

The core may have the characteristics of a dried colloid in which the active ingredient is dispersed in a matrix of hydrogel-forming polymer. Thus, the core may be in the form of a dried colloid, wherein the colloid includes a continuous phase and a discontinuous phase, wherein the continuous phase is or contains a hydrogel-forming polymer, and the discontinuous phase is or contains a pharmaceutically active ingredient, e.g., several pharmaceutically active ingredients. . The dispersed phase may contain a medium containing the active ingredient, for example containing it in the form of a solution or suspension. The medium may be hydrophobic and may contain or may be a solution of a hydrophobic active ingredient or a suspension of a hydrophilic active ingredient. The dispersed phase may, by way of example, be liquid, semi-solid or solid. The dried colloid may be a dried emulsion, i. the core may have the characteristics of a dried colloid.

Such cores comprising a water-soluble polymer, in particular a hydrogel-forming polymer, and a discontinuous phase comprising cyclosporin A are described in more detail below.

Delayed release coatings.

The present invention relates to coating formulations that comprise or are a coating polymer, wherein the coating polymer is a hydrogel-forming polymer; the cover may be a first cover outside of which is a second cover. The second coating may be a delayed release coating, although the present invention does not require the second coating to be a delayed release coating. The second coating may contain or may be a delayed release polymer.

Thus, according to one embodiment of the present invention, there is provided a pharmaceutical composition comprising a core, a first coating, and a second coating on the outside of the first coating, wherein the core contains a pharmaceutically active ingredient and the first coating contains or is a water-soluble cellulose ester.

The first coating may be present in the amount described elsewhere in the present description.

The second coating may be present in an amount described elsewhere in this document. Preferably, the second coating provides a coating thickness on the composition from about 10 µm to about 1 mm, such as from about 10 µm to about 500 µm, from about 50 µm to about 1 mm, or from about 50 µm to about 500 µm. The thickness may therefore be from about 100 µm to about 1 mm, for example from 100 µm to about 750 µm, or from about 100 µm to about 500 µm. The thickness may be from about 250 µm to about 1 mm, such as from about 250 µm to about 750 µm, or from 250 µm to about 500 µm. The thickness may be from about 500 µm to about 1 mm, for example from about 750 µm to about 1 mm, or from about 500 µm to about 750 µm. The thickness may therefore be from about 10 µm to about 100 µm, for example from about 10 µm to about 50 µm, or from about 50 µm to about 100 µm.

The core is preferably in the form of a mini-granule, such as described in more detail below, such as the form of a solid colloid. The second coating may be a film or it may be a membrane. A second coating, such as a film or membrane, may serve to delay release until the stomach has been passed; the coating may therefore be an enteric coating. The delayed release coating may contain one or more delayed release agents, preferably of a polymeric nature (e.g. methacrylates and the like, polysaccharides and the like, as described in more detail below), or a combination of more than one such agent, optionally including others. auxiliaries, such as plasticizers.

Preferred plasticizers, if used, include hydrophilic plastics.

- 28 040614 stifiers, such as triethyl citrate (TEC), which is particularly preferred when using the Eudragit® family of polymers as coatings, as described below. Another preferred plasticizer, described in more detail below with respect to ethyl cellulose coating, is dibutyl sebacate (DBS). As an alternative or addition, optionally included aids are glidants. A glidant is a substance that is added to a powder or other medium to improve its fluidity. A typical glidant is talc, which is preferred when using the Eudragit® family of polymers as coatings.

The delayed release coating may be applied as described below and may vary in thickness and density. The amount of coating is determined by the additional mass added (obtained from it) to the dry composition (eg, granule) to which it is applied. The weight gain is preferably in the range of 0.1 to 50%, preferably 1 to 15% of the dry weight of the granule, more preferably in the range of 3 to 10%, or in the range of 5-12%, or in the range of 8-12%.

The polymeric coating material for a delayed release coating may comprise methacrylic acid copolymers, ammonium methacrylate copolymers, or mixtures thereof. Methacrylic acid copolymers such as, for example, EUDRAGIT™ S and EUDRAGIT™ L (Evonik) are particularly suitable. These polymers are gastric acid resistant and enteric soluble polymers. Polymer films made from them are insoluble in pure water and dilute acids. They can dissolve at higher pH values depending on their carboxylic acid content. EUDRAGIT™ S and EUDRAGIT™ L can be used as single components in a polymer coating or in combination in any ratio. When using a combination of polymers, the polymeric material may exhibit solubility at various pH levels, such as pH levels at which EUDRAGIT™ L and EUDRAGIT™ S are individually soluble. In particular, the coating may be an enteric coating comprising one or more of the copolymers described in this paragraph. A particular coating material to be mentioned is Eudragit L 30 D-55.

The trademark EUDRAGIT is further used to refer to methacrylic acid copolymers, in particular those sold by Evonik under the trademark EUDRAGIT.

The delayed release coating, if present, may comprise a polymeric material comprising a major portion (e.g., more than 50% of the total polymer coating content) of at least one pharmaceutically acceptable water-soluble polymer, and optionally a minor portion (e.g., less than 50% of the total polymer coating content). polymer) of at least one pharmaceutically acceptable water-insoluble polymer. Alternatively, the membrane coating may comprise a polymeric material comprising a major portion (e.g., more than 50% of the total polymer content) of at least one pharmaceutically acceptable water-insoluble polymer and optionally a minor portion (e.g., less than 50% of the total polymer content) of at least one pharmaceutically acceptable water-soluble polymer.

Ammonium methacrylate copolymers such as, for example, EUDRAGIT™ RS and EUDRAGIT™ RL (Evonik) are suitable for use in the present invention. Such polymers are insoluble in pure water, dilute acids, buffers and/or digestive juices over the full physiological pH range. Polymers swell in water and in digestive juices regardless of pH. When swollen, they become permeable to water and dissolved active agents. The permeability of polymers depends on the ratio of ethyl acrylate (EA), methyl methacrylate (MMA), and trimethylammonioethyl methacrylate chloride (TAMC1) groups in the polymer. For example, those polymers with 1:2:0.2 EA:MMA:TAMC1 ratios (EUDRAGIT™ RL) are more permeable than those with 1:2:0.1 ratios (EUDRAGIT™ RS). EUDRAGIT™ RL polymers are high permeability insoluble polymers. EUDRAGIT™ RS polymers are low permeability insoluble films. The pH independent diffusion controlled polymer in this family is RS 30 D which is a copolymer of ethyl acrylate, methyl methacrylate and low methacrylic acid ester content with quaternary ammonium groups present as salts to provide permeability to the polymer. RS 30 D is available as an aqueous dispersion.

The aminomethacrylate copolymers can be combined in any desired ratio and the ratio can be modified to modify the drug release rate. For example, a ratio of EUDRAGIT™ RS:EUDRAGIT™ RL 90:10 can be used. Alternatively, the EUDRAGIT™ RS:EUDRAGIT™ RL ratio may be from about 100:0 to about 80:20, or from about 100:0 to about 90:10, or any ratio in between. In such formulations, the less permeable EUDRAGIT™ RS polymer typically contains most of the polymeric material with the more soluble RL, which should form gaps upon dissolution through which solutes can come into contact with

- 29 040614 core, which allows the active ingredient to exit in a controlled manner.

Aminomethacrylate copolymers can be combined with methacrylic acid copolymers in the polymeric material to provide the desired delay in drug release and/or coating poration and/or effect on the formulation in the coating to provide drug release and/or dissolution of immobilization or water-soluble polymeric matrices. A ratio of ammonium methacrylate copolymer (eg, EUDRAGIT™ RS) to methacrylic acid copolymer in the range of from about 99:1 to about 20:80 can be used. The two types of polymers can also be combined in the same polymer material or presented as separate coatings that are applied to the pellets.

Eudragit™ FS 30 D is an anionic water based acrylic polymer dispersion consisting of methacrylic acid, methyl acrylate and methyl methacrylate and is pH sensitive. This polymer contains fewer carboxyl groups and thus dissolves at a higher pH (>6.5). The advantage of such a system is that it can be easily produced on an industrial scale with reasonable processing times using conventional powder and fluid bed coating techniques. Another example is EUDRAGIT® L 30D-55, which is an aqueous dispersion of anionic polymers with methacrylic acid as a functional group. It is available as a 30% aqueous dispersion.

In addition to the EUDRAGIT™ polymers described above, a number of other similar copolymers can be used to control drug release. These include methacrylate ester copolymers such as, for example, the EUDRAGIT™ NE and EUDRAGIT™ nm series. Additional information on EUDRAGIT™ polymers can be found in Chemistry and Application Properties of Polymethacrylate Coating Systems, in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, ed. James McGinty, Marcel Dekker Inc., New York, pg 109-114, the entire contents of which are incorporated herein by reference.

Some hydroxypropyl methylcellulose (HPMC) derivatives also exhibit pH dependent solubility and can be used according to the present invention for delayed release coating. Examples of such derivatives may be mentioned HPMC esters, such as hydroxypropyl methylcellulose phthalate (HPMCP), which dissolves rapidly in the upper intestines, and hydroxypropyl methylcellulose acetate succinate (HPMCAS), in which the ionizable carboxyl groups present provide polymer solubility at high pH (>5 .5 for grade LF and >6.8 for grade HF). These polymers are commercially available from Shin-Etsu Chemical Co. Ltd. As with other polymers described herein as useful for delayed release coatings, HPMC and derivatives (e.g. esters) can be combined with other polymers, e.g. EUDRAGIT RL-30 D.

Other polymers may be used to provide the coating, in particular enteric or pH dependent polymers. Such polymers may include phthalate, butyrate, succinate and/or mellitate groups. Such polymers include, without limitation, cellulose acetate phthalate, cellulose acetate succinate, cellulose hydrogen phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, starch acetate phthalate, amylose acetate phthalate, polyvinyl acetate phthalate, and polyvinyl butyrate phthalate.

Delayed release coatings from a pH independent polymer.

In a specific embodiment, the second coating, if present, is or contains a polymeric coating that is pH independent in its dissolution profile and/or in its ability to release the active ingredient included in the formulations of the present invention. The pH independent polymer delayed release coating comprises a delayed release polymer, optionally a plurality of delayed release polymers, and one or more other optional components. Other components can serve as modulators of the properties of the composition. Examples have already been given (eg Eudragit RS and RL).

Another example of a pH independent polymer coating is a coating that contains or is ethyl cellulose; therefore, the pH-independent polymer coating may contain a delayed release polymer that is ethyl cellulose. It should be understood that the ethyl cellulose composition for use in coating the dosage form may contain, in addition to ethyl cellulose and in the case of a liquid liquid medium composition, one or more other components. Other components may serve as modulators of formulation properties, such as stability, or physical properties of the coating, such as film coating ductility. Ethylcellulose may be the only delayed release polymer in this formulation. The amount of ethyl cellulose may be at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by weight of the dry weight of the coating composition for use in the dosage coating. forms. Therefore, the ethylcellulose coating may include components other than ethylcellulose. The amount of ethylcellulose can be

- 30 040614 at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% by weight of the ethylcellulose coating. Therefore, the amount of ethylcellulose may be at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% by dry weight of the second coating. Preferably, the ethyl cellulose coating further comprises a plasticizer, as described below, to improve the plasticity of the film and to improve the film forming properties of the coating composition upon application of the coating.

A particular ethyl cellulose coating composition that can be applied to the first coating is a dispersion of ethyl cellulose with a particle size in the submicron micron range, for example, about 0.1 to 10 microns in size, homogeneously suspended in water using an emulsifier, such as ammonium oleate. The ethylcellulose dispersion may optionally and preferably contain a plasticizer. Preferred plasticizers include, for example, dibutyl sebacate (DBS), diethyl phthalate, triethyl citrate, tributyl citrate, triacetin or medium chain triglycerides. The amount of plasticizer present in the coating formulation will vary depending on the desired properties of the coating. Typically, the plasticizer contains from 1 to 50%, for example from about 8% to about 50%, of the combined weight of the plasticizer and ethylcellulose. Such ethylcellulose dispersions, for example, can be made according to US patent No. 4502888, which is incorporated herein by reference. One such ethylcellulose dispersion suitable for use in the present invention is commercially available and sold under the trademark Surelease® by Colorcon of West Point, Pa, USA. In this marketed product, ethyl cellulose particles, for example, are mixed with oleic acid and a plasticizer, then optionally extruded and melted. The molten plasticized ethylcellulose is then directly emulsified, for example in ammoniated water, optionally in a high shear mixer, for example under pressure. Ammonium oleate can be formed in situ, for example, to stabilize and form a dispersion of particles of plasticized ethyl cellulose. Additional purified water may then be added to reach the final solids content. See also US patent No. 4123403, which is incorporated herein by reference.

The trademark Surelease® is used below to refer to coatings of ethyl cellulose material, such as a dispersion of ethyl cellulose with a particle size in the submicron micron range, such as a size of approximately 0.1 to 10 microns, homogeneously suspended in water using an emulsifier, such as ammonium oleate. Specifically, the Surelease® trademark is used in this document to refer to a product sold by Colorcon under the Surelease® trademark.

The Surelease® dispersion is an example of a combination of film-forming polymer, plasticizer and stabilizers that can be used as a second coating to control active agent release rates with reproducible profiles that are relatively insensitive to pH. The main method of drug release is diffusion through the membrane of the Surelease® dispersion and direct control of film thickness. The use of Surelease® is particularly preferred and the amount of Surelease® applied as a coating can be increased or decreased to modify the solubility of the coated composition. Unless otherwise provided, the term Surelease may apply to Surelease E-7-19020, E-7-19030, E-7-19040, or E-7-19050. An ethyl cellulose coating formulation, such as Surelease E-7-19020, may include ethyl cellulose mixed with oleic acid and dibutyl sebacate, then extruded and melted. The molten plasticized ethylcellulose is then directly emulsified in ammoniated water in a pressurized high shear mixer. Ammonium oleate can be generated in situ to stabilize and form a dispersion of plasticized ethylcellulose particles. Additional purified water may then be added until the final solids content is reached. An ethyl cellulose coating composition, such as Surelease E-7-19030, may further comprise colloidal anhydrous silica dispersed in the material. An ethyl cellulose coating formulation, such as Surelease E-7-19040, may contain medium chain triglycerides in place of dibutyl sebacate, particularly in a formulation comprising colloidal anhydrous silica and oleic acid. An ethyl cellulose coating formulation, such as Surelease E-7-19050, can be prepared by mixing ethyl cellulose with oleic acid prior to melting and extrusion. The molten plasticized ethylcellulose is then directly emulsified in ammoniated water in a pressurized high shear mixer. Ammonium oleate is generated in situ to stabilize and form a dispersion of plasticized ethylcellulose particles. However, formulations that contain medium chain triglycerides, colloidal anhydrous silica and oleic acid are preferred. Surelease E-7-19040 is particularly preferred.

The present invention also relates to the use of combinations of ethyl cellulose, eg Surelease formulation, with other coating components, eg sodium alginate, eg sodium alginate, available under the trademark Nutrateric™.

In addition to the EUDRAGIT™ and Surelease® polymers discussed above, if compatible, any combination of coating polymers disclosed herein may be blended to provide additional delayed release profiles.

The delayed release coating may further comprise at least one soluble adjuvant for increasing the permeability of the polymeric material. Such soluble adjuvants may also be referred to as blowing agents or be such. Preferably, the at least one soluble adjuvant or blowing agent is selected from a soluble polymer, a surfactant, an alkali metal salt, an organic acid, a sugar, a polysaccharide, and a sugar alcohol. Such soluble adjuvants include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol (PVA), polyethylene glycol, water-soluble hydroxypropyl methylcellulose, sodium chloride, surfactants such as, for example, sodium lauryl sulfate and polysorbates, organic acids, such as, for example, acetic acid. , adipic acid, citric acid, fumaric acid, glutaric acid, malic acid, succinic acid and tartaric acid, sugars such as, for example, dextrose, fructose, glucose, lactose and sucrose, sugar alcohols, such as, for example, lactitol, maltitol , mannitol, sorbitol and xylitol, xanthan gum, dextrins and maltodextrins, and a polysaccharide susceptible to enzyme degradation of bacteria normally found in the large intestine, such as polysaccharides including chondroitin sulfate, pectin, dextran, guar gum and amylase, chitosan, etc. .d., as well as derivatives of any of the above. In some embodiments, polyvinylpyrrolidone, mannitol, and/or polyethylene glycol can be used as soluble adjuvants. The at least one soluble adjuvant may be used in an amount ranging from about 0.1% to about 15% by weight of the total dry weight of the polymer coating, such as from about 0.5% to about 10%, from about 0.5 % to about 5%, from about 1% to about 3%, preferably about 2% of the total dry weight of the polymer coating. The delayed release coating may not contain HPMC.

Modifications to release rates, such as providing a delayed or extended release, can be achieved in any number of ways. Mechanisms may or may not be dependent on local pH in the gut, and may also depend on local enzymatic activity to achieve the desired effect. Examples of modified release formulations are known in the art and are described, for example, in US Pat. Nos. 3,845,770; 3,916,899; by reference in its entirety.

The addition of a second polymer (e.g., a polysaccharide, such as a heteropolysaccharide) to Surelease™ or other pH-independent polymeric material that is susceptible to degradation by colonic bacterial enzymes (and optionally or alternatively by pancreatic or other appropriate enzymes) helps provide targeted release of the active ingredient in the site or sites of the gastrointestinal tract, while the second polymer is degradable. By varying the amount of added second polymer present in the coating, the dissolution profile can be optimized to provide the desired release of cyclosporin A from the formulation.

In specific embodiments, the delayed release coating provides for release of the active agent, at least in the colon. Therefore, in one embodiment, the coating comprises a combination of ethyl cellulose (preferably as described above and in particular formulated with an emulsifier such as, for example, ammonium oleate and/or with a plasticizer, such as, for example, dibutyl sebacate or medium chain triglycerides) and a polysaccharide susceptible to degradation by enzymes of bacteria normally found in the colon. Such polysaccharides include chondroitin sulfate, pectin, dextran, guar gum and amylase, chitosan, etc., as well as derivatives of any of the above. Chitosan can be used in connection with obtaining a colon-specific release profile; additionally or alternatively, pectin can also be used.

The use of polysaccharides by themselves to cover the delayed release has had limited success. Most of the non-starch polysaccharides have the disadvantage of not having satisfactory film-forming properties. They also tend to swell in the gastrointestinal tract and become porous, leading to early release of the drug. Even amorphous amylose, which is resistant to degradation by pancreatic alpha-amylase but susceptible to degradation by colonic bacterial enzymes, has the disadvantage of swelling in aqueous media, although this can be controlled by incorporating an insoluble polymer such as ethyl cellulose and/or acrylate into amylose film. amylose, however,

- 32 040614 is insoluble in water, and although water-insoluble polysaccharides are not excluded, the use of a water-soluble polysaccharide (WSP) susceptible to degradation by bacterial enzymes is particularly advantageous when used as a coating according to this embodiment of the present invention. A particularly preferred polysaccharide according to this embodiment of the present invention is pectin. Various types of pectin may be used, including the various grades of pectin available, i.e. with different degrees of methylation (DM), i.e. the percentage of carbonyl groups esterified with methanol, for example pectins with a DM greater than 50%, known as high methoxyl (HM) pectins or low methoxyl (LM) pectins, or a combination of pectins including HM pectin and LM pectin. According to this embodiment, it is also possible to use pectins with different degrees of acetylation (DAc). Together, DM and DAc or the degree of substitution is known as the degree of esterification (DE). Pectins with different DE can be used according to the present invention. As an alternative to pectin, sodium alginate can be used as the polysaccharide according to an embodiment of the present invention. However, other embodiments may conveniently include amylose and/or starch that contains amylose. Various grades of starch containing different percentages of amylose can be used, including, for example, Hylon V (National Starch Food Innovation), which has a 56% amylose percentage, or Hylon VII, which has a 70% amylose percentage. The rest, in percentage terms, is accounted for by amylopectin. The polysaccharides pectin, amylose and sodium alginate are particularly preferred in order to achieve colonic delivery of the active ingredient.

It has been found that a water-soluble polysaccharide, preferably pectin, can act as a pore former in a coating, otherwise represented by ethyl cellulose (preferably Surelease). The term pores does not mean well-like openings from the surface to the core of the formulation, but rather areas of low or no coverage occurring stochastically on and in the coating of the present invention. As mentioned above, pore formation can also be achieved by including other soluble adjuvants in the polymer coating to enhance the permeability of the polymer material.

Blowing agents have been described above with respect to Surelease (see, for example, US Patent Application No. 2005/0220878).

According to a specific embodiment of the present invention, the delayed release coating comprises ethyl cellulose, such as Surelease™, and a water-soluble polysaccharide (WSP), while the proportion of ethyl cellulose (specifically Surelease™) to WSP is ideally in the range of 90:10-99:1 , preferably 95:5-99:1, more preferably 97:3-99:1, eg about 98:2, based on the dry weight of the coating.

Preferably, in this embodiment and other embodiments described herein in which ethyl cellulose (Surelease) is used as a coating, the weight gain of a coating composition comprising ethyl cellulose (e.g., Surelease™ and WSP) is in the range 1% to 30% (e.g. 3% to 25%, 5% to 15%, 8% to 14%, 10% to 12%, 12% to 18%, or 16% to 18%, preferably the weight gain is about 11% %, about 11.5% or about 17%). It is particularly preferred that when using the WSP according to this embodiment, the WSP is pectin. In particular, favorable weight gains when using coatings comprising ethyl cellulose, such as Surelease™, are in the range of 5-12%, 8-12%, 5-10%, preferably about 8%, about 8.5%, about 9 %, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5% or about 12%.

Therefore, in an embodiment, the second coating comprises ethyl cellulose and a water-soluble polysaccharide (particularly pectin), wherein the water-soluble polysaccharide (WSP) is present in an amount of 0.1% to about 10% by weight of the dry weight of the second coating. Preferably WSP is present in an amount of from about 0.5% to about 10%, such as from about 0.5% to about 5%, from about 1% to about 3%, preferably about 2%, based on the total dry weight of the second coating. In this embodiment, the WSP is preferably pectin. According to this embodiment, the second composition preferably further comprises a plasticizer. Acceptable plasticizers include those described above with respect to Surelease™. Preferably, the weight gain of the formulation by applying the second coating according to this embodiment is in the range of 1 to 30% (e.g., 3 to 25%, 5 to 15%, 8 to 14%, 10 to 12%, 12 up to 18% or from 16 to 18%, preferably the increase in weight is about 11%, about 11.5% or about 17%).

In an embodiment, the delayed release polymer is a water-insoluble cellulose ether. If the second coating contains or is a delayed release polymer, then the delayed release polymer may not be the same as the water soluble cellulose ether of the first coating. Therefore, the second coating may not be the same as the first coating.

External barrier or protective coating.

The formulation compositions described herein may include a protective coating on the outside of the second coating. The protective coating may assist in protecting the second coating from damage occurring, for example, during formulation of the composition into the final dosage form or during processing, transport, or storage of the composition. The protective coating is preferably applied to the outer surface of the composition. The protective coating may be applied directly to the second coating such that the protective coating is in contact with the second coating. The protective coating is preferably a water-soluble coating that does not interfere with the release of the active ingredient(s) from the formulation upon application. Preferably, the protective coating is or contains a water-soluble polymer. The protective coating may comprise a water-soluble cellulosic or PVA film-forming polymer. Preferably, the protective coating may be or may contain Opadry (HPMC/HPC based), Opadry II (PVA/PEG based), or the polyvinyl alcohol/polyethylene glycol graft copolymers (Kollicoat IR) described herein. The protective coating may be present in the form of a layer from about 2 microns to about 50 microns. Preferably, a protective coating is applied to give a weight gain of from about 0.5 to about 10% based on the weight of the formulation prior to application of the protective coating.

Polymer matrix of continuous phase (water phase).

In this section of the present description, relating to the polymer matrix, the number of components in percent by weight of the composition. In the context of this section of the present description, refers to the percentage by weight of the dry weight of the kernel, i. cover(s) exclude(s).

It should be recalled that the core may contain a matrix or a continuous phase, and optionally, but not always, also a dispersed phase or a discontinuous phase. Preferably, the continuous core phase is or contains a hydrogel-forming polymer. A hydrogel-forming polymer is a polymer capable of forming a hydrogel. A hydrogel can be described as a solid or semi-solid material that is not fluid at rest, includes a network (matrix) of hydrophilic polymer chains that span the volume of an aqueous liquid medium.

The core may contain a hydrogel-forming polymer selected from the group consisting of gelatin; agar; agarose; pectin; carrageenan; chitosan; alginate; starch; xanthan gum; gum arabic; guar gum; locust bean gums; polyurethane; polyester polyurethane; cellulose; cellulose ester, cellulose acetate, cellulose triacetate; cross-linked polyvinyl alcohol; polymers and copolymers of acrylic acid, hydroxyalkyl acrylates, hydroxyethyl acrylate, diethylene glycol monoacrylate, 2-hydroxypropylacrylate, 3-hydroxypropylacrylate; polymers and copolymers of methacrylic acid, hydroxyethyl methacrylate, diethylene glycol monomethacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate, dipropylene glycol monomethyl acrylate; vinylpyrrolidone; acrylamide polymers and copolymers, N-methylacrylamide, N-propylacrylamide; methacrylamide polymers and copolymers, N-isopropylmethacrylamide, N-2-hydroxyethylmethacrylamide and vinylpyrrolidone, and combinations thereof. According to specific embodiments, double or triple, etc. are provided. combinations of any of the above substances.

In a further embodiment, the hydrogel-forming polymer is selected from the group consisting of gelatin, agar, polyethylene glycol, starch, casein, chitosan, soy protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, phthalated gelatin, succinated gelatin, cellulose phthalate acetate, oleoresin , polyvinyl acetate, acrylic or methacrylic ester polymers and polyvinyl acetate phthalate, as well as any derivative of any of the above, or a mixture of one or more such hydrogel-forming polymers.

The hydrogel-forming polymer may also be referred to as a hydrocolloid, i. colloid system in which colloid particles are dispersed in water and the amount of water available allows gel formation. In embodiments, it is preferred to use reversible hydrocolloids, preferably thermoreversible hydrocolloids (eg, agar, agarose, gelatin, etc.), as opposed to irreversible (single state) hydrocolloids. Thermoreversible hydrocolloids can be in the state of a gel and a sol, with alternating states upon the addition or removal of heat. Gelatin, agar and agarose are thermoreversible, rehydratable colloids and are particularly preferred. Gelatin derivatives are also contemplated, such as, for example, succinate or phthalated gelatins. Thermoreversible hydrocolloids which may be used according to the present invention, either alone or in combination, include those derived from natural sources such as, for example, carrageenan (extracted from seaweed), gelatin (extracted from bovine, porcine, fish or vegetable sources), agar (from seaweed), agarose (polysaccharide derived from agar), and pectin

- 34 040614 (extracted from citrus peel, apple and other fruits). A non-animal derived hydrocolloid may be preferred for some uses, such as for administration to vegetarians or individuals who do not wish to consume animal products for religious or health reasons. With respect to the use of carrageenan, reference is made to US Patent Application No. 2006/0029660 Al (Fonkwe et al.), the entire contents of which are incorporated herein by reference. The hydrogel-forming polymer may comprise or may be a combination of gelatin with one or more other thermoreversible hydrocolloids, for example one or more of the other thermoreversible hydrocolloids just listed. The hydrogel-forming polymer may contain or may be a combination of gelatin with agar; optionally, at least one additional thermoreversible hydrocolloid, such as the one just mentioned, may be included in the combination.

Thermoreversible colloids have an advantage over other hydrogel-forming polymers. Thickening or solidification of thermoreversible colloids occurs when the colloid is cooled, for example, in a liquid cooling bath or air flow. Thickening of other hydrogel-forming polymers, which is chemically controlled, may cause the contents of the composition to bleed into the thickening medium, since the solidification process may take some time. Leakage of the contents of the formulation may result in an inaccurate amount of the active ingredient in the formulation. Thermo-reversible colloids are also known as thermo-reversible gels, and therefore it is preferred that the hydrogel former be a thermo-reversible thickener.

Another term that can be applied to hydrogel formers that are advantageous is thermotropic, whereby a thermotropic thickener (which the reader will find preferred as a hydrogel former used in the present invention) is a thickener that causes thickening with temperature change, and such thickeners are capable of thickening faster than those whose thickening is chemically induced, such as ionotropic thickeners, whose thickening is induced by ions, such as chitosan. According to embodiments of the present invention, therefore, the hydrogel former is a thermotropic gelling polymer or a combination of such polymers.

The preparation of the core formulation may require that the hydrogel-forming polymer be present in solution, preferably an aqueous solution. The hydrogel-forming polymer makes up 5 to 50%, preferably 10 to 30%, even more preferably 15 to 20% by weight of the aqueous phase when formulated as described herein. In addition, the hydrogel-forming polymer may contain from 8 to 35% (eg 15-25%, preferably 17-18%) of the hydrogel-forming polymer; 65-85% (preferably 77-82%) water and optionally 1-5% (preferably 1.5-3%) sorbitol.

The surfactant (e.g., anionic surfactant), if present, may be present in the aqueous phase premix in an amount of 0.1-5% (preferably 0.5-4%), with all parts determined by weight. water phase.

In embodiments, the composition contains at least 25%, preferably at least 40% by weight, by dry weight, of the hydrogel-forming polymer composition. For example, the hydrogel-forming polymer makes up 25% to 70%, eg 40% to 70%, preferably 45% to 60% of the composition, with percentages determined by weight of the dry weight of the composition.

In embodiments, the hydrogel-forming polymer is a pharmaceutically acceptable polymer.

In some embodiments, the hydrogel-forming polymer is gelatin. In some embodiments, the hydrogel-forming polymer comprises gelatin. In some embodiments, gelatin makes up at least 40%, such as 40 to 70%, preferably 45 to 60%, of the composition, with percentages determined by weight of the dry weight of the composition.

The hydrogel-forming polymer may optionally contain a plasticizer, such as sorbitol, or glycerol, or a combination thereof. In particular, one or more plasticizers may be combined with the gelatin.

In embodiments in which the hydrogel-forming polymer comprises or is gelatin, reference is made to Bloom strength, a measure of gel or gelatin strength developed in 1925 by O.T. Bloom. The test determines the weight (in grams) required to force a plunger (typically 0.5 inch diameter) into the gel surface to a depth of 4 mm without destroying it. The result is expressed in blooms (points), and it usually varies from 30 to 300 blooms. To perform the Bloom test on gelatin, a 6.67% gelatin solution is incubated for 17-18 hours at 10° C. prior to testing.

If the hydrogel-forming polymer contains or is gelatin, the bloom strength of the gelatin may be in the range of 125 to 300 bloom, 200 to 300 bloom, and preferably 250 to 300 bloom. It should be appreciated that higher bloom strength gelatin can be substituted for lower bloom strength gelatin at higher concentrations.

- 35 040614

In accordance with the present invention, in embodiments in which the hydrogel-forming polymer matrix contains or is gelatin, the gelatin can be produced in a number of ways. For example, it can be obtained by partial hydrolysis of collagen material such as skin, white connective tissues or animal bones. Type A gelatin is obtained mainly from pigskins by acid treatment and exhibits an isoelectric pH of 7 to 9, while type B gelatin is obtained by alkaline treatment of animal (bovine) bones and skins and exhibits an isoelectric pH of 4.7 to 5. ,2. Type A gelatin is somewhat preferred. Gelatin for use according to the present invention can also be obtained from the skin of cold water fish. A mixture of type A and type B gelatins can be used according to the present invention to produce gelatin with the desired viscosity and bloom gel strength characteristics for the manufacture of granules.

Low temperature gelatin (or gelatin derivatives, or mixtures of gelatins with melting point depressants) or other polymeric matrices capable of curing at lower temperatures (eg sodium alginate) may also be used. Therefore, a polymer that contains or is low temperature gelatin is believed to be the preferred matrix polymer.

In accordance with the present invention, in embodiments where the polymer contains or is gelatin, the gelatin starting material is preferably modified prior to manufacture to form soft gelatin by adding a plasticizer or softener to the gelatin to control the hardness of the composition of the present invention. The addition of a plasticizer provides enhanced softness and ductility, which may be desirable to optimize solubility and/or additional processing such as, for example, coating. Useful plasticizers according to the present invention for combination with gelatin or other hydrogel-forming polymer include glycerol (1,2,3-propanetriol), D-sorbitol (D-glucite), sorbitol BP (non-crystallizing sorbitol solution), or an aqueous solution of D-sorbitol. , sorbitans (eg Andidriborb 85/70), mannitol, maltitol, gum arabic, triethyl citrate, tri-nbutyl citrate, dibutyl sebacate. Other or similar low molecular weight polyhydric alcohols are also contemplated, such as ethylene glycol and propylene glycol. Polyethylene glycol and polypropylene glycol can also be used, although they are less preferred. Glycerin and D-sorbitol can be obtained from Sigma Chemical Company, St. Louis, Mo, USA, or Roquette, France. Some active agents and adjuvants included for other functions may act as plasticizers.

Softeners or plasticizers, if used, can ideally be included in proportions rising up to 30%, preferably up to 20% and more preferably up to 10% of the dry weight of the composition according to the present invention, even more preferably from 3 to 8% and most preferably from 4 until 6%.

Although optional, the hydrogel-forming polymer matrix may also contain a disintegrant, and it is particularly desirable to increase the rate of disintegration of the composition of the present invention. Examples of disintegrants that may be included are alginic acid, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium starch glycolate.

A crystallization inhibitor (eg, about 1% dry weight of the composition) can also be included in the composition according to the present invention. An example is hydroxypropyl/methylcellulose (HPC or HPMC, hypromellose, etc.), which can play other roles such as, for example, an emulsifier.

In another embodiment, the hydrogel-forming polymer matrix is chitosan, which can exist in the form of biogels with or without additives, as described, for example, in US Pat. No. 4,659,700 (Johnson &Johnson); Kumar Majeti N.V. Ravi, Reactive and Functional Polymers, 46, 1, 2000; and Paul et al., ST.P. Pharma Science, 10, 5, 2000, the entire contents of which are incorporated herein by reference. Chitosan derivatives, such as thiolated compounds, are also contemplated.

The hydrogel-forming polymer matrix may be a non-hydrocolloid gum. Examples are cross-linked salts of alginic acid. For example, aqueous solutions of sodium alginate gums extracted from the walls of brown algae have a well-known thickening property when exposed to di- and trivalent cations. A typical divalent cation is calcium, often in the form of an aqueous solution of calcium chloride. According to this embodiment, it is preferred that the crosslinking or thickening occurs upon reaction with such a multivalent cation, in particular calcium.

The hydrogel-forming polymer matrix may have a low water content, so the composition may have a low water content. As described below, during the manufacture of the core, the discontinuous phase, optionally including the active ingredient, is mixed with an aqueous solution of a hydrogel-forming polymer and the formulation is thickened, for example, to provide cores that are minigranules. Preferably, the cores are dried after shaping to reduce the amount of water present in the core.

In some embodiments, the composition does not contain compounds containing a disulfide bond. In embodiments, the hydrogel-forming polymer does not contain compounds containing a disulfide bond.

The hydrogel-forming polymer matrix forming the core continuous phase (aqueous phase) may further contain a surfactant.

Surfactants that may be used in the formulation are described in the Surfactants section below.

A surfactant that may be present in the continuous aqueous phase of the core includes, for example, a surfactant selected from the group consisting of cationic, amphoteric (zwitterionic), anionic surfactants, such as perfluorooctanoate (PFOA or PFO ), perfluoro-octane sulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate and other alkyl sulfate salts, sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES), and alkyl benzene sulfonate, as well as nonionic surfactants such as perfluorocarbons, polyoxyethylene glycol dodecyl ether (e.g. Brij such as Brij 35), Myrj (e.g. Myrj 49, 52 or 59), Tween 20 or 80 (also known as polysorbate) (Brij, Myij and Tween products are commercially available from Croda), poloxamers, which are non-ionic ternary block copolymers consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide) ), flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), or a combination of the above. In particular, the surfactant may be selected from, or may contain, anionic surfactants and combinations thereof, with the anionic surfactants not necessarily being those mentioned in this paragraph. A particular class of surfactant contains sulfate salts. The preferred anionic surfactant in the aqueous phase is SDS. Mixtures of anionic surfactants can be used. Mixtures of additional surfactants are also contemplated, for example mixtures including perfluorocarbons.

According to embodiments of the present invention, the core contains a hydrophilic surfactant, which is believed without going into theory, at least partially separates the aqueous phase (polymer matrix).

Such surfactants intended for such incorporation into the aqueous phase of the core are preferably easily diffusible or diffusible surfactants to facilitate the manufacture and processing of the formulation of the present invention.

The surfactant may have an HLB of at least 10 and optionally at least 15, such as at least 20 or at least 30 and optionally 38-42, such as 40. Such surfactants may be of any particular type (ionic, non-ionic, zwitterionic) and can be as part of the dry weight of the composition from 0.1 to 6%, for example from 0.1 to 5%, from 0.1 to 4% or from 0.1 to 3%, more preferably in the form part constituting at least 1% and in particular from 1.0 to 4.5 or 5%, ideally in the range or close to the range of 2-4%, for example from 2 to 3%, or about 2%, or approximately 4%.

Unless otherwise stated or required, all percentages and ratios are by weight.

In one embodiment, the anionic surfactant may be an anionic surfactant selected from alkyl sulfates, carboxylates, phospholipids, or combinations thereof.

The physical form of the surfactant at the point of introduction into the aqueous phase during the production of the core plays the role of facilitating the manufacture of the core. Thus, although liquid surfactants can be used, it is preferable to use a surfactant that is in solid form (eg, crystals, granules or powder) at room temperature, particularly if the aqueous phase contains gelatin.

Generally mixtures of surfactants can be used, e.g. to achieve optimum long term stability of the composition of the present invention, with shorter chain surfactants generally facilitating shorter term stability (treatment additive) and surfactants substances with longer chains facilitating longer term stability (additive to increase shelf life). In some embodiments, shorter chain surfactants contain a maximum of C ₁₀ alkyl (e.g., C ₆ -C ₁₀ alkyl) as the hydrophobic portion of the surfactant, while longer chain surfactants contain C ₁₀ alkyl or higher alkyl (eg C ₁₀ -C ₂₂ alkyl) as the hydrophobic part of the surfactant. It is contemplated that C ₁₀ alkyl surfactants may facilitate handling or help extend shelf life, or both, depending on the identity of the other adjuvants and active agent(s). Higher alkyl in specific embodiments of the present invention may be Sc-C ₂₂ - or C ₁₂ -C ₂₂ -alkyl, and in some embodiments it has a length greater than C ₁₈ .

The matrix phase may contain the pharmaceutically active agent in solution in the matrix phase. Such active agents in solution in the matrix phase are therefore not present as a separate phase, but are part of the continuous matrix phase. Active agents suitable for being in solution in the matrix phase are those which are soluble in the aqueous premixture which is used during manufacture to form the matrix phase. Additionally or alternatively, the pharmaceutically active agent may be contained in the discontinuous phase.

dispersed phase.

The core polymer matrix described above (eg, from a hydrogel-forming polymer) may contain a discontinuous phase. Preferably, the discontinuous phase, if present, may contain a pharmaceutically active agent, in particular a hydrophobic active agent. The present invention also relates to compositions in which the discontinuous phase contains a hydrophilic pharmaceutically active agent. In embodiments, therefore, the discontinuous phase contains cyclosporin A or another hydrophobic active ingredient. According to such embodiments, the hydrophobic active ingredient is preferably soluble in the discontinuous phase, ie. the dispersed phase contains a medium in which the active ingredient is dissolved. Embodiments where the hydrophobic active ingredient is dispersed phase soluble are preferred because such formulations release the cyclosporine in solubilized form, which can enhance the therapeutic effect of the drug at the release site, for example, by enhancing absorption in the colonic mucosa.

In embodiments, the pharmaceutically active agent is or is contained in a discontinuous phase.

The dispersed phase may contain a water-immiscible phase (also referred to herein as an oil phase). The water-immiscible phase may be solid, semi-solid or liquid at ambient temperature (eg at 25° C.), and therefore the oil phase may, for example, be waxy at ambient temperature. The oil phase may be or may contain a liquid lipid and optionally a solvent miscible therewith. The pharmaceutically active ingredient may be present in the oil phase. Preferably the active ingredient is soluble in the oil phase.

The dispersed phase may contain a combination of oils. The liquid lipid may be a composition of short, medium and long chain triglycerides, or a combination thereof. Medium chain triglyceride(s) (MCTs) include(s) one or more triglycerides of at least one fatty acid selected from C ₆ -, C7 -, C ₈ -, C ₉ -, Cu -, Cu - and C ₁₂ fatty acids. It should be understood that commercially available triglyceride formulations, in particular MCTs, useful according to the present invention are mixtures derived from natural products and usually or always contain minor amounts of compounds that are not MCTs; the term is a medium chain triglyceride compound, therefore, contemplates such compounds. Short chain triglyceride(s) includes(s) one or more triglycerides with at least one short chain fatty acid selected from C ₂ -C ₅ fatty acids. Long chain triglyceride(s) include(s) one or more triglycerides with at least one long chain fatty acid containing at least 13 carbon atoms.

The liquid lipid may include or may be triglycerides and/or diglycerides. Such glycerides may be selected from medium chain glycerides or short chain triglycerides, or combinations thereof.

The liquid lipid may be a caprylic/capric acid triglyceride, ie. the composition of caprylic/capric acid triglyceride (which, as it should be understood, may contain minor amounts of compounds that are not caprylic/capric acid triglycerides).

Said solvent, which is optionally contained in the oil phase, may be miscible with both the liquid lipid and water. Examples of acceptable solvents are 2-(2-ethoxyethoxy)ethanol commercially available under the trademarks Carbitol™, Carbitol cellosolve, Transcutol™, Dioxitol™, Poly-solv DE™ and Dowanal DE™ or the purer Transcutol™ HP (99.9). Preferred are Transcutol P or HP, which are commercially available from Gattefosse. Another possible co-solvent is polyethylene glycol. In this embodiment, PEGs of molecular weight 190-210 (eg PEG 200) or 380-420 (eg PEG 400) are preferred. Acceptable PEGs may be commercially available under the name Carbowax, manufactured by the Union Carbide Corporation, although many alternative manufacturers or suppliers are possible.

- 38 040614

The dispersed phase can be 10-85% of the dry weight of the core.

As discussed above, the dispersed phase may be an oily phase, including any pharmaceutically acceptable oil, such as a liquid lipid. The oil phase may be present as oil droplets. With regard to the dry weight of the core, the oil phase may comprise 10 to 85%, such as 15 to 50%, such as 20 to 30% or 35 to 45%. The term oil means any substance which is wholly or partially liquid at or near ambient temperature, for example 10 to 40°C or 15 to 35°C, and which is hydrophobic but soluble in at least one organic solvent. Oils include vegetable oils (eg margosa seed oil) and petroleum-derived oils.

Oils that may be present in the oil phase include polyunsaturated fatty acids such as, for example, omega-3 oils, e.g., eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linoleic acid (ALA), acid (CLA). Preferably, ultrapure EPA, DHA or ALA or CLA is used, for example up to 98% or higher purity. Omega oils can be obtained, for example, from any suitable plant, such as the Inca peanut. Such oils may be used alone, such as EPA, or DHA, or ALA, or CLA, or in any combination. Combinations of such components are also contemplated, including doubles, triples, etc. combinations in any ratio, for example a 1:5 dual mixture of EPA and DHA is commercially available under the trademark Epax 6000. The oil portion of the oil phase may contain or may be the oil mentioned in this paragraph.

Oils that may be present in the oil phase are, in particular, natural triglyceride oils, which include olive oil, sesame oil, coconut oil, palm kernel oil, margosa seed oil. The oil may be or may include saturated coconut and palm kernel derived caprylic and capric fatty acids and glycerin, such as those sold under the trademark Miglyol™, a number of which are available and from which one or more oil phase components may be selected according to of the present invention, including Miglyol™ 810, 812 (caprylic/capric acid triglyceride); Miglyol™ 818 (caprylic/capric/linoleic acid triglyceride); Miglyol™ 829 (caprylic/capric/succinic acid triglyceride);

Miglyol™ 840 (propylene glycol dicaprylate/dicaprate). It should be noted that Miglyol™ 810/812 are MCT formulations that differ only in the C ₈ /C _1o ratio and due to its low C ₁₀ content, the viscosity and cloud point of Miglyol™ 810 are lower. The Miglyol™ range is commercially available from Sasol Industries. As noted above, the oils that may be contained in the oil phase need not be liquid or completely liquid at room temperature. Waxy-type oils are also possible: they are liquid at manufacturing temperatures, but solid or semi-solid at normal ambient temperatures. The oil portion of the oil phase may contain or may be the oil referred to in this paragraph.

Alternatively or in addition, oils that may be contained in the oil phase of the present invention are other medium chain triglyceride formulations such as, for example, Labrafac™ Lipophile manufactured by Gattefosse, in particular product number WL1349. Miglyol™ 810, 812 are also medium chain triglyceride formulations.

Therefore, the oil phase may be or may contain medium chain mono-, di-, or triglycerides.

Medium chain glyceride(s) (e.g., mono-, di-, or triglyceride(s)) referred to herein are(are) such that they contain(at) one or more triglycerides at least one fatty acid selected from fatty acids with 6, 7, 8, 9, 10, 11 or 12 carbon atoms, for example from C ₈ -C ₁₀ fatty acids.

The oil phase may further contain one or more surfactants, as described below in the Surfactants section. For example, the oil phase may contain one or more non-ionic or amphoteric surfactants. In particular, the oil phase may contain one or more of the non-ionic surfactants listed in the Surfactants section below. The presence of a surfactant in the oil phase may also provide increased solubility of the active ingredient contained therein (i.e., act as a solubilizer) and/or may provide increased emulsification when the discontinuous phase is mixed with the aqueous polymer phase to form the core (i.e., e. acts as an emulsifier).

The surfactant in the oil phase, for example, may be or may contain polyethoxylated castor oils (polyethylene glycol ethers), which can be obtained by reacting ethylene oxide with castor oil. Commercial preparations can also be used as a surfactant/solubilizer, for example

- 39 040614 those commercial preparations which contain minor components such as, for example, polyethylene glycol esters of ricinoleic acid, polyethylene glycols and polyethylene glycol esters of glycerol. A preferred example is Kolliphor EL, formerly known as Cremophor EL. Another surfactant that may be present in the oil phase is, for example, a phospholipid.

In embodiments, the oil phase surfactant may be or may contain a non-ionic surfactant selected from sorbitan surfactants, PEG fatty acids, glyceryl fatty acid derivatives, or poloxamers.

In embodiments, the HLB of the oil may be in the range 0-10 (optionally 1-8, such as 1-6 and sometimes 1-5).

In another embodiment, the oil phase comprises an oil with an HLB in the range 0-10 (preferably 1-5) and a surfactant (preferably a non-ionic surfactant) with an HLB in the range 10-20 and optionally 11-20 (preferably 11-15) in the range 0-10 (preferably 1-5).

In another embodiment, the oil phase comprises an oil and a surfactant (preferably a non-ionic surfactant), with both the oil and the surfactant having an HLB in the range of 0-10. For example, an oil has an HLB of 1-5, such as 1-4 or 1-2, and a surfactant has an HLB of 2-8, such as 3-7, 2-6, or 3-4).

Acceptable low HLB oils (HLB less than 10) include medium chain triglycerides, linoleoyl macrogol glycerides (polyoxyl glycerides), caprylocaproyl macrogol glycerides, and caprylic/capric acid triglyceride. For commercial products, especially preferred lower HLB range oils are Labrafac™ Lipophile (e.g. 1349 WL), Captex 355 and Miglyol 810.

One example of a high HLB surfactant that can be used in a low HLB oil includes polyethoxylated castor oils (polyethylene glycol ethers), such as the commercial product Kolliphor EL.

In an embodiment, an oil phase consisting of a high HLB surfactant and a low HLB oil in a ratio of 1-4:1 by weight, e.g. 1.2-3.0:1 by weight, preferably 1.5-2, 5:1 by weight and most preferably 1.8-2.2:1 by weight (high HLB:low HLB) successfully stabilizes the emulsion before and after immobilization of the oil droplets in the aqueous phase. In this context, to stabilize means, in particular, that according to this embodiment, the solubility and/or dispersion of the composition in vitro is improved. In this embodiment, the term high HLB generally implies an HLB above 10, preferably between 10 and 14, more preferably between 12 and 13. The term low HLB generally implies an HLB below 10, preferably between 1 and 4, more preferably 1 to 2 .

It should be understood that the oil phase according to the above embodiments may further contain one or more solvents, such as 2-(2-ethoxyethoxy)ethanol or low molecular weight PEG as mentioned above.

The specific oil phase contains an oil (low HLB), a high HLB non-ionic surfactant and a co-solvent, such as the following three commercial products: Transcutol P (as co-solvent), Myglyol 810 (as oil) and Kolliphor EL (superficial -active substance). Miglyol has a low HLB and Kolliphor EL has a high HLB. The oil phase may therefore contain a combination of the following, and optionally the pharmaceutically active ingredient: 2-ethoxyethanol, MCT, and in particular a caprylic/capric acid triglyceride formulation, and polyethoxylated castor oil, or may consist of these.

The hydrophobic active ingredient is preferably soluble in the oil phase. As discussed below with respect to obtaining the core, the hydrophobic active ingredient is preferably dissolved in the oil phase, and the oil phase is mixed with an aqueous phase, which includes a hydrogel-forming polymer.

The dispersed phase (oil phase) may be or may contain a glyceride composition, optionally the dispersed phase is or contains a fatty acid monoglyceride, diglyceride, or triglyceride, or a combination thereof, or the dispersed phase is or contains a caprylic/capric acid triglyceride composition .

The dispersed phase of the colloidal core may contain self-assembling structures, such as micelles, vesicles, liposomes, or nanoparticles, or at least structures that result from drying of these types of aqueous colloids (have the characteristics of structures that result from drying of these types of aqueous colloids). The present invention relates in particular to formulations in which the dispersed phase is micellar, ie. formed from micelles and/or promicelles. The term promicelle refers to the portion of a formulation that will form a micelle upon contact with water, such as the contents of the gastrointestinal tract.

The following discussion refers to micelles for convenience, but is generally applicable to other self-assembling structures. The micelle-forming surfactant is present as micelles dispersed in the hydrogel-forming polymer in a wet (but already dried) composition obtained as an intermediate in the manufacturing process described herein. It is also believed to be present as micelles in the dried composition, but the presence of micelles or micelle-like structures in the dried composition is not necessary according to the present invention. This paragraph mentions that the presence of surfactant in micellar form does not require that the entire surfactant content of the composition be in micellar form, since it is considered more likely that some of the surfactant will be outside the micelles. Thus, in a wet composition, a hydrogel-forming polymer, either in a gel state or in a sol (liquid) state, may contain a micelle-forming surfactant at a concentration above the critical micelle concentration.

The diameter of the dispersed micelles can be 0.5 to 200 nm, 1 to 50 nm, or 5 to 25 nm. The micelle size can be determined by dynamic light scattering or NMR diffusion methods known in the art. Although the size of the micelles is given in terms of diameter, this does not imply that the micelles must be exclusively spherical, only that they may have some nearly circular cross section.

The surfactant may be a non-ionic surfactant. The surfactant may be a polyoxyethylated surfactant. The surfactant has a hydrophilic head, which may be a hydrophilic chain, such as a polyoxyethylene chain or a polyhydroxylated chain.

The surfactant, of course, has a hydrophobic part and in particular a hydrophobic backbone. The hydrophobic chain may be a hydrocarbon chain, for example, containing at least 6 carbon atoms, optionally at least 10 carbon atoms, and in particular at least 12 carbon atoms; however, some hydrocarbon chains contain no more than 22 carbon atoms, for example hydrocarbon chain C ₁₀ -C ₂₀ , C ₁₂ -C ₂₀ or C ₁₅ -C ₂₀ . This may be an alkyl chain, for example, with the number of carbon atoms just mentioned. This may be an alkenyl chain including one or more carbon-carbon double bonds, for example with the number of carbon atoms just mentioned. The surfactant may contain a hydrocarbon chain, such as an alkyl chain or an alkenyl chain, which is substituted, provided that it retains its hydrophobic character. This may be, for example, one or two substituents, for example one substituent, for example, selected from halogen (eg F or Cl), hydroxy, thiol, oxo, nitro, cyano; while hydroxy or thiol substituents can be esterified, for example, with a fatty acid. One class of surfactants contains a hydrocarbon monosubstituted with hydroxy; optionally, at least a portion of the hydroxy groups of an aliquot of a surfactant, e.g., a surfactant in a granule, may be esterified with a fatty acid or a monohydroxy fatty acid disclosed herein, or esterified with a fatty alcohol, e.g., having at least 6 carbon atoms , optionally at least 10 carbon atoms and in particular at least 12 carbon atoms; while some hydrocarbon chains have no more than 22 carbon atoms, for example C ₁₀ -C ₂₀ , C12-C20 or C ₁₅ -C ₂₀ fatty alcohols.

The hydrophobic chain may be part of an esterified fatty acid R1-COOH or an esterified or esterified fatty ester R1-COH, wherein R ¹ is a hydrophobic chain, for example as mentioned in the previous paragraph. The ester-forming or, as the case may be, ester-forming group will generally contain a hydrophilic chain.

As mentioned, the surfactant may have a hydrophilic chain and may be a non-ionic surfactant, or may meet both conditions. The hydrophilic chain may be polyethylene glycol, also known as polyoxyethylene or macrogol. The hydrophilic chain may be characterized by the formula -(O-CH ₂ -CH ₂ ) _n -OR, in which n is 5 or 6-50 and R is H or alkyl, eg ethyl or methyl. The present invention relates to embodiments in which n is 6-40, such as 6-35. In some embodiments, n is 6-25 and is optionally 8-25 or 8-15. In other embodiments, n is 8-50 or 8-40, such as 10-50, 10-40, or 10-35. In a specific embodiment, n is 15. In all hydrophilic chains of the formula -(O-CH ₂ -CH ₂ ) _n -OR in one group of embodiments, R is H.

The hydrophilic chain may be a polyhydroxylated chain (eg C ₅ -C ₂₀ chain, eg C ₅ -C ₁₀ ), eg having a hydroxy group on the carbon atoms of the chain, eg glucamide.

The micelle-forming surfactant may contain a combination of the hydrophobic chain described above and the hydrophilic chain described above. Therefore, it may be or may contain a macrogol fatty acid ester as described herein, or a macrogol fatty alcohol ester as described herein.

Micelle-forming surfactants comprising a hydrophobic backbone and

- 41 040614 hydrophilic chain may be selected from the group consisting of macrogol esters; macrogol esters; double block copolymers; ternary block copolymers; and amphiphilic polymers. According to some embodiments of the present invention, any combination of groups is contemplated by the present invention.

Examples of macrogol esters suitable for use in the present invention are macrogol esters of fatty acids having at least 6 carbon atoms, optionally at least 10 carbon atoms, and in particular at least 12 carbon atoms; while some fatty acids have no more than 22 carbon atoms, such as C ₁₀ -C ₂₀ , C ₁₂ -C ₂₀ or C15-C20 fatty acids. Fatty acids may be saturated or unsaturated, but in particular are saturated. Mention should be made of cetostearyl ester of macrogol 25 (Cremophor® A25); cetostearyl ester of macrogol 6 (Cremophor® A6); macrogol-glycerol ricinoleate 35 (Cremophor® EL); macrogol-glycerol hydroxystearate 40 (Cremophor® RH 40); macrogol-15-hydroxystearate (Solutol® HS 15). Examples of macrogol esters suitable for use in the present invention are macrogol esters of fatty alcohols having at least 6 carbon atoms, optionally at least 10 carbon atoms, and in particular at least 12 carbon atoms; while some fatty alcohols have no more than 22 carbon atoms, for example, C ₁₀ -C ₂₀ , C ₁₂ -C ₂₀ or C ₁₅ -C ₂₀ fatty alcohols. Fatty alcohols may be saturated or unsaturated, but in one embodiment are saturated.

Examples of amphiphilic polymers suitable for use in the present invention are alkylglucamides; fatty alcohol polyethoxylates, also known as polyethoxylated alkyl ethers; polyethoxylated fatty acid esters (Myrj or Solutol); fatty amide polyethoxylate; fatty amine ethoxylate; alkylphenol ethoxylate; polyethoxylated sorbitan esters (polysorbates); polyethoxylated glycerides; or polyglycerol esters.

Examples of copolymers suitable for use in the present invention are pluronics (poloxamers); polyvinylpyrrolidone-polyvinyl acetate (Plasdone S630); aminoalkyl methacrylate copolymer (Eudragit EPO); copolymer of methacrylic acid and methyl methacrylate (Eudragit S100, L100); polycaprolactone-PEG; polycaprolactone-methoxy-PEG; poly(aspartic acid)-PEG; poly(benzyl-L-glutamate)-PEG; poly(D,L-lactide)methoxy-PEG; poly(benzyl-L-aspartate-PEG or poly(Llysine)-PEG.

In a preferred embodiment, the micelle-forming surfactant is a macrogol ester, more preferably a macrogol ester, which complies with European Pharmacopoeia article number 2052, a macrogol-15-hydroxystearate such as Kolliphor® HS 15 sold by BASF.

Kolliphor® HS 15 is composed of mono- and diesters of polyglycol and 12-hydroxystearic acid and approximately 30% free polyethylene glycol. The main components of the ester part are characterized by the following chemical structures:

He

O

where x and y are integers and a small portion of the 12-hydroxy group may be esterified with polyethylene glycol.

Suitable surfactants include those which, during manufacture, combine with the aqueous phase (including the hydrogel-forming polymer) in excess of their CMC to form a clear liquid. Such a surfactant is Kolliphor® HS 15.

In some embodiments, the weight ratio of micelle-forming surfactant to antigen is from 10:1 to 100:1, optionally from 50:1 to 100:1. In some embodiments, the ratio is between 80:1 and 90:1. In specific embodiments, the ratio is between 50:1 and 60:1.

In specific embodiments, the compositions of the present invention comprise a combination of micelle-forming compounds. Such a combination of micelle-forming compounds may consist of two or more of the surfactants mentioned in the previous section of this disclosure. Alternatively, the surfactant may be combined with one or more other compounds at least potentially capable of forming micelles with the surfactant, optionally selected from cationic lipids and glycolipids, among others. As an additional option, the composition may contain several of the surfactants mentioned in the previous section of this disclosure and one or more other compounds at least potentially capable of forming micelles with a surfactant, optionally selected from cationic lipids and glycolipids, among others.

The present invention therefore relates to the compositions described herein, which contain two or more micelle-forming surfactants, for example two or more surfactants having a hydrophobic chain and a hydrophilic chain;

a compound, for example one compound or two or more compounds selected from cationic lipids and glycolipids;

two or more micelle-forming surfactants and a compound, for example one compound or two or more compounds selected from cationic lipids and glycolipids.

The dispersed phase, which is or contains a surfactant, can enhance the absorption of the active ingredient, e.g., cyclosporin A, into the tissue of the gastrointestinal tract, for example, by forming self-assembling structures, such as micelles, which are associated with the active ingredient and thus , provide a gastrointestinal mucosal tissue drug in a form that enhances uptake/absorption into tissue.

The oil phase may also include one or more volatile or non-volatile solvents, which may be the same as or different from the previously mentioned solvent or co-solvent. Such solvents, for example, may remain in the composition according to the present invention after processing, for example, upon initial dissolution of the components present in the core, and do not perform a specific function in the composition of the core. Alternatively, such solvents, if present, may function to keep the ciclosporin dissolved (in solution) in the oil phase, or to facilitate dispersion, yield, etc. In other embodiments, the solvent may partially or completely evaporate during processing and may therefore only be present in small amounts, if at all. According to a related embodiment, the solvent, in particular when using a solvent that is both oil and water soluble, may be partly or wholly present in the aqueous phase of the core. An example of such a solvent is ethanol. Another example is Transcutol, which has already been mentioned as a co-solvent.

Therefore, the core may comprise a hydrogel-forming polymer matrix that forms a continuous phase and a discontinuous phase comprising an active ingredient, in particular a hydrophobic active ingredient, a high HLB nonionic surfactant compound, a low HLB oil, and optionally a co-solvent. Optionally, the active ingredient may be a hydrophobic active ingredient.

The core may contain a continuous phase that is or contains a hydrogel-forming polymer, and a discontinuous phase that is or contains an active ingredient, optionally a hydrophobic active ingredient, such as cyclosporine, and an oil phase that includes an oil and one or more surfactants. substances, with the oil and surfactant having an HLB of up to 10. The presence of a surfactant with an HLB of up to 10 has been found to provide beneficial effects in formulation, such as inhibiting the crystallization of cyclosporine from the oil phase when mixing the discontinuous phase with a continuous phase to form a colloid, such as an oil-in-water emulsion. Such compositions constitute a further aspect of the present invention.

The presence of a surfactant with an HLB of up to 10 in the oil phase can increase the rate and/or degree of release of the active ingredient, optionally a hydrophobic active ingredient, such as cyclosporine, from the composition after oral administration. The presence of a surfactant may act to maintain a large portion of the active ingredient, optionally a hydrophobic active ingredient such as cyclosporine, in solubilized form after it is released from the composition into an aqueous environment such as that found in the lower gastrointestinal tract, in particular the colon .

The core may be in the form of a solid colloid, wherein the colloid includes a continuous phase that is or includes a hydrogel-forming polymer, and a discontinuous phase that is or includes an active ingredient, optionally a hydrophobic active ingredient, such as cyclosporine, and an oil phase. , which includes oil and one or more surfactants, while the surfactant has an HLB of up to 10, for example an HLB in the range of 1-10. The pharmaceutical formulation is preferably a modified release formulation. However, the core can be used to provide an immediate release composition, for example by using an uncoated modified core.

- 43 040614 bath release.

The HLB value of the surfactant present in the oil phase can be up to 8, up to 7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2- 4, 3-4, 5-8, 6-8, or 6-7, for example, the HLB value can be about 1, about 2, about 3, about 4, about 5, about 6, or about 7. The surfactant can be any surfactant with an HLB value in the ranges described above, such as any surfactant described herein in the Surfactants section of this document or elsewhere in the specification and examples.

The surfactant is preferably a non-ionic surfactant. The cyclosporine may be dissolved in the surfactant, for example the cyclosporine may have a solubility greater than about 200 mg/g in the surfactant. Thus, the surfactant may have a ciclosporin solubility greater than about 200 mg/g, optionally greater than about 250 mg/g. The surfactant may have a cyclosporine solubility of about 200 mg/g to about 500 mg/g, optionally from about 250 mg/g to about 500 mg/g, from about 200 mg/g to about 400 mg/g, from about 225 mg/g to about 375 mg/g, about 250 mg/g to about 375 mg/g, about 200 mg/g to about 300 mg/g, about 300 mg/g to about 400 mg/g, about 250 mg/g to about 350 mg/g, about 225 mg/g to about 275 mg/g, about 350 mg/g to about 400 mg/g. Preferably, the surfactant has a cyclosporine solubility of about 200 mg/g to about 400 mg/g, or about 225 mg/g to about 375 mg/g. Dissolution of the cyclosporine in the surfactant can be performed according to the protocol described in Development of a Self Micro-Emulsifying Tablet of Cyclosporine-A by the Liquisolid Compact Technique, Zhao et al. (International Journal of Pharmaceutical Sciences and Research, 2011, vol. 2(9), 2299-2308), which is incorporated herein by reference.

The surfactant may have an HLB of up to 6 and a ciclosporin solubility of 200 to 400 mg/g. The surfactant may have an HLB value of 2-6 (optionally 3-6) and a ciclosporin solubility of about 200 mg/g to about 400 mg/g. The surfactant may have an HLB value of 2-6 (optionally 3-6) and a ciclosporin solubility of about 250 mg/g to about 400 mg/g. The surfactant may have an HLB value of 2-6 (optionally 3-6) and a ciclosporin solubility of about 225 mg/g to about 275 mg/g. The surfactant may have an HLB value of 2-6 (optionally 3-6) and a ciclosporin solubility of about 250 mg/g to about 350 mg/g.

The surfactant may be or may include a surfactant selected from fatty acid glycerides, polyethylene glycol fatty acid esters, propylene glycol fatty acid esters, fatty acid lactic acid esters, sucrose fatty acid esters, acid, sorbitan fatty acid esters, polyethylene glycol fatty alcohol esters, ethylene oxide-propylene oxide and polyoxyethylene block copolymer esters; wherein the surfactant has an HLB value of up to 10, up to 8, or in particular an HLB value as described above, for example 1 to 8 or 1 to 4.

The surfactant may be or may contain a surfactant selected from fatty acid glycerides, polyethylene glycol fatty acid esters, propylene glycol fatty acid esters, fatty acid lactic acid esters, or sucrose fatty acid esters, wherein the surfactant has an HLB value of up to 10, up to 8, or in particular an HLB value as described above, for example 1 to 8 or 1 to 4.

The surfactant may be or may contain a fatty acid glyceride, wherein the surfactant has an HLB value of up to 10, up to 8, or in particular an HLB value as described above, such as 1 to 8 or 1 to 4 .

The surfactant may be or may contain a sorbitan fatty acid ester, such as a sorbitan mono-, di- or triester of a fatty acid, and wherein the surfactant has an HLB value as described above, for example, from 1 to 8 or from 1 to 4. The fatty acid may be or may contain, for example, one or more C ₁₀ -C ₂₀ , C ₁₂ -C ₂₀ or C ₁₅ -C ₂₀ fatty acids. Fatty acids can be saturated or unsaturated. The particular surfactant is or contains sorbitan trioleate (commercially available as Span 85). Another particular surfactant is or contains sorbitan monopalmitate (commercially available as Span 40).

The surfactant may be or may contain esters of polyethylene glycol and fatty acids, preferably esters of, for example, one or more C ₁₀ -C ₂₀ , C ₁₂ -C ₂₀ or C ₁₅ -C ₂₀ fatty acids, wherein the acid may be saturated or unsaturated. Preferably the surfactant is or contains a mixture,

- 44 040614 comprising esters of polyethylene glycol and fatty acids and glycerides of fatty acids, while the fatty acid is C ₁₅ -C ₂₀ fatty acid, which may be saturated or unsaturated.

The surfactant may be or may contain a polyglyceride-linked fatty acid, such as polyglyceryl dioleate. Therefore, the surfactant may act as an emulsifier and may be polyglyceryl-3-dioleate (eg, products sold under the trademark Plurol® Oleique).

The weight ratio of surfactant having an HLB value of up to 10 to oil may be from about 5:1 to about 1:5, from about 3:1 to about 1:2, from about 3:1 to about 1:1, or approximately 2.5:1 to 1.5:1. Preferably, the weight ratio may be about 1:1, about 2:1, about 2.5:1, about 3:1, about 1:1.5, or about 1:2.

A surfactant having an HLB value of up to 10 may be present in the composition in an amount of from about 5% to about 20%, from about 8% to about 15%, or from about 10% to about 14% by weight of the dry weight of the core. It should be understood that reference to the dry weight of the core means the weight of non-water components present in the uncoated core.

The oil may be any of the oils described herein, in particular the oils described in the Dispersed Phase section. The oil may be or may contain a short, medium and long chain triglyceride composition, or a combination thereof. Medium chain triglyceride(s) (MCT) include(s) one or more triglycerides of at least one fatty acid selected from C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , SC and C ₁₂ fatty acids acids. A particular oil phase is or contains a triglyceride based oil such as commercially available as Miglyol™, eg Miglyol™ 810, 812 (caprylic/capric acid triglyceride); Miglyol™ 818 (caprylic/capric/linoleic acid triglyceride); Miglyol™ 829 (caprylic/capric/succinic acid triglyceride).

The oil may be present in the pharmaceutical composition in an amount of from about 2% to about 25%, from about 3% to about 20%, from about 3% to about 10%, or from about 5% to about 10% by weight of the dry weight of the kernel.

The oil phase may also contain a solvent. Acceptable solvents are those described herein in relation to the discontinuous phase, as well as those that are acceptable miscible with both oil and water. The solvent may be present in the composition in an amount of from about 1% to about 30%, from about 5% to about 30%, from about 10% to about 25%, or from about 12% to about 22% by weight of the dry weight of the core. A particular solvent is 2-(2-ethoxyethoxy)ethanol (commercially available, eg as Transcutol™ P or HP).

The hydrogel-forming polymer may be, or may contain, one or more of the hydrogel-forming polymers described herein, particularly those described in the Continuous Phase Polymer Matrix section. Preferably, the hydrogel-forming polymer is or comprises a hydrogel-forming polymer selected from the group consisting of gelatin, agar, polyethylene glycol, starch, casein, chitosan, soy protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, phthalated gelatin, succinate gelatin, cellulose ophthalate acetate, oleoresin, polyvinyl acetate, hydroxypropyl methylcellulose, acrylic or methacrylic ester polymers and polyvinyl acetate phthalate, as well as any derivative of any of the above; or a mixture of one or more of these hydrogel-forming polymers. The specific hydrogel-forming polymer is selected from carrageenan, gelatin, agar and pectin, or a combination thereof, in particular gelatin and/or agar, more specifically gelatin. The hydrogel-forming polymer is preferably present in the core in a gelled state such that the polymer forms a solid matrix in which the discontinuous phase is dispersed to provide, for example, a solid colloid. The hydrogel-forming polymer is preferably sufficiently thickened to provide a core that is sufficiently rigid to be processed and further processed into a dosage form or coated, for example, with a modified release coating as described herein.

The hydrogel-forming polymer may be present in an amount of from about 20% to about 70%, from about 20% to about 55%, from about 25% to about 50%, from about 30% to about 50%, or from about 40% to about 45%. % by weight based on the dry weight of the kernel.

The continuous phase may preferably contain a plasticizer, in particular if the hydrogel-forming polymer is or contains gelatin. A specific plasticizer is sorbitol. If present, the plasticizer may comprise, for example, up to about 20% or up to about 10%, preferably from about 3% to about 8% or from about 4% to about 6% by weight of the dry weight of the core.

The continuous phase may contain a surfactant. The surfactant present in the continuous phase is preferably different from the surfactant present in the oil phase. Suitable surfactants that may be present in the continuous phase are those described herein in the Continuous Phase Polymer Matrix section. Therefore, specific surfactants that may be present in the continuous phase may be cationic, amphoteric (zwitterionic), or anionic surfactants. Preferably, the surfactant present in the continuous phase is or contains an anionic surfactant, more particularly a hydrophilic anionic surfactant. The surfactant in the continuous phase may be or may contain at least one surfactant selected from fatty acid salts, alkyl sulfates and bile salts, in particular an alkyl sulfate, eg C1o- _C22 alkyl sulfate, preferably sodium dodecyl sulfate. The surfactant present in the continuous phase, in particular the anionic surfactant, is present in the composition in an amount of 0.1 to 6%, for example 0.1 to 5%, 0.1 to 4%, 0 1 to 3%, 1 to 4%, 1.5 to 4.5% or 2.5 to 4.5%, preferably in an amount of 2-4% by weight based on the dry weight of the kernel.

Cyclosporin A is preferably present in the composition in an amount of from about 5% to about 20%, from about 8% to about 15%, or from about 9% to about 14% by weight of the dry weight of the kernel.

According to a specific embodiment, a pharmaceutical composition is provided, comprising a core in the form of a solid colloid, wherein the colloid includes a continuous phase, which is or includes a hydrogel-forming polymer, and a dispersed phase, wherein the dispersed phase is or contains cyclosporine A;

an oil that is or includes a short, medium and long chain triglyceride composition, or a combination thereof, such as caprylic/capric acid triglyceride, caprylic/capric/linoleic acid triglyceride, and caprylic/capric/succinic acid triglyceride;

one or more non-ionic surfactants with an HLB value up to 10, up to 8, up to 7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2- 4, 3-4, 5-8, 6-8, or 6-7, such as about 1, about 2, about 3, about 4, about 5, about 6, or about 7;

optionally, the surfactant is or contains a fatty acid glyceride, a sorbitan fatty acid ester, or a polyethylene glycol fatty acid ester; and optionally a solvent, wherein the solvent is miscible with both oil and water, such as 2-(2ethoxyethoxy)ethanol, wherein the continuous phase is or contains a hydrogel-forming polymer, such as a hydrogel-forming polymer that is or includes carrageenan, gelatin, agar and pectin, or a combination thereof, optionally gelatin or agar, or a combination thereof, more optionally, the matrix polymer of the hydrogel-forming polymer is or contains gelatin;

an anionic surfactant, optionally an anionic surfactant selected from fatty acid salts, alkyl sulfates and bile salts, in particular alkyl sulfate, eg C ₁₀ -C ₂₂ alkyl sulfate, preferably sodium dodecyl sulfate; and optionally a plasticizer, such as sorbitol.

According to another embodiment, a pharmaceutical composition is provided comprising a core in the form of a solid colloid, wherein the colloid includes a continuous phase that is or includes a hydrogel-forming polymer, and a dispersed phase, wherein the discontinuous phase is or contains approximately 8% to about 15% cyclosporin A;

from about 2% to about 20%, for example from about 3% to about 10% of an oil that is or includes a caprylic/capric acid triglyceride, a caprylic/capric/linoleic acid triglyceride and a caprylic/capric/succinic acid triglyceride, preferably a triglyceride caprylic/capric acid;

one or more non-ionic surfactants with an HLB value up to 10, up to 8, up to 7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2- 4, 3-4, 5-8, 6-8, or 6-7, such as about 1, about 2, about 3, about 4, about 5, about 6, or about 7;

optionally, the surfactant is or contains a fatty acid glyceride, a sorbitan fatty acid ester, or a polyethylene glycol ester of fatty acids, optionally, the nonionic surfactant is present in an amount of from about 8% to about 15 %; and optionally from about 12% to about 22% solvent, wherein the solvent is miscible with both oil and water, for example 2-(2-ethoxyethoxy)ethanol, wherein the continuous phase is or contains from about 30% to about 70 %, for example from about 30% to about 50% of the hydrogel-forming polymer, optionally, the hydrogel-forming polymer is or contains carrageenan, gelatin, agar and pectin, or a combination thereof, optionally gelatin or agar, or a combination thereof, to a greater extent optionally the hydrogel-forming polymer matrix is or contains gelatin;

anionic surfactant, optionally an anionic surfactant selected from fatty acid salts, alkyl sulfates and bile salts, in particular alkyl sulfate, for example C ₁₀ -C ₂₂ -alkyl sulfate, preferably sodium dodecyl sulfate, optionally an anionic surfactant present in an amount of from about 0.1% to about 5%, preferably from 2 to 4%; and optionally up to about 10% of a plasticizer, such as sorbitol;

while all percentages are wt.% from the dry weight of the core.

According to another embodiment, an orally administered modified release composition is provided, comprising a core in the form of a solid colloid, wherein the colloid includes a continuous phase that is or includes a hydrogel-forming polymer, and a dispersed phase, wherein the dispersed phase is or contains from about 8% to about 15% cyclosporine A;

about 3% to about 10% of an oil that is or includes caprylic/capric acid triglyceride;

one or more non-ionic surfactants with an HLB value of up to 7, such as 1-7 or 2-4, wherein the surfactant is or contains a fatty acid glyceride, a sorbitan fatty acid ester, or a polyethylene glycol fatty acid ester, optionally, the nonionic surfactant is present in an amount of from about 8% to about 15%; and optionally from about 12% to about 22% solvent, wherein the solvent is miscible with both oil and water, for example, 2-(2ethoxyethoxy)ethanol, wherein the continuous phase is or contains from about 30% to about 50% a hydrogel-forming polymer selected from gelatin or agar, or a combination thereof, optionally the hydrogel-forming polymer matrix is or contains gelatin;

0.1% to about 5%, preferably 2 to 4% anionic surfactant, eg sodium dodecyl sulfate; and optionally up to about 10% of a plasticizer, such as sorbitol, all percentages being wt.% of the dry weight of the core.

In a specific embodiment, the core is in the form of a solid colloid including a continuous phase and a dispersed phase, wherein the continuous phase comprises a hydrogel-forming polymer, wherein the discontinuous phase is or contains a pharmaceutically active ingredient such as cyclosporine A or other hydrophobic active ingredient;

a medium chain mono-, di- or triglyceride, for example a medium chain triglyceride, in particular caprylic/capric acid triglyceride;

polyethoxylated castor oil and a co-solvent (e.g., 2(ethoxyethoxy)ethanol), wherein the continuous phase is or contains a hydrogel-forming polymer matrix that is or contains a hydrocolloid selected from carrageenan, gelatin, agar, and pectin, or combinations thereof, optionally selected from gelatin and agar, or a combination thereof, more specifically the matrix polymer of the hydrogel-forming polymer is or contains gelatin;

a plasticizer, optionally a plasticizer selected from glycerol, a polyhydric alcohol, for example sorbitol, polyethylene glycol and triethyl citrate, or mixtures thereof, in particular sorbitol; and an anionic surfactant, eg at least one surfactant selected from fatty acid salts, alkyl sulfates and bile salts, in particular alkyl sulfate, eg sodium dodecyl sulfate.

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In a further specific embodiment, the core comprises a hydrogel-forming polymer matrix comprising 300 to 700 mg/g gelatin, wherein the core further comprises the active ingredient, medium chain mono-, di-, or triglycerides ( for example, a medium chain triglyceride, in particular caprylic/capric acid triglyceride), in an amount of from 20 to 200 mg/g, and the core additionally contains the following components co-solvent (for example, 2-(ethoxyethoxy)ethanol), in an amount of from 150 up to 250 mg/g;

non-ionic surfactant in an amount of 80 to 200 mg/g; and an anionic surfactant in an amount of 15 to 50 mg/g, the weights being based on the dry weight of the core.

Preferably, according to an embodiment in the immediately preceding paragraph, the active ingredient is cyclosporine and cyclosporine A may be present in an amount of 60 to 180 mg/g, for example 60 to 150 mg/g, 80 to 120 mg/g, or in particular 80 up to 100 mg/g. Nonionic and anionic surfactants are defined herein, for example an anionic surfactant selected from alkyl sulfates, carboxylates, or phospholipids (particularly SDS); or a nonionic surfactant selected from sorbitan surfactants, PEG fatty acids or glyceryl derivatives of fatty acids or poloxamers. A particular non-ionic surfactant is polyethoxylated castor oil (eg Cremophore EL).

The cores described above, comprising a matrix of hydrogel-forming polymer and a pharmaceutically active ingredient, in particular cyclosporin A, are coated as described herein to provide the composition of the present invention. A specific coating according to these embodiments is a coating comprising a first coating (inner coating) which is or contains a water-soluble cellulose ether, in particular hydroxypropyl methylcellulose;

a second coating on the outside of the first coating, which is or contains a modified release coating, in particular a pH-independent modified release coating, more specifically a coating including ethyl cellulose (e.g. Surelease), even more specifically a coating including ethyl cellulose and soluble in in water, a polysaccharide such as pectin (e.g., the Surelease/pectin coating described herein), and wherein the first coating is present in an amount corresponding to the weight gain due to the first coating, in the range selected from (i) from 8 to 12 %, for example about 10%; or (ii) 4 to 6%, such as about 5%, by weight based on the weight of the composition prior to application of the first coating, while the second coating is present in an amount corresponding to the increase in weight of the composition due to the second coating, selected from (a) from 10 up to 12%, such as about 11% or about 11.5%; or (b) from 16 to 18%, for example about 17%, by weight based on the weight of the composition before applying the second coating.

The dispersed phase may contain active ingredient particles dispersed in a matrix. The particles may be microparticles (eg, 1-999 µm) or nanoparticles (eg, 1-999 nm). In particular, therefore, the discontinuous phase may contain a particulate hydrophobic drug dispersed in a matrix.

Surface-active substance.

The composition may contain one or more surfactants, for example surfactants may be present in the core (including the hydrogel-forming polymer matrix and the discontinuous phase, or both). Surfactants may also be present in one or more of the coatings applied to the core.

Suitable surfactants may be anionic, cationic, zwitterionic or non-ionic. In the description and in the claims of this specification, the term surfactant is used as an abbreviation for the term surfactant. For the purposes of this description and claims, it is assumed that there are four main classifications of surfactants; in this regard, the surfactant can be anionic, cationic, nonionic and amphoteric (zwitterionic). The non-ionic surfactant remains intact, has no charge in aqueous solutions, and does not dissociate into positive and negative ions. Anionic surfactants are water-soluble, have a negative charge, and dissociate into positive and negative ions when placed in water. The negative charge reduces the surface tension of water and acts as a surfactant. Cationic surfactants have a positive charge and also dissociate into positive and negative ions when placed in water. In this case, the positive ions lower the surface tension of the water and act as a surfactant. An amphoteric (zwitterionic) surfactant assumes a positive charge in acidic solutions and acts as a cationic surfactant, or it assumes a negative charge in an alkaline solution and acts as an anionic surfactant.

The surfactant(s) may be selected from anionic surfactants and combinations thereof;

nonionic surfactants and combinations thereof; and from a combination of an anionic surfactant (eg, one or a plurality of surfactants) and a non-ionic surfactant (eg, one or a plurality of surfactants).

Surfactants can also be classified according to their hydrophilic-lipophilic balance (HLB), which is a measure of the degree to which a surfactant is hydrophilic or lipophilic, determined by calculating values for different regions of the molecule, as described (originally for non-ionic surfactants). substances) from Griffin in 1949 and 1954 and later from Davies. The methods use a formula for the molecular weight of the whole molecule and the hydrophilic and lipophilic portions to give an arbitrary (semi-empirical) scaling up to 40, although the usual range is between 0 and 20. An HLB value of 0 corresponds to a fully hydrophobic molecule, while a value of 20 would correspond to a molecule , consisting entirely of hydrophilic components. The HLB value can be used to predict the surface active properties of the molecule.

HLB value Intended Properties 0 to 3 defoamer means 4 to 6 W/Ο emulsifier 7 to 9 moisturizer 8 to 18 Ο/W emulsifier 13 to 15 typical representative of detergents 10 to 18 solubilizer or hydrotrope

Although HLB values are assigned to surfactants other than the nonionic ones for which this system was invented, the HLB values for anionic, cationic, nonionic, and amphoteric (zwitterionic) surfactants can be of lower value and often show a close or comparable number and not which is the result of a mathematical calculation. Therefore, surfactants exceeding a maximum of 20 may appear. However, HLB values can be used to describe the required HLB values for the desired application in a given emulsion system in order to achieve a good result.

Non-ionic surfactants.

The surfactant may be or may include at least one surfactant selected from the following non-ionic surfactants.

PEG monoester and fatty acid surfactants, PEG diester and fatty acid surfactants, mixtures of monoester and PEG diester and fatty acid surfactants, esters of fatty acid, PEG and glycerol, interesterified products of oils and alcohols, lower alcohol fatty acid esters, polyglycerinated fatty acids, propylene glycol fatty acid esters, mono- and diglyceride surfactants, sterol surfactants and sterol derivatives, PEG fatty acid esters of sorbitan, sorbitan fatty acid esters, polyethylene glycol alkyl ethers , sugar ester surfactants, polyethylene glycol alkylphenol surfactants, POE-POP block copolymers, fatty acid salts, bile salts, phospholipids, phosphate esters, carboxylates, acyl lactylates, sulfates and sulfonates, and cationic surfactants.

A PEG monoester fatty acid surfactant, such as PEG 4-100 monolaurate, PEG 4-100 monooleate, PEG 4-100 monostearate, PEG laurate, PEG oleate, PEG stearate, and PEG ricinoleate. PEG fatty acid diester surfactant, eg PEG dilaurate; PEG dioleate, PEG distearate, PEG dipalmitate. Blend of PEG mono- and diesters and fatty acid.

An ester of PEG fatty acid and glycerol, eg PEG glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate.

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Сложные эфиры жирной кислоты PEG и сорбитана, например сорбитанлаурат PEG, сорбитанмонолаурат PEG, сорбитанмонопальмитат PEG, сорбитанмоностеарат PEG, сорбитантристеарат PEG, сорбитантетрастеарат PEG, сорбитанмоноолеат PEG, сорбитанолеат PEG, сорбитантриолеат PEG, сорбитантетраолеат PEG, сорбитанмоноизостеарат PEG, сорбитгексаолеат PEG, сорбитгексастеарат PEG.

Сложные эфиры жирной кислоты и пропиленгликоля, например монокаприлат пропиленгликоля, монолаурат пропиленгликоля, олеат пропиленгликоля, миристат пропиленгликоля, моностеарат пропиленгликоля, гидроксистеарат пропиленгликоля, рицинолеат пропиленгликоля, изостеарат пропиленгликоля, моноолеат пропиленгликоля, дикаприлат/дикапрат пропиленгликоля, диоктаноат пропиленгликоля, каприлат/капрат пропиленгликоля, дилаурат пропиленгликоля , propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dicaprate.

Fatty acid ester of sorbitan, for example sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate.

Fatty acid esters of lower alcohols, eg ethyl oleate, isopropyl myristate, isopropyl palmitate, ethyl linoleate, isopropyl oleate.

Polyoxyethylene-polyoxypropylene block copolymers, e.g. poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212.1 poloxamer 212.5 Poloxamer 231, shelter 234, shelter 235, shelter 237, shelter 238, shelter 282, shelter 284, shelter 288, shelter 331, shelter 333, shelter 334, shelter 335, shelter 338, shelter 401, shelter 402, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shelter 403, shepherdsome .

Полиглициринизированные жирные кислоты, например полиглицерилстеарат, полиглицерилолеат, полиглицерилизостеарат, полиглицериллаурат, полиглицерилрицинолеат, полиглицериллинолеат, полиглицерилпентаолеат, полиглицерилдиолеат, полиглицерилдистеарат, полиглицерилтриолеат, полиглицерилсептаолеат, полиглицерилтетраолеат, полиглицерилдекаизостеарат, полиглицерилдекаолеат, полиглицерилмоноолеат, диолеат, полиглицерилполирицинолеат.

PEG alkyl ethers, for example PEG oleyl ether, PEG lauryl ether, PEG cetyl ether, PEG stearyl ether.

PEG alkylphenols, eg simple PEG nonylphenol, PEG octylphenol ether.

Interesterified alcohol or polyalcohol products with natural or hydrogenated oils, such as PEG castor oil, PEG hydrogenated castor oil, PEG corn oil, PEG almond oil, PEG apricot kernel oil, PEG olive oil, PEG-6 peanut oil, PEG hydrogenated coconut oil, PEG Coconut Oil, PEG Triolein, PEG Corn Glycerides, PEG Almond Glycerides, PEG Trioleate, PEG Caprylic/Capric Triglyceride, Lauroyl Macrogol Glyceride, Stearoyl Macrogol Glyceride, Vegetable Oil Mono, Di, Tri, Tetraesters, Sorbitol, Pentaerythrityl Tetraisostearate, Pentaerythrityl Distearate, Pentaerythrityl Tetraoleate , pentaerythrityl tetrastearate, pentaerythrityl tetracaprylate/tetracaprate, pentaerythrityl tetraoctanoate.

Fat-soluble vitamins, for example, vitamins A, D, E, K and their isomers, analogues and derivatives. Derivatives include, for example, organic acid esters of said fat-soluble vitamins, for example, vitamin E or vitamin A esters of succinic acid. Derivatives of these vitamins include PEG-1000 tocopheryl succinate (vitamin E TPGS) and other PEG tocopheryl succinate derivatives with various PEG fragment molecular weights, such as PEG 100-8000.

Sterols and sterol derivatives (eg esterified or esterified sterols, such as PEGylated sterols), eg cholesterol, sitosterol, lanosterol, PEG cholesterol ether, PEG cholestanol, phytosterol, PEG phytosterol.

Sugar esters such as sucrose distearate, sucrose distearate/monostearate, sucrose dipalmitate, sucrose monostearate, sucrose monopalmitate, sucrose monolaurate, alkyl glucoside, alkyl maltoside, alkyl maltotrioside, alkyl glycosides, derivatives, and other types of sugars - glucamides.

Carboxylates (particularly carboxylate esters), e.g. ether carboxylates, succinylated monoglycerides, sodium stearyl fumarate, hydrosuccinated stearoyl propylene glycol, mono/diacetylated esters of tartaric acid and mono- and diglycerides, esters of citric acid and mono-, diglycerides, glyceryl-lacto esters of fatty acids; acyl lactylates: esters of lactic acid and fatty acids, calcium/sodium stearoyl-2 lactylate, calcium/sodium stearoyl lactylate, alginate salt, propylene glycol alginate.

A fatty acid monoglyceride, diglyceride, or triglyceride, or a combination thereof.

Anionic surfactants.

Anionic surfactants may be selected from the following anionic surfactants.

Fatty acid salts and bile salts, eg sodium caproate, sodium caprylate, caprate

- 50 040614 sodium, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate, sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate; sodium cholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium glycochenodeoxycholate, sodium cholylsarkosinate, sodium N-methyltaurocholate.

Phospholipids, eg egg/soy lecithin, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, phosphatidylserine.

Phosphoric acid esters having the general formula RO-PO3-M+ wherein the R group is an ester-forming group, e.g. fragment. R may be a long chain residue (eg >C9) of an alcohol or phenol. Specific examples include diethanolammonium polyoxyethylene-10-oleyl ether phosphate, fatty alcohol esterified products, or fatty alcohol ethoxylates with phosphoric acid or anhydride.

Sulfates or sulfonates (particularly their esters), for example ethoxylated alkyl sulfates, alkyl benzene sulfones, α-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, disodium octyl sulfosuccinate, disodium undecylenamideo-MEA-sulfosuccinate, alkyl phosphates and alkyl ether phosphates.

Cationic surfactants.

Cationic surfactants may be selected from the following cationic surfactants.

Hexadecyltriammonium bromide, dodecyl ammonium chloride, alkylbenzyldimethylammonium salts, diisobutylphenoxyethoxydimethylbenzylammonium salts, alkylpyridinium salts; betaines (trialkylglycine): lauryl betaine (N-lauryl, N, N-dimethylschlicine); ethoxylated amines: polyoxyethylene-15 coconut amine, alkyl amines/diamines/quaternary amines and alkyl ester.

Emulsifiers.

The surfactant may act as an emulsifier. Such surfactants include non-ionic emulsifiers, for example, selected from a mixture of triceteareth-4 phosphate, ethylene glycol palmitostearate and diethylene glycol palmitostearate (eg sold under the tradename SEDFOS™ 75); esters of sorbitan, eg sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate (eg products sold under the trade name Span®), PEG-8 beeswax, eg sold under the trade name Apifil®; mixtures of cetyl alcohol, ceteth-20 and steareth-20 (eg Emulcire™ 61 WL 2659); mixtures of glyceryl monostearate EP/NF and PEG-75 palmitostearate (eg Gelto™ 64); mixtures of PEG-6 stearate and PEG-32 stearate (eg Tefose® 1500); mixtures of PEG-6 palmitostearate, ethylene glycol palmitostearate and PEG-32 palmitostearate (eg Tefose 63); triglycerol diisostearate (eg products sold under the tradename Plurol Diisostearique®); polyglyceryl-3 dioleate (eg products sold under the trade name Plurol® Oleique).

Other fillers.

The composition optionally contains one or more of the following additional substances or categories of substances. For example, the composition may contain a protective agent, such as, for example, a proteolytic enzyme inhibitor or a protectant against acid degradation, or both (eg, alkali, in particular sodium hydroxide);

an adhesive agent such as, for example, a muco- or bio-adhesive agent;

excipients to maximize the solubility of the active ingredient;

excipients to maximize the penetration of the active ingredient into the gastrointestinal tract.

Exemplary epithelial barrier permeability excipients include, but are not limited to, sodium caprate, sodium dodecanoate, sodium palmitate, SNAC, chitosan and derivatives thereof, fatty acids, fatty acid esters, polyesters, bile salts, phospholipids, alkyl polyglucosides, hydroxylase inhibitors, antioxidants (e.g. , ascorbic acid) and/or nitric oxide donors. The foregoing list is of particular interest in terms of increased permeability in the ileum.

With regard to enhancing colonic permeability, exemplary excipients include, but are not limited to, sodium caprate, sodium dodecanoate, sodium palmitate, SNAC, chitosan and its derivatives, fatty acids, fatty acid esters, polyesters, bile salts, phospholipids, alkyl polyglucosides, hydroxylase inhibitors, antioxidants and/or nitric oxide donors, including groups of nitric oxide donors covalently attached to various pharmaceutically active ingredients.

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The formulation may also contain excipients to enhance the therapeutic potential of the active ingredient, such as cyclosporine A or another immunosuppressant, in the ileum or colon, including, but not limited to absorption limiters, essential oils such as, for example, omega 3 oils, natural plant extracts such as e.g. neem, ion exchange resins, bacterial degradable conjugation linkers, such as e.g. azo bonds, polysaccharides such as e.g. amylose, guar gum, pectin, chitosan, inulin, cyclodextrins, chondroitin sulfate, dextrans, guar gum and locust bean gum, nuclear factor kappa B inhibitors, acids such as, for example, fumaric acid, citric acid, and others, and modifications thereof.

The formulation may also contain excipients to reduce systemic side effects associated with absorption of a particular active ingredient, such as cyclosporine or other immunosuppressants, from the gastrointestinal tract, such as the small intestine, including, but not limited to, antioxidants such as, for example, curcuminoids, flavonoids, or more specifically including curcumin, beta-carotene, α-tocopherol, ascorbate, or lazaroid.

The composition may also or in addition contain antioxidants (such as, for example, ascorbic acid or BHT butylhydroxytoluene), taste-masking agents, or light-sensitive components, or light-protective components. Antioxidants can be included in the aqueous phase (for example, hydrophilic antioxidants) or the dispersed core phase (for example, hydrophobic antioxidants, such as, for example, vitamin E), for example, up to 1% by weight, preferably between 0.01 and 0, 50% by weight, more preferably between 0.10 and 0.20% by weight.

The formulation may also contain immune-boosting nutrients such as vitamins A/B/C/E; carotenoids/beta-carotene and iron, manganese, selenium, zinc, especially if the formulation contains an immunosuppressant, as in the case of an immunosuppressant targeting the ileum and/or the colon, eg the colon. Such nutrients may be present in the formulation, or if the formulation is coated, for example if it is in the form of a granule, the nutrients may be included in the coating formulation.

The composition may also include other well-known excipients used in pharmaceutical formulations, including colorants, taste-masks, diluents, fillings, binders, and the like. The presence of such optional additional components will, of course, depend on the particular dosage form administered.

active ingredients.

Active ingredients suitable for use in pharmaceutical compositions and methods according to the present invention are not particularly limited, as these compositions surprisingly allow the delivery of active ingredients with a wide variety of physico-chemical properties, although still characterized by a higher overall release of the active ingredient from the formulation and/or a higher rate of release of the active ingredient compared to a formulation that is uncoated. The active ingredient may be hydrophilic, lipophilic, amphiphilic or hydrophobic. The active ingredient may be dissolved in the formulation. The active ingredient may be suspended in the formulation. The active ingredients may be any compound or mixture of compounds of therapeutic or other value when administered to an animal, especially a human or other mammal (compositions of the present invention are intended in particular for administration to humans or other mammals), e.g. -cosmetics, diagnostics, nutritional products. In particular, the active ingredient is a pharmaceutically active. It should be appreciated that the classification of an active ingredient as hydrophilic or hydrophobic may vary depending on the specific salts, isomers, analogs and derivatives used. The active ingredient may be the ingredient mentioned in the examples of this specification.

The active ingredient may be hydrophobic. Hydrophobic active ingredients are compounds with little or no water solubility. True water solubility (ie, water solubility for non-ionized forms) for hydrophobic active ingredients can be less than about 1% by weight and typically less than about 0.1 or 0.01% by weight. The active ingredient is in particular a hydrophobic drug.

Suitable hydrophobic active ingredients are not limited to the therapeutic category and may be, for example, analgesics, anti-inflammatory agents, anthelmintic agents, antiarrhythmic agents, antibacterial agents, antiviral agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antifungal agents, antigout agents, antihypertensive agents , antimalarials, antimigraine agents, antimuscarinics, antineoplastic agents, erectile dysfunction improvers, immunosuppressants, antiprotozoals, antithyroid agents, anxiolytics, sedatives, hypnotics, neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, diuretics, en

- 52 040614 Tiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, hydroxylase inhibitors (e.g. asparaginyl hydroxylase inhibitors, prolyl hydroxylase inhibitors), keratolytics, lipid regulators, antianginal agents, COX-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants , nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognitive impairment correctors, urinary incontinence agents, nourishing oils, benign prostatic hypertrophy agents, essential fatty acids, non-essential fatty acids acids and their mixtures.

More specifically, non-limiting examples of suitable hydrophobic active ingredients are acitretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benzepril, benzonatate, betamethasone, bicalutamide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamazepine, carotenes, celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, codeine, coenzyme Q10, cyclobenzaprine, cyclosporins, danazol, dantrolene, dexchlorpheniramine, diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, DMOG, donezepil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etoposide, etodolac famotidine, fenofibrate , fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosfenytoin, frovatriptan, flurazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isovermizolnitrate, irinotecan, isovermizolticonitine, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-triroxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, minoxidil , montelukast, nabumeton, nalbuphine, naratriptan, nelfinavir, nifedipine, nilsoledipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkine, estradiol, oxaprozin, paclitaxel, paracalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone , pyridistigmine, rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutin, rifapentine, p imexolone, ritanovir, rizatriptan, rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, steroids, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terbinafine, terabinazoin, tetrathicannazosin , ticlopidine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileitone, zolmitriptan, zolpidem and zopiclone. Of course, salts, isomers and derivatives of the hydrophobic active ingredients listed above, as well as mixtures thereof, can also be used.

Among the above hydrophobic active ingredients, particular mention should be made of celecoxib, cyclosporins and especially cyclosporin A, sirolimus, steroids, tacrolimus, their pharmaceutically acceptable salts, isomers and derivatives and mixtures thereof.

The active ingredient may be hydrophilic. Amphiphilic compounds are also included within the class of hydrophilic active ingredients. True water solubilities for hydrophilic active ingredients are greater than about 0.1% by weight and typically greater than about 1% by weight. The hydrophilic active ingredient is in particular a hydrophilic drug. The hydrophilic active ingredient may be a cosmetic, diagnostic, or nutritional agent.

Suitable hydrophilic active ingredients are not limited to the therapeutic category and may be, for example, analgesics, anti-inflammatory agents, anthelmintic agents, antiarrhythmic agents, antibacterial agents, antiviral agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antifungal agents, antigout agents, antihypertensive agents , antimalarial agents, antimigraine agents, antimuscarinic agents, antineoplastic agents, erectile dysfunction ameliorating agents, immunosuppressants, antiprotozoal agents, antithyroid agents, anxiolytics, sedatives, hypnotics, neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, hydroxylase inhibitors (eg, asparagine inhibitors inylhydroxylase, prolyl hydroxylase inhibitors), keratolytics, lipid regulators, antianginal agents, COX-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognitive impairment correctors, urinary incontinence agents, nourishing oils, benign hypertrophy agents

- 53 040614 prostate, essential fatty acids, non-essential fatty acids and mixtures thereof.

Similarly, the hydrophilic active ingredient may be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a piece of genetic material, a nucleic acid, or mixtures thereof.

More specifically, non-limiting examples of suitable hydrophilic active ingredients are acarbose; acyclovir; acetylcysteine; acetylcholine chloride; alatrofloxacin; alendronate; agglucerase; amantadine hydrochloride; ambenomy; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human), antihemophilic factor (porcine); antihemophilic factor (recombinant), aprotinin; asparaginase; atenolol; atracurium besilate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladonna; bepridil hydrochloride; bleomycin sulfate; human calcitonin; salmon calcitonin; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafat; cefazolin sodium; cefeprim hydrochloride; cefixime; sodium cephonicide; cefoperazone; cefotetan disodium; cefotaxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cefapirin sodium; cholera vaccine; chorionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clodronate; sodium colistimethate; colistin sulfate; corticotropin; cosyntropin; cromolyn sodium; cytarabine; dalteparin sodium; danaparoid; desferrioxamine; denileukin diphlitox; desmopressin; meglumine diatrizoate and sodium diatrizoate; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; dornase alfa; doxacurium chloride; doxorubicin; disodium etidronate; enalaprilat; enkephalin; enoxaparin; enoxaprin sodium; ephedrine; epinephrine; epoetin alfa; erythromycin; esmolol hydrochloride; factor IX; famciclovir; fludarabine; fluoxetine; sodium foscarnet; ganciclovir; granulocyte colony stimulating factor, granulocyte macrophage stimulating factor; recombinant human growth hormones; bovine growth hormone; gentamicin; glucagon; glycopyrolate; gonadotropin-releasing hormone and its synthetic analogues; GnRH; gonadorelin; grepafloxacin; a vaccine based on a conjugate of Haemophilus influenzae B; inactivated vaccine against hepatitis A virus; inactivated vaccine against hepatitis B virus; sodium heparin; hydralazine, indinavir sulfate; flu vaccine; interleukin-2; interleukin-3; human insulin, insulin lispro; porcine insulin; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide; ifosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate, levofloxacin; lincomycin and lincomycin derivatives; lobukavir; lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine; menotropins; mepenzolate bromide; mesalamine; methenamine; methotrexate; metscopolamine; metformin hydrochloride; metoprolol; mesocillin sodium; mivacurium chloride; mumps vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neurotin; norfloxacin; octreotide acetate; ofloxacin; olpadronate; oxytocin; disodium pamidronate; pancuronium bromide; paroxetine; perfloxacin; pentamidine isethionate; pentostatin; pentoxifylline; pericyclovir; pentagastrin; pentolamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; human platelet growth factor; pneumococcal polyvalent vaccine; inactivated poliovirus vaccine; live poliovirus vaccine (OPV); polymyxin B sulfate; pralidoxime chloride; pramlintide, pregabalin; propafenone; propentaline bromide; pyridostigmine bromide; rabies vaccine; resideronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmeterol xinafoate; sinealide; smallpox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopet; ticarcillin; tiludronate; timolol; tissue plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosis factor; live typhoid vaccine; urea; urokinase; vancomycin; valaciclovir; valsartan; live varicella-zoster virus vaccine; vasopressin and vasopressin derivatives; vecuronium bromide; vinblastine; vincristine; vinorelbine; vitamin B12; warfarin sodium; yellow fever vaccine; zalcitabine; zanamivir; zolendronate; zidovudine; their pharmaceutically acceptable salts, isomers and derivatives; and their mixtures.

Among the hydrophilic active ingredients mentioned above, hydralazine and mesalamine are particularly to be mentioned.

Optionally, the active ingredient may be cyclosporine A, hydralazine, mesalamine, or celecoxib.

Shape, size and geometry.

The composition according to the present invention can be formed into an unlimited number of shapes and sizes. In the section below, describing the process of preparing the composition, various methods are given, including pouring or introducing a liquid dispersion into a mold where it solidifies or may undergo solidification. Therefore, the composition can be prepared in any desired form by creating a suitable form (for example, in the form of a disk, pill or tablet). However, the use of the form is not essential. For example, the composition may be formed in the form of a sheet,

- 54 040614 for example, by pouring a liquid dispersion onto a flat surface, where it solidifies or may undergo solidification.

Preferably, the composition may be in the form of spheres or sphere-like forms prepared as described below. Preferably, the composition of the present invention is in the form of substantially spherical, seamless mini-granules. The absence of seams on the surface of the minigranules is an advantage, for example, in subsequent processes, such as coating, as it allows for more uniform coating, spreadability, and the like. The absence of seams on the minigranules also enhances the uniformity of dissolution of the granules.

The preferred range of sizes or diameters of the minigranules according to the present invention can be selected in order to avoid gastric retention following oral administration of the minigranules. Large dosage forms remain in the stomach for various periods of time and pass through the pyloric sphincter only with food, while smaller particles pass through the pyloric sphincter independently of food. The choice of a suitable size range (see below) thus gives a more stable therapeutic effect after administration of the drug. Compared to a single large monolithic oral form, such as, for example, a traditional compressed pill, the population of granules released in the gastrointestinal tract (as provided by the dosage form of the present invention) allows greater distribution in the intestinal lumen, thus enhancing absorption through the action of over a larger epithelial area, and achieves a greater area of local coverage in certain parts of the gastrointestinal tract, such as the large intestine. The reduction in residence time at the ileocecal junction is another potential benefit.

The composition according to the present invention is preferably monolithic, which means internally (ie, cross-sectional) homogeneous, excluding possible thin sheathing of the matrix substance and excluding any coating layers.

The minigranules provided by the composition according to the present invention generally vary in diameter from 0.5 to 10 mm, with an upper limit preferably of 5 mm, for example 2.5 mm. A particularly suitable upper limit is 2 or 1.7 mm. The lower limit may preferably be 1 mm, for example 1.2 mm, more preferably from 1.3 mm, most preferably from 1.4 mm. In one embodiment, the diameter is 0.5 to 2.5 mm, such as 1 to 3 mm, 1 to 2 mm, 1.2 to 3 mm, or 1.2 to 2 mm. The minigranules may have a diameter of no more than 2.5 mm, regardless of their minimum size. The granules may have a diameter of no more than 2 mm, regardless of their minimum size.

A minigranule as described herein may have an aspect ratio of no more than 1.5, such as no more than 1.3, such as no more than 1.2, and in particular 1.1 to 1.5, from 1 .1 to 1.3 or 1.1 to 1.2. A population of minibeads as described herein, such as at least 10 beads, may have an average aspect ratio of no greater than 1.5, such as no greater than 1.3, such as no greater than 1.2, and in particular from 1 to 1.5, 1 to 1.3, or 1 to 1.2. The aspect ratios mentioned in this paragraph are not necessarily applicable to coated mini-beads and are not necessarily applicable to uncoated mini-beads. The average aspect ratio is suitably determined for a population of minibeads, eg at least 10 beads, using a particle size analyzer, eg Euesop™ particle analyzer from Innopharma Labs, Dublin 18, Ireland.

Thus, the minigranules of the present disclosure may have a size as disclosed above and an aspect ratio of 1 to 1.5. The granules according to the present disclosure may have a size as disclosed above and an aspect ratio of not more than 1.3, for example not more than 1.2 and in particular from 1.1 to 1.5, from 1.1 to 1, 3 or from 1.1 to 1.2.

Bead size (diameter) can be measured by any suitable technique, such as microscopy, sieving, sedimentation, optical sensing zone method, electrical sensing zone method, or laser light scattering. For purposes of this specification, granule size was measured by analytical sieving according to USP General Test <786> Method I (USP 24-NF 18 (U.S. Pharmacopeial Convention, Rockville, MD, 2000), p. 1965-1967).

In embodiments, the minigranules of the present invention are monodispersed. In other embodiments, the minigranules of the present invention are not monodispersed. By monodisperse is meant that for a population of granules (e.g., at least 100, more preferably at least 1000), the minigranules have a coefficient of variation (CV) of their diameters of 35% or less, optionally 25% or less, such as 15% or less, as eg 10% or less, and optionally 8% or less, eg 5% or less. A particular class of polymer beads has a CV of 25% or less. The CV referred to in this specification is defined as 100 times (standard deviation) divided by the mean, where the mean is the mean particle diameter and the standard deviation is the standard deviation of the particle size. This determination of CV is feasible using a mesh filter.

The present invention includes minigranules having a CV of 35% and an average diameter of 1 to 2 mm,

- 55 040614 e.g. 1.5 mm.

The present invention also includes minigranules having a CV of 20% and an average diameter of up to 2 mm, such as 1.5 mm, as well as minipellets having a CV of 10% and an average diameter of 1 to 2 mm, for example 1.5 mm. According to one class of embodiments, 90% of the minigranules have a diameter of

0.5 to 2.5 mm, for example 1 to 2 mm.

medicinal forms.

The composition according to the present invention is prepared in the form of an orally administered dosage form suitable for pharmaceutical use. In these embodiments, in which the composition is in the form of a mini-granule, the present invention provides a dosage form containing a plurality of mini-granules, for example in the form of a capsule, tablet, openable capsule or sachet.

In embodiments, a dosage form comprising a population of granules may be presented as a single unit dosage form, eg, contained in a single hard gel capsule that releases the granules, eg, in the stomach. Alternatively, the granules may be presented as a sachet or other container allowing the granules to be dispensed into food or drink, or for administration via a feeding tube, such as a nasogastric tube or duodenal feeding tube. Alternatively, the granules can be administered as a tablet, for example, if the population of granules is compressed into a single tablet, as described below. Alternatively, the granules can be filled into a mold, for example compressed into a dedicated vial with a cap, or, in other words, filled in a space in a specialized vial with a cap or in another element of a sealed container (or container to be sealed) so that, for example, after screwing the cap of the bottle , the granules are released into the liquid or other contents of the bottle or vial, such that the granules are distributed (or dissolved) with or without shaking into such contents. An example is a Smart Delivery Cap manufactured by Humana Pharma International (HPI) S.p.A, Milan, Italy.

The dosage form can be formulated so that the granules of the present invention can be further expanded to create a larger mass of granules, for example, by compression with a suitable oil or powder-based binder and/or filling known to those skilled in the art. The large (eg, compressed) mass may itself take various forms, including pill forms, tablet forms, capsule forms, and the like. A particular problem that the present version of the bead embodiment addresses is the dead space (above the steady state content of the particles) and/or void space (between the elements of the contained particles) typically found in hard gel capsules filled with powders or granules. In the case of such capsules filled with powders or granules with dead space/void space, the patient is required to swallow a larger capsule than would be necessary if the capsule did not contain such dead space. The granules according to this embodiment of the present invention can be easily compressed into a capsule to conform to the internal shape of any capsule, or a shell may be desirable leaving a substantially reduced, eg virtually non-existent, dead space/void space. Alternatively, dead space or void space can be used to advantage by suspending the granules in a base such as, for example, an oil, which may be inert or may have functional properties such as increased permeability or enhanced solubility, for example, or may contain an active ingredient that is the same as or different from any of the active ingredients in the granule. For example, hard gelatin or HPMC capsules may be filled with a liquid medium mixed with uncoated and/or coated beads. The liquid medium may be one or more of the surfactant phase components described herein, or it may be one or more surfactants. Particularly preferred, but non-limiting examples are corn oil, sorbitan trioleate (marketed under the trade name SPAN 85), propylene glycol dicaprylocaprate (marketed under the trade name Labrafac), 2-(2-ethoxyethoxy)ethanol (marketed under the trade name Transcutol P) and polysorbate 80 (marketed under the brand name Twin 80).

In an exemplary embodiment, the dosage form granule is prepared as described herein, for example, by mixing together at least the following: a hydrogel-forming polymer; and cyclosporin A, cyclosporin A is suitably dissolved in a hydrophobic substance such as an oil to form a dispersion of cyclosporin A in a hydrogel-forming polymer. The dispersion is immobilized within the hardened granule by ejection from one sprayer opening into a suitable coolant. Following removal of the drying liquid, the bead is coated with a release-modifying coating (second coating) (respectively with a sub-coating under the release-modifying coating), the coated beads are filled into a gelatin or HPMC capsule suitable for pharmaceutical use.

- 56 040614

Accordingly, the dosage form is prepared in the form of a unit dosage form containing an oral administration form comprising from 0.1 to 1000 mg, optionally from 1 to 500 mg, for example from 10 to 300 mg, or from 25 to 250 mg, respectively, about 25 mg , about 35 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 180 mg, about 200 mg, about 210 mg, or about 250 mg of ciclosporin A.

Determination of content and distribution of compositions.

The identity and/or distribution of one or more components of the composition according to the present invention can be determined by any method known to experts in this field. The distribution of one or more components of the composition, for example, can be determined by the method of chemical imaging in the near infrared region of the spectrum (NIR). Chemical imaging can be used to create images of the surface or cross section of a composition, such as a mini-bead. The image obtained by this method shows the distribution of one or more components of the composition. In addition to a chemical imaging technique, the distribution of one or more components of a formulation, such as a mini-bead, for example, can be determined using time-of-flight secondary ion mass spectrometry (ToFSIMS). Visualization with ToFSIMS can show the distribution of one or more components in a composition. Images obtained using ToFSIMS analysis or NIR analysis may show the distribution of components over the surface of the composition or the cross section of the composition. The methods described in this paragraph are applicable, for example, to compositions that include a polymeric matrix, such as a dried colloid, solution or dispersion.

manufacturing processes.

Various methods can be used to obtain compositions according to the present invention.

In these embodiments, in which the formulation contains the active ingredient in a water-insoluble polymer matrix, the main method for producing the core is to mix the liquid form of the matrix material, e.g., the water-insoluble polymer matrix material (e.g., polyamides, polyamino acids, hyaluronic acid; lipoproteins; complex polyesters, polyorthoesters, polyurethanes or polyacrylamides, polyglycolic acid, polylactic acid and the corresponding copolymers (copolymer of lactic acid and glycolic acid; PLGA), siloxane, polysiloxane, dimethylsiloxane-methylvinylsiloxane copolymer, (dimethylsiloxane/methylvinylsiloxane/methylhydrosiloxane)dimethylvinyl or trimethyl copolymer; silicone polymers, alkyl silicone, silicon dioxide, aluminum silicate, calcium silicate, aluminum magnesium silicate, magnesium silicate, diatomaceous silica, and the like, as described more broadly elsewhere herein), with an active ingredient an agent to form a mixture, which may take the form of a suspension, solution, or colloid. The mixture is processed to form a nucleus. For example, the formulation can be formulated into the desired shape using a molding or hot melt extrusion process to form pellets.

Methods for preparing cores comprising the active ingredient and a water-soluble polymer matrix are described below. Typically, such cores are coated to form the final composition of the present invention.

Typically, the manufacturing processes described herein involve mixing the liquid(s). Such mixing processes should be carried out at temperatures at which the substances to be mixed in the liquid state are in liquid form. For example, thermoreversible thickeners should be mixed at a temperature at which they are in a liquid state, for example at a temperature of from 50 to 75°C, for example from 50 to 70°C, or from 55 to 75°C, for example from 60 to 70°C, and in specific embodiments at about 55 or 65° C. in the case of mixing formulations including aqueous gelatin. Likewise, other components of the composition may need to be heated to melt the component, such as waxes or surfactants, which can be used in the discontinuous phase.

Cores comprising a hydrogel-forming polymer and an active ingredient disclosed herein can be prepared by mixing materials including, for example, water, a hydrogel-forming polymer and a surfactant to form an aqueous continuous phase and mixing the discontinuous phase . At least one of the aqueous phase and the discontinuous phase contains the pharmaceutically active ingredient, and the active ingredient may be dissolved in the phase that contains it, for example, both phases may be clear liquids before being mixed together. For example, the dispersed phase may contain an active ingredient (eg, a dispersed phase including an oil, an optional solvent, cyclosporine A or other hydrophobic active ingredient, and a surfactant) with an aqueous phase to form a colloid; the active ingredient, in particular, may be a hydrophobic active ingredient, for example cyclosporin A, or alternatively it may be a hydrophilic active

- 57 040614 ingredient or combination, including, for example, a hydrophobic active ingredient and a hydrophilic active ingredient. The colloid may be in the form of an emulsion or a microemulsion, with the discontinuous phase being dispersed in an aqueous continuous phase. The hydrogel-forming polymer is then thickened or allowed to thicken. Preferably, the process involves formulating or processing the core composition into a desired shape, such as a granule (also referred to as a minigranule), the shaping process may involve shaping, but preferably involves pushing an aqueous colloid through a single-channel nozzle to form droplets that are conditioned or provided to pass into a cooling medium , for example in a water-immiscible coolant in which the droplets are cooled to form, for example, granules.

The mixing of materials may involve mixing an aqueous premix (or aqueous phase) and a dispersed phase premix (e.g., an oil phase premix), wherein the aqueous premix contains water and water-soluble substances, while the premix disperse phases may contain a medium containing the active ingredient. The medium may be a hydrophobic liquid, such as a liquid lipid, or it may be or may contain a material, such as a surfactant, to form self-assembling structures. In particular, the discontinuous phase premix may contain an active ingredient such as cyclosporine A, an oil and other oil soluble components such as a surfactant and an optional solvent. The premixes may contain one or more surfactants suitable for the phase they form, as previously mentioned.

The aqueous pre-blend contains or typically consists of an aqueous solution of the water-soluble constituents, namely the hydrogel-forming polymer and the water-soluble adjuvant(s), and any water-soluble active ingredient intended for the matrix phase. The aqueous premix may include a plasticizer for the hydrogel-forming polymer, as described elsewhere in the present specification. The aqueous pre-blend may include a surfactant, for example, to increase the viscosity of the polymer and improve emulsification and thereby prevent precipitation of the active agent during processing. SDS is an example of such a surfactant. In any event, the constituents of the aqueous premix can be agitated for a period sufficient to dissolve/melt the components, eg 1 to 12 hours, to form the finished aqueous premix.

The discontinuous phase premix may contain the hydrophobic active ingredient as a dispersion, or preferably a solution, in a medium as described above, for example, in a liquid including an oil or in a liquid including self-assembly component(s). For example, the oil phase premix may therefore be a liquid lipid, such as a medium chain triglyceride (MCT) formulation, wherein the medium chain triglyceride(s) is one or more triglycerides of at least one fatty acid selected from C ₆ -C ₁₂ fatty acids, and cyclosporine A or other hydrophobic active ingredient. Preferably, the oil phase pre-blend is stirred at ambient temperature to form a solution of the active ingredient in the oil. In some embodiments, the oil phase premix components are mixed (or otherwise agitated) for a period of, for example, 10 minutes to 3 hours to form the premix. The discontinuous phase premix may contain the hydrophilic active ingredient in particulate form, eg microparticles or nanoparticles; the particulate active ingredient, for example, may be suspended in a medium comprising or consisting of an oil, such as a liquid lipid.

The two pre-blends may be combined and agitated, for example, for a period of a few seconds to an hour, such as 30 seconds to 1 hour, preferably 5 minutes to 1 hour, to form a dispersion of the discontinuous phase in an aqueous hydrogel-forming polymer, wherein the dispersion can then be further processed to obtain the final composition. The two premixes can be combined into a dispersion by mixing in a mixing vessel; they can, as a complement or alternative, be combined in a continuous mixer.

If the dispersed phase is in particulate form, the manufacturing process may not involve combining the two liquid premixes, but may instead involve combining the particulate ingredient directly with the liquid that forms the continuous phase (water, hydrogel-forming polymer, and any other constituents). ) or with a liquid precursor. Thus, a liquid is formed comprising the particulate dispersed active ingredient, and this dispersion is then nucleated by a process in which the polymer is thickened or made to thicken.

The main method for obtaining the core, which includes the active ingredient and the matrix from the image

- 58 040614 hydrogel-forming polymer, therefore, involves mixing a liquid form (preferably a solution) of a hydrogel-forming polymer (or mixtures of polymers) with the active ingredient (and other components of the dispersed phase) to form a dispersion in the polymer, while the latter forms a hydrogel in the process. The method typically involves mixing together a premix of an aqueous polymer phase and a premix of a discontinuous phase. Subject to the desired final composition (described elsewhere herein), the discontinuous phase pre-blend and liquid hydrogel-forming polymer (i.e., hydrogel-forming polymer solution or suspension) can be mixed in a weight ratio of 1:1 to 1:10 , in particular from 1:4 to 1:9, for example from 1:5 to 1:7. As a rule, only gentle mixing of the components using a magnetic or mechanical system, such as an overhead stirrer, as will be known to a person skilled in the art, is necessary to achieve dispersion of the dispersed phase in the aqueous phase to form a colloid (which may be in the form of, for example, an emulsion or microemulsion , in which the aqueous hydrogel is in the continuous phase). Continuous mixing is preferred. Mixing can also be achieved using the inline mixing system. Any suitable laboratory stirrer or industrial mixer may be used for this purpose, such as the Magnetic Stirrer (manufactured by Stuart) or the Overhead Stirrer (available from KNF or Fisher). It is preferable to set up the equipment in such a way as to minimize the evaporation of contents such as, for example, water. According to one embodiment of the process according to the present invention, it is preferable to use a closed mixing system to achieve this goal. Inline mixing may be particularly suitable for a closed processing system. Preferably, the mixing of the two components is carried out at a temperature of 50 to 70°C or 55 to 75°C, for example 60 to 70°C.

Mixing the two phases results in a colloid, wherein the aqueous hydrogel-forming polymer is the aqueous continuous phase and the component(s) insoluble in the aqueous phase is(are) the discontinuous phase. The colloid may be in the form of an emulsion or a microemulsion.

In embodiments, if the dispersed phase is or contains a surfactant, then the amount of surfactant may be adjusted such that when the discontinuous phase premix is combined with an aqueous premix, the concentration of surfactant in the combined mixture is greater than the CMC for the surfactant used, so that micelles are formed in the aqueous phase, which includes the hydrogel-forming polymer. Depending on the concentration of surfactant used, self-assembling structures other than micelles can also form. The CMC for a particular surfactant can be determined using well known methods, such as those described in Surfactants and Polymers in Aqueous Solutions Second Edition, Chapter 2, Holmberg et al. In embodiments, mixing an aqueous phase and a dispersed phase that is or contains a surfactant may result in the formation of a clear liquid, such as a microemulsion, in which the aqueous phase, including the hydrogel-forming polymer, is the continuous phase. Microemulsions are a thermodynamically acceptable dispersion of self-assembling structures in an aqueous phase, the size of the self-assembling structures being small enough to provide transparency. The size of the self-assembling structures present as a discontinuous phase resulting from the mixing of the aqueous phase and the surfactant phase may be from about 0.5 to 200 nm, for example from about 1 to 50 nm, or from about 5 to 25 nm. The size of self-assembling structures formed and other characteristics, such as optical isotropy, of composition (eg microemulsions) can be determined using well-known methods such as dynamic light scattering.

If the polymer matrix primarily consists of gelatin with the addition of sorbitol, then the aqueous phase of the polymer matrix is prepared by adding appropriate amounts of sorbitol (and surfactant, if desired) to water, heating to approximately 50-75°C, for example 60- 75°C, until dissolved, and then add gelatin, although the exact order and time of addition is not critical. A typical gelatin solution contains 8-35% (e.g. 15-25%, preferably 17-18%) gelatin, 65-85% (preferably 77-82%) water and 1-5% (preferably 1.5-3% ) sorbitol. If a surfactant (e.g. an anionic surfactant) is present in the aqueous phase pre-blend, may be present in an amount of 0.1 to 5% (preferably 0.5 to 4%), with all parts being parts by weight of the aqueous phase .

Optionally, the processing temperature required for standard gelatin can be lowered to a desired target temperature, such as 37° C., by using lower melting gelatin (or gelatin derivatives or mixtures of gelatins with melting point depressants).

- 59 040614 leniya) or other material of the polymer matrix, such as, for example, sodium alginate. If gelatin droplets are formed by machine extrusion and immediately cooled, for example in a cooling bath, an additional suitable inlet tube can be used to introduce the oil phase containing cyclosporin A at ambient temperature into a hotter gelatin solution medium (and the mixture can be immediately homogenized) just prior to ejection from the granulating nozzle or other dropping process so that the duration of exposure of the cyclosporin A to the higher gelatin temperature is limited, thus reducing the extent of any heat dependent degradation of the active ingredient. Any suitable device can be used in this process, such as, for example, a homogenizer, such as a screw homogenizer, in combination with an extrusion type apparatus, such as described in WO 2008/132707 (Sigmoid Pharma), the entire contents of which are incorporated herein by reference.

The colloid is formed by combining a premixed disperse phase or particulate active ingredient with a liquid aqueous phase with stirring as described above. The resulting colloidal dispersion then has the solidified core composition described above, but with liquid water still present in the core composition.

Optionally, the active ingredient may be added after mixing the aqueous phase and other components of the discontinuous phase of the type comprising a medium in addition to the active ingredient, however, it is preferable to add the active ingredient together with the other components of the discontinuous phase as a premix.

The resulting colloid is then poured or injected into a mold or other vessel, or poured onto or between sheets, or dropped (or extruded) into another medium such that the polymer matrix-containing aqueous phase solidifies into the intended shape of the mold. , vessel, sheet or drop/granule. It is preferable to perform molding with a mold, for example the formation of granules without delay.

Solidification (thickening) can occur in various ways depending on the matrix polymer, for example, by changing the temperature around the mold, vessel, sheet, drop/granule, etc. or by applying a solidification medium or a solidification solution such that the molded shape thickens or solidifies. In some embodiments, both the change in temperature and the use of a solidification medium or solidification solution are used together or simultaneously.

According to a preferred embodiment, in which the core comprising the active ingredient takes the form of granules, the granules can be formed, for example, by dropping drops of a colloid into a liquid that causes solidification. If the viscosity of the composition to be granulated reaches a certain point, then droplet formation becomes more difficult, and then a special apparatus is preferable.

The use of the term dry does not imply that a drying step is necessary to obtain a dry core (although it is not excluded), but rather that the solid or solidified aqueous outer phase is substantially free of water or free of available water. Solidification of the aqueous phase (outer phase) can be accomplished by various means, including chemically (eg, by crosslinking) or physically (eg, by cooling or heating). In this regard, the term aqueous phase is nevertheless used herein to refer to the outer (continuous) phase of the core, even though water is, in some embodiments, primarily absent from (or trapped in the crosslinked matrix) in the core. The outer phase of the core, however, is soluble in water and is soluble in the aquatic environment.

If curing can be achieved by raising or lowering the temperature, then the temperature of the curing medium can be adjusted to achieve curing of the core at the desired rate. For example, if gelatin is used as the hydrogel-forming polymer, then the setting medium is at a lower temperature than the emulsion temperature, thus causing setting, i. thickening, polymer matrix. In this case, the solidification medium is called the coolant.

Where curing can be achieved chemically, such as by inducing crosslinking when exposed to a component of the curing medium, then the concentration of such component in the curing medium and/or its temperature (or other characteristic or content) may be adjusted to achieve the desired rate and degree of curing. For example, if alginate is selected as the polymeric matrix, one component of the solidification medium may be a calcium-containing compound (such as, for example, calcium chloride) capable of inducing alginate crosslinking and subsequent solidification. Alternatively, the same or similar calcium-containing compound may be contained (e.g., dispersed) in the aqueous phase of the liquid emulsion prior to granulation and induction of crosslinking, for example, by applying a higher or lower pH to the solidification medium into which the emulsion drops are dropped or introduced. Such electrostatic crosslinking can be varied depending on the resulting characteristics

- 60 040614 granules by controlling the availability (concentration) of calcium ions and other physical conditions (especially temperature). The solidifying medium can be a gas (eg air) or a liquid or both. For example, if gelatin is used as the matrix of the hydrogel-forming polymer, then the solidifying medium may initially be gaseous (eg, droplets passing through cooling air) and then liquid (eg, droplets passing into cooling liquid). The reverse sequence can also be used, although gaseous or liquid coolants alone can also be used. Alternatively, the medium may be spray cooled, wherein the emulsion is sprayed into a cooling gas to solidify.

In the case of gelatin or other water-soluble polymer (or mixture of polymers) intended to form the immobilization matrix, it is preferred that the solidification medium be a non-aqueous liquid (such as, for example, medium chain triglycerides, mineral oil or the like, preferably with low HLB to ensure minimal moisture) which can be conveniently placed in a bath (cooling bath) to obtain colloid droplets as they solidify to form core granules. The use of a non-aqueous liquid provides greater flexibility in the choice of temperature at which cooling is carried out.

If a liquid cooling bath is used, it is generally maintained at less than 20°C, preferably maintained in the range of 5-15°C, more preferably 8-12°C using standard gelatin as the hydrogel-forming polymer. If triglyceride is chosen as the cooling medium in the cooling bath, Miglyol 810 from Sasol is a preferred example.

If alginate is chosen as the polymeric matrix, a typical method for preparing granules involves dropping a 3% solution of sodium alginate, in which oil drops are dispersed, as described above, into a crosslinking bath at 4°C containing 0.1 M calcium chloride, with obtaining calcium alginate (this method can be called diffusion curing, since calcium is believed to diffuse into the granules with the implementation of crosslinking or curing). Using a syringe pump or an Inotech machine, drops can be formed or extruded (for example, at 5 ml/hr if a pump is used) through a sterile needle or other nozzle (described elsewhere herein) that can be vibrated as discussed elsewhere. or in this document. If necessary, an air flow of 15 to 20 L/min can be applied through a 4.5 mm tube from top to bottom through the needle to reduce droplet size. The newly formed granules can then be stirred in a calcium chloride bath for 1 hour. If carrageenan is used as the polymer matrix, both salt and lowering the temperature, for example by dripping into a cooling oil, can be used to effect hardening.

An alternative approach using alginate is internal thickening, in which calcium ions are dispersed in the aqueous phase before being activated to effect thickening of the hydrocolloid particles. For example, this can be achieved by adding an inactive form of an ion that will cause crosslinking of the alginate, which is then activated by changing e.g. pH after sufficient dispersion of the ion has been completed (see Glicksman, 1983a; Hoefler, 2004, which are incorporated herein by links). This approach is particularly useful when rapid thickening is desired and/or where the diffusion approach may result in loss of API by diffusing into the crosslinking bath.

When using an ionotropic polymer other than alginate, acceptable processes similar to those described herein for alginate can be used.

After shaping, shaping or granulating, the resulting articles or molds can be washed, then dried if necessary. In the case of pellets cured in a solidification medium, an optional final step in the preparation process described above therefore involves the removal of the hardened granules from the solidification medium. This can be achieved, for example, by collecting in a mesh basket, through which the solidification medium (for example, medium chain triglycerides) drains and the granules remain, and is preferably carried out without delay, for example, immediately after the formation of granules or within 5, 10, 15, 20, 25 or 30 min after their formation. Excess solidification medium can then be removed using a centrifuge (or other apparatus or device adapted to remove excess medium) followed by drying of the pellets to remove water or free water and/or remove some or all of any additional solvent, such as ethanol or isopropyl alcohol. used to dissolve or facilitate the dissolution of the active agent in the previous steps, optionally followed by washing (eg using ethyl acetate) and a subsequent drying step to remove excess solvent (eg ethyl acetate).

Isopropyl alcohol is an example of a solvent that is preferably removed later in processing to reduce residues in the oil or aqueous phase. Drying can be achieved by any suitable process known in the art, such as using a drum dryer (for example, a Freund Drum dryer, which can be part of the Spherex equipment line,

- 61 040614 if used) with air heated from 15 to 25°C, preferably about 20°C, which leads to evaporation or entrainment of water with the help of air. Alternatively, drying can be carried out using a fluid bed dryer (eg Glatt GPCG 1.1) with air heated from 40 to 60°C. The use of gelatin as a polymeric matrix (eg the main constituent of the aqueous immobilization phase) in most cases requires a drying step, and for granules this is preferably achieved by air drying as described above. The resulting composition (composition according to the present invention) is essentially dry, as described in more detail above.

Typically, granules can be created by applying surface tension between a liquid dispersion (mixture of aqueous phase and surfactant phase) and a suitable solidification medium, such as, for example, a gas or liquid, to create a spherical or nearly spherical shape of the final granules.

Alternatively, granules can be produced by forcing or extruding a liquid dispersion through a channel or nozzle of a certain diameter and optionally subjected to vibration (using selected vibration frequencies) and/or gravity flow. Examples of devices that can be used are encapsulation prilling, drop pelletizing, spray cooling or spray curing devices such as Freund Spherex, ITAS/Lambo, Globex, Inotech, GEA Niro, Droppo, Buchi, Gelpell process equipment. Operation of the Freund Spherex machine, which may be desirable for making pellets of the present invention, is described in US Pat. No. 5,882,680 (Freund), the entire contents of which are incorporated herein by reference. It is preferable to choose a vibration frequency in the range of 2-200 Hz, preferably 10-15 Hz, although the final choice (and separately the amplitude of the selected vibration) depends on the viscosity of the dispersion to be granulated. If a polymer matrix that cures at a lower temperature is chosen, then it may be beneficial to maintain the lines to the channel/nozzle at a certain temperature to maintain the fluidity of the solution. Preferably, the colloid is forced through a single-channel nozzle, for example having a diameter of 0.1 to 5 mm (for example, 0.5-5 mm), to form droplets, which are then made to fall or allowed to fall into the cooling oil or other solidification medium and provide solidification with the formation of seeds, after which the seeds are removed from the cooling oil and dried.

It should be appreciated that the present invention relates to a method for manufacturing a core comprising a pharmaceutically active ingredient in a polymeric matrix, the method comprising the formation of an aqueous premix that contains water and water-soluble/dispersible materials (including therefore forming hydrogel polymer), and a dispersed phase premix (e.g., an oil phase premix) that contains the active ingredient and optionally a vehicle and other adjuvants (e.g., oil(s) and oil-soluble/dispersible materials), and combining the two pre-mixed to form a colloid (dispersed phase) in an aqueous phase comprising a hydrogel-forming polymer. The colloid can then be formulated into a shaped unit, such as a granule, to provide a core containing the active ingredient. More specifically, the manufacture of a core comprising a pharmaceutically active ingredient and a polymeric matrix (preferably a matrix of a hydrogel-forming polymer) may involve (i) forming a premixed aqueous phase comprising an aqueous solution of the water-soluble constituents (e.g., a hydrogel-forming polymer , any water-soluble adjuvant(s) described elsewhere herein);

(ii) forming a premixed discontinuous phase, typically comprising a dispersion or preferably a solution of the active ingredient, e.g., cyclosporin A, in a liquid, optionally the liquid being an oil (and optionally together with other constituents of the discontinuous phase (e.g., surfactant, solvents, etc., described elsewhere in this document));

(iii) mixing the aqueous phase premix (i) and the discontinuous phase premix (ii) to form a colloid;

(iv) pushing the colloid through the nozzle to form droplets;

(v) causing or causing the hydrogel-forming polymer to thicken or solidify to form a matrix of water-soluble polymer; and (vi) drying the solid.

Some manufacturing methods include steps (A)-(D) below, or alternatively, the manufacturing method may include one step or some combination of steps (A)-(D).

(A) Typical preparation of an aqueous phase.

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The aqueous phase components are added to the water, eg purified water, with agitation, eg sonication or agitation. The temperature is gradually increased, for example, up to 60-70°C and in particular up to 65°C, to achieve complete dissolution of the solids. The aqueous phase components include a hydrogel-forming polymer, such as gelatin or agar, and optionally one or more other adjuvants, such as D-sorbitol (plasticizer), and a surfactant (eg, SDS). Possible components of the aqueous phase are described elsewhere in this document.

The gelatin may be type A gelatin. In some less preferred embodiments, the gelatin is type B gelatin. agitate for a period, eg 1 to 12 hours, until the aqueous phase (aqueous premix) is complete.

(B) Typical preparation of the dispersed phase.

The hydrophobic active ingredient, for example cyclosporin A, is mixed with the other components of the continuous phase (for example, oil, surfactant and co-solvent) with agitation, for example, sonication or agitation, preferably at ambient temperature with dispersion or preferably dissolution of the active ingredient.

(C) Typical mixing of two phases.

Mix the aqueous phase and the dispersed phase. The two phases can be mixed into the desired mass; for example, the weight ratio of the dispersed phase to the aqueous phase may be from 1:1 to 1:10, for example from 1:4 to 1:9 and optionally from 1:5 to 1:8, for example about 1:5 or about 1:7 . The resulting colloid is agitated, for example by sonication or stirring, at a temperature of 60-70° C. and in particular 65° C. to achieve a homogeneous dispersion, then the homogeneous dispersion is formed into granules. In particular, the homogeneous dispersion is forced through a single-channel nozzle to form droplets which fall into the cooling medium. The nozzle preferably vibrates to facilitate droplet formation. The nozzle may vibrate at a frequency of 2-200 Hz and optionally 15-50 Hz.

The cooling medium may, for example, be air or oil; preferably an oil is physiologically acceptable, such as for example in the case of medium chain triglycerides, eg Miglyol 810N. The cooling medium may have a cooling temperature often less than 15°C, for example less than 10°C but above 0°C. In some embodiments, the cooling temperature is 8-10°C. The size (diameter) of the nozzle is typically 0.5 to 7.5 mm, for example 0.5 to 5 mm and optionally 0.5 to 4 mm. In some embodiments, the nozzle diameter is 1 to 5 mm, such as 2 to 5 mm, optionally 3 to 4 mm, and in particular may be 3.4 mm.

The flow rate through the 3.4 mm nozzle is 5 to 35 g/min and optionally 10 to 20 g/min, and for other nozzle sizes can be adjusted as appropriate for nozzle area.

(D) Typical processing of granules.

The cooled granules are recovered, for example, they can be removed from the cooling oil after a residence time of 15-60 minutes, for example after about 30 minutes. Granules extracted from coolant (such as oil) can be centrifuged to remove excess coolant and then dried. Preferably, drying is carried out at room temperature, for example 15 to 25°C and optionally 20 to 25°C. Drying can be carried out in a tumble dryer, for example over a period of 6 to 24 hours, for example about 12 hours in the case of pellets dried at room temperature. The dried granules may be washed, preferably with a volatile non-aqueous liquid at least partially miscible with water, for example they may be washed with ethyl acetate. The washed granules can be dried at room temperature, for example 15 to 25°C and optionally 20 to 25°C. Drying can be carried out in a tumble dryer, for example, for a period of 6 to 48 hours, for example about 24 hours in the case of pellets dried at room temperature. Drying can be achieved by any suitable means, for example using a drum dryer, preferably under vacuum; either by simply passing heated air through the pellet bath, or by fluidizing the pellets in suitable heated air equipment, such as a fluid bed dryer. After drying, the granules are passed through a sieve with a pore size of 1 to 10 mm, optionally 2 to 5 mm to remove oversized granules, and then through a sieve with a pore size of 0.5 to 9 mm, optionally 1 to 4 mm. to remove granules with a size below the nominal.

It should be understood that it is possible to process granules that deviate during the screening process.

As a further aspect of the present invention, there is provided a composition obtainable by (having the characteristic of) any of the processes described herein.

It should be understood that the processes described herein can therefore be used to provide any of the specific cores described according to the embodiments herein by dispersing suitable components that form a dispersed core phase in suitable components that form an aqueous continuous matrix phase. kernels.

The preceding paragraphs describe the formation of uncoated cores comprising the pharmaceutically active ingredient, for example, in a matrix of hydrogel-forming polymer. The cores are preferably coated to provide the composition of the present invention. The cores may first be coated with an internal coating and then further coated with a second coating (also called a modified release coating). Suitable internal coatings and modified release coatings are any of those described herein and any of the first coating (for internal coating) or the second coating (for modified release coating). Optionally, the composition is further coated with an optional outer protective coating described herein. The coating(s) may be applied using well-known techniques, such as spray coating, as described below, to obtain the desired weight gains due to internal coating and modified release coating.

With respect to one of the methods described above (pushing the emulsion through an optionally vibrating nozzle) with two concentric channels (center and outside), the environment can form a coating (outside the bead) as described herein. Preferably, a Spherex device manufactured by Freund (see US Pat. No. 5,882,680 belonging to Freund) is used (the entire content of this patent is incorporated herein by reference). Other similar pusher or extrusion apparatus may be used, such as the pusher apparatus described above.

Very high monodispersity is achieved with the Spherex device. For example, from a typical 100 g batch, 97 g of pellets had a diameter of 1.4 to 2 mm, or 1 to 2 mm. Desired size ranges can be achieved by methods known in the art to deflect/sieve particles of various sizes. For example, larger/smaller granules can be rejected/screened out by passing the batch first through, for example, a 2 mm sieve and then through a 1.4 mm sieve.

A diameter range of 1.4 to 2 mm is a good size, if needed, to spray coat the granules (if smaller, the spray coater may miss the granule; if much larger, the granules may be too heavy to fluidize, which is necessary to achieve a uniform coatings).

Coating process.

The coating process can be carried out by any suitable means, such as, for example, the use of a coating device that applies a polymer coating solution (described above, in particular) to the composition. Coating polymers are either provided by the manufacturer in ready-to-use solutions for direct application or may be prepared prior to use according to the manufacturers instructions.

Coating is preferably carried out using a fluidized bed coating system such as a Wurster core coating(s) column. Suitable coating devices are known to those skilled in the art and include, for example, a perforated drum or fluidization system, such as GLATT, Vector (eg CF 360 EX), ACCELACOTA, Diosna, O'Hara and/or HICOATER process equipment. Mention should be made of the Fluid Bed Coater MFL/01 (Freund) used in the Bottom Spray configuration.

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Typical coverage conditions are as follows.

Process parameter Values Fluidizing air flow (m ³ /h) 20-60 (preferably 3060) Air inlet temperature (°C) 20-65 Air outlet temperature (°C) 20-42 Product temperature (°C) 20-45 (preferably 4042) Air spray pressure (bar) Up to 1.4, for example, 0.8-1.2 Spray rate (g/minute) 2-10 and 3-25 rpm

Preferably, the coating is applied as a solution or dispersion of the polymers (and other components) of the coating. Generally, coatings are applied as an aqueous solution or dispersion, although other solvent systems may be used if desired. The coating dispersion is sprayed onto the cores in a fluidized bed coater to obtain the desired weight gain due to the coating. As a rule, the coating process is carried out at a temperature at which support cores, from 35 to 45°C, preferably from 40 to 42°C.

After coating, the composition can be dried, for example by drying at 40-45°C.

The present invention further provides a product having the characteristics of the composition obtained as described herein, the product being defined by its characteristics determined by the characteristics of the composition, with the exception of the way in which it was obtained.

As mentioned herein, the described methods can be used to provide any of the formulations described according to various embodiments herein. An exemplary formulation of the present invention is provided comprising a core and a coating comprising a water-soluble cellulose ether or a water-soluble cellulose ether derivative, wherein the core comprises a hydrogel-forming polymer matrix comprising gelatin, cyclosporine A, or another hydrophobic active ingredient, medium chain mono-, di/or triglycerides, a co-solvent and a surfactant, wherein the core has the characteristics of a core obtained by a method comprising steps (i) to (vi) described above for forming a core, wherein the aqueous phase premix in process step (i) contains gelatin and a surfactant (preferably an anionic surfactant), and the oil phase premix in process step (i) contains mono-, di- and/or medium chain triglycerides, hydrophobic active ingredient, surfactant ( preferably a non-ionic surfactant) and a co-solvent; and wherein the core is optionally coated with a coating including a water-soluble cellulose ether or a water-soluble cellulose ether derivative, and the thus coated core is optionally coated with a second coating; wherein the coatings are any of those described herein. Therefore, the above-described composition including the first coating can be obtained by the method. In addition, the method can be used to obtain a composition that includes a first coating and a second coating located outside the first coating.

In addition, the method for preparing the composition according to the present invention may include the steps of mixing the first group and the second group, while the first group has a coating that is or contains a water-soluble cellulose ether, but does not have an external coating, for example, as described herein ; and the second group has a first coating that is or contains a water-soluble cellulose ether and a second coating that is or contains a delayed release coating, for example as described herein, for example a coating that is or contains a delayed release polymer .

Kernels described in this document to which the following characteristics apply, for example in the immediately preceding paragraph, may have the following characteristics:

gelatin may be present in an amount of 300 to 700 mg/g;

medium chain mono-, di- and/or triglycerides (eg caprylic/capric acid triglyceride) may be present in an amount of 20 to 200 mg/g;

-65040614 co-solvent (eg 2-(ethoxyethoxy)ethanol) may be present in an amount of 150 to 250 mg/g;

the non-ionic surfactant (eg sorbitan surfactants, PEG fatty acids or glyceryl derivatives of fatty acids or poloxamers, or in particular polyethoxylated castor oil, eg Kolliphor EL) may be present in an amount of 80 to 200 mg /G;

the anionic surfactant (eg alkyl sulfates, carboxylates or phospholipids (particularly SDS)) may be present in an amount of 15 to 50 mg/g; and the active ingredient, in particular cyclosporin A, may be present in an amount of 60 to 180 mg/g, preferably 60 to 150 mg/g or 80 to 100 mg/g, for example 81 to 98 mg/g, all weights are based on the dry weight of the kernel before coating.

The core is coated with a first coating (inner coating) which is or contains a water-soluble compound selected from cellulose ethers and their derivatives, in particular hydroxypropyl methylcellulose; wherein the first coating is present in an amount corresponding to the increase in weight due to the first coating in the range selected from (i) from 8 to 12%, for example about 10%, or (ii) from 4 to 6%, for example about 5%, or (iii) about 6% to about 10%, such as about 7%, about 7.5%, about 8%, about 8.5%, about 9%, or about 9.5%, by weight based on the weight of the kernel up to applying the first coating. The first coating may have a modified release coating (or second coating) deposited thereon.

Preferably any modified release coating, in particular, according to the embodiments in the immediately preceding paragraphs is or contains a pH-independent modified release coating, more specifically the second coating may be a modified release coating including ethyl cellulose (for example, Surelease), even more specifically a modified release coating comprising ethyl cellulose and a water-soluble polysaccharide, pectin (eg, the Surelease/pectin coating described herein); and wherein the modified release coating is present in an amount corresponding to the weight gain of the composition due to the second coating selected from (a) from 10 to 12%, for example about 11% or about 11.5%; or (b) 16 to 18%, such as about 17%; or (c) about 8% to about 12%, such as about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, or about 11%, by weight based on the weight of the composition before applying the second coat.

Applications.

The compositions according to the present invention can advantageously be used for the oral delivery of pharmaceutically active ingredients through the enhanced dissolution profiles achieved.

The formulations of the present invention include modified release formulations that contain cyclosporin A as the active ingredient and a release-modifying coating, for example containing a pH independent polymer to target release of cyclosporin A to the lower intestine. Such formulations result in low systemic exposure to cyclosporin A while providing high levels of cyclosporin A in the lower gastrointestinal tract, especially in the colon. Such formulations release cyclosporin A in an active form, eg, as a solution, which provides enhanced absorption of cyclosporin A into the local tissues of the lower gastrointestinal tract. If the formulation is used in the form of minigranules, the minigranules are advantageously distributed along large areas of the gastrointestinal tract after oral administration, and in this regard, it is expected to provide a more uniform effect of cyclosporine on large areas, such as the large intestine. Needless to say, the present invention includes such formulations in which cyclosporine A is substituted or supplemented with another active ingredient for topical treatment of the lower gastrointestinal tract, eg the colon. The other active ingredient may be another immunosuppressant or hydroxylase inhibitor such as DMOG or hydralazine, or it may be a combination of active ingredients containing at least one of those mentioned herein. Tacrolimus and sirolimus are examples of other immunosuppressants.

Thus, modified release formulations of the present invention containing an active ingredient for topical treatment of the lower gastrointestinal tract are expected to be useful in the treatment or prevention of a gastrointestinal condition. In particular, the composition of the present invention may contain cyclosporin A and/or another immunosuppressant and may be useful in the prevention or treatment of inflammatory conditions affecting the lower gastrointestinal tract, especially conditions affecting the large intestine.

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The composition according to the present invention is administered orally. The dose required will vary depending on the particular condition being treated and the stage of the condition. In the case of formulations containing cyclosporin A, the formulation will generally be administered to provide a dose of cyclosporin A of 0.1 to 100 mg, such as a dose of 1 to 500 mg, or in particular a dose of 25 up to 250 mg of cyclosporine A, for example a dose of 37.5, 75 or 150 mg. The composition is suitably administered as a single daily dose. Optionally, the composition can be administered twice a day, for example 37.5, 75 or 150 mg twice a day.

According to one aspect of the present invention, there is provided a composition of the present invention which contains an immunosuppressant as an active ingredient and is for the treatment or prevention of inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft versus host disease, graft versus host disease of the gastrointestinal tract, myasthenia gravis, irritable bowel syndrome (eg, with constipation, diarrhea, and/or pain symptoms), celiac disease, gastric ulcer, diverticulitis, inflammation of the ileoanal pocket, proctitis, mucositis, chemotherapy-associated enteritis, radiation-associated enteritis, disease of the short bowel or chronic diarrhea, gastroenteritis , duodenitis, jeunitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, diverticulosis, endometriosis, colorectal carcinoma, adenocarcinoma, inflammatory disorders such as inflammation in the disconnected gut, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, undifferentiated colitis, jejunoileitis, ileitis, ileocolitis, or granulomatous colitis, for the prevention of bone marrow transplant rejection, psoriasis, atopic dermatitis , rheumatoid arthritis or nephrotic syndrome, primary sclerosing cholangitis, familial adenomatous polyposis, or perianal Crohn's disease, including perianal fistula.

In one embodiment, the composition of the present invention, which contains an immunosuppressant as an active ingredient, is for the treatment of inflammatory bowel disease. The main forms of inflammatory bowel disease are Crohn's disease and ulcerative colitis. Accordingly, the composition of the present invention may be useful in the treatment of both of these conditions.

Crohn's disease can affect the entire gastrointestinal tract, including the large intestine. However, ulcerative colitis is a condition that only affects the large intestine and rectum. Accordingly, the release profile contemplated by a colon-targeting formulation of the present invention containing an immunosuppressant (eg, containing cyclosporine A) is expected to be particularly beneficial in the treatment of ulcerative colitis.

According to one aspect of the present invention, a composition according to the present invention is provided which contains an immunosuppressant as an active ingredient and is intended for the treatment or prevention of a condition of the gastrointestinal tract, for example an inflammatory condition of the gastrointestinal tract, and optionally the condition of the gastrointestinal tract is selected from irritable bowel syndrome , celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis, mucositis, radiation-associated enteritis, short bowel disease or chronic diarrhea, gastroenteritis, duodenitis, jejunitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, diverticulosis, endometriosis, colorectal carcinoma, adenocarcinomas, inflammatory disorders such as inflammation in the gut, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis itis, autistic enterocolitis, undifferentiated colitis, jejunoileitis, ileitis, ileocolitis or granulomatous colitis, fibrosis, graft versus host disease, graft versus host disease of the gastrointestinal tract, or HIV or enteropathies.

A colon-targeted formulation of the present invention containing an immunosuppressant primarily releases the immunosuppressant, eg, cyclosporin A, into the colon. However, the drug may also be released higher in the gastrointestinal tract and, accordingly, the formulation may also provide therapeutic benefit in conditions affecting other parts of the lower gastrointestinal tract.

Gastrointestinal graft-versus-host disease (GI-GVHD) is a life-threatening condition and one of the most common causes of bone marrow and stem cell graft failure. In patients with GI-GVHD, donor cells begin to attack the patient's body most often in the intestines, liver, and skin. Patients with mild to moderate GI-GVHD typically develop symptoms of anorexia, nausea, vomiting, and diarrhea. Left untreated, GI-GVHD can progress to ulceration of the gastrointestinal mucosa, and in its most severe form, the disease can be fatal. Accordingly, in one embodiment, the formulation containing the immunosuppressant is for

- 67 040614 treatment or prevention of graft-versus-host disease of the gastrointestinal tract (GI-GVHD).

In another embodiment, a formulation of the present invention is provided comprising an immunosuppressant for the treatment of celiac disease.

In one embodiment, the composition of the present invention, which contains an immunosuppressant as an active ingredient, is for the treatment of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and vascular dementia) or pediatric diseases, including, but not limited to, ulcerative colitis, Crohn's disease, and GvHD.

A coating according to the present invention containing a water-soluble cellulose ether can be used to reduce differences between the release profiles of different batches of minigranules. It has been demonstrated (see FIG. 10) that the first coating under the second coating gives granules with a similar (±5% release) percent release of the active ingredient at specific time points in the release profile. This advantageously improves the uniformity of in vitro release profiles as well as in vivo dissolution and hence the uniformity of release of the active agent along the gastrointestinal tract.

The term batch means a certain quantity of a medicinal product or other material, which must be of a uniform nature and quality within certain limits, and it is obtained according to the same production order during the same production cycle. The term batch means a lot or a specially defined part of a lot, having a uniform character and quality within certain limits; or in the case of a medicinal product obtained by a continuous process, it means a specially defined amount obtained per unit of time, or quantitative parameter, so that its uniform nature and quality is ensured within certain limits. The terms batch number, reference number, or lot number means any distinctive combination of letters, numbers, or symbols, or any combination thereof, from which the complete history of manufacture, processing, packaging, storage, and distribution of a lot or batch of a medicinal product or other material can be determined.

Examples

Example 1 Preparation of a hydroxypropyl methylcellulose coated minigranule.

A mini-bead was generally obtained by composing a core according to the following procedure, and then coating the core with a dispersion of Opadry White 20A28380 (supplied by Colorcon).

Core manufacturing.

Cores in the form of whole mini-beads were obtained using the Spherex method, as described below.

The aqueous phase was obtained by mixing sodium dodecyl sulfate (SDS) and D-sorbitol with purified water with constant stirring. Gelatin was then added to this solution and heating to approximately 60-70° C. was carefully applied to achieve complete melting of the gelatin.

The oil phase was prepared by mixing together 2-(2-ethoxyethoxy)ethanol (Transcutol HP), polyethoxylated castor oil (Kolliphor EL) and capric/caprylic acid triglyceride (Miglyol 810) with stirring at room temperature to form a solution. Cyclosporine A was added and mixed until a clear solution was obtained. The oil phase was mixed with the heated aqueous phase in a ratio of approximately 1:7 (oil phase:water phase). The resulting mixture was stirred at 60-70° C. until homogeneous.

The resulting mixture was then fed (using a temperature controlled tube) through a vibrating nozzle with a single nozzle outlet of 3 mm in diameter. Whole minigranules were formed by flowing the solution through a vibrating nozzle into a cooling chamber of a constantly flowing cooling oil with medium chain triglyceride (Miglyol 810) at a temperature of 10°C.

The minigranules were removed from the cooling oil and placed in a centrifuge to remove excess oil. After centrifugation, the first drying step was started with a refrigerator temperature of 10°C and a heater temperature of 20°C. The dryer was rotated at 15 rpm. When free rotation of the granules was observed in the dryer drum, they were considered dry.

The minigranules were washed with ethyl acetate and then dried for another 24 hours under the same drying conditions as mentioned above in the first drying step. The dried minigranules were then sieved to remove the larger and smaller granules, resulting in cores of 1-2 mm in diameter. This procedure provided the core with the composition shown in table. 1, with the values representing the weight percentage of the total weight for each component.

- 68 040614

Table 1

Component % mass/mass Cyclosporin A 10, 8 Miglyol 810 N 4, 6 Transcutol HP 16.4 Kolliphor EL 9, 2 SDS 4.0 Sorbitol 5, 7 Gelatin 49, 3

Core coverage.

The minigranule cores were loaded into a fluid bed coater (Wurster column) and coated with Opadry White 20A28380 (available from Colorcon Limited) as a dispersion. Processing parameters, such as inlet air temperature and inlet air volume, were adjusted to maintain minigranule temperatures from 40 to 42°C until the desired increase in coating mass was achieved. The resulting internally coated minigranules were dried for 5 minutes at 40° C. in a coater.

The composition of the minigranule.

Minigranule with the composition shown in the following table. 2 was obtained by the above procedure. The minigranule is characterized by an increase in mass due to Opadry 2.7% relative to the mass of the core.

Example 2 Preparation of hydroxypropyl methylcellulose coated minigranules.

According to the procedure described in Example 1, hydroxypropyl methylcellulose coated minigranules were obtained with various percentages of weight gain due to Opadry. The percentage of weight gain due to Opadry is shown in the table below. 3.

Table 3

% weight gain due to Opadry Example 2a 6.3% Example 2b 10% Example 2c 15%

The minigranules of examples 2a-2c had the composition shown in table. 4.

Table 4

Component Example 2a Example 2b Example 2 with % mass/mass Cyclosporine A 10.2 9, 8 9, 4 Miglyol 810N 4.3 4.2 4.0 Transcutol HP 15.5 14.9 14.3 Kolliphor EL 8.7 θ,4 8.0 SDS 3.8 3, 6 3.5 Sorbitol 5, 3 5, 2 50 Gelatin 46.3 44.8 42.8 Opadry 5, 9 9, 1 13.0

- 69 040614

Example 3 In vitro dissolution profile of the minigranules of examples 1, 2a, 2b and 2c up to 4 hours.

In vitro dissolution profiles of a sample of the minigranules prepared in Examples 1, 2a, 2b and 2c were measured in water. As a typical example, the core dissolution profile was tested without the Opadry coating prepared in Example 1. Dissolution testing was performed according to USP <711> 37±5°С.

Aliquots of the medium were taken for analysis after 1, 2 and 4 hours for all tested media. In addition to these time points, aliquots were also taken at the following time points for the indicated minigranules: for minigranules of examples 1 and 2a - 20, 40 min and 1.5 h;

for minigranules of examples 2b, 2c and uncoated core of example 1 - 30 min.

Aliquots were analyzed for cyclosporin A using reverse phase HPLC with UV detection at 210 nm.

The amount of dissolved cyclosporine A in the dissolution medium is expressed as a percentage based on the initial content of cyclosporine in the test formulation (percent release). The percent release values represent the release profile when plotted against time, and the release profile for each of the minibead samples from Examples 1, 2a, 2b, 2c and the uncoated core of Example 1 is shown in FIG. 1.

The release profiles of the tested minigranules clearly show that the additional inner coating of hydroxypropyl methylcellulose (Opadry) enhances the dissolution of the active ingredient during the first 2 hours of the dissolution test. All of the hydroxypropyl methylcellulose (HPMC) coated minigranules released cyclosporine into solution at a much faster rate than the uncoated core of Example 1. This is unexpected and contrary to general principles. General principles suggest that the addition of additional material to the core, as occurs when coating the core with HPMC, should increase the time required for the release of the active ingredient into solution.

Example 4 In vitro dissolution profile of the minigranules of examples 1, 2a, 2b and 2c up to 24 hours.

Following the same protocol as described in Example 3, a dissolution profile was created for the minigranules of Examples 1, 2a, 2b, 2c and the bare core of Example 1 in 24 hours.

In addition to aliquot samples taken at the time points mentioned in Example 3, samples were also taken from each of the dissolution tests at 6, 12, 18 and 24 hours. Each sample taken from the dissolution tests was analyzed for cyclosporin A using reversed -phase HPLC with detection in the ultraviolet region of the spectrum at 210 nm.

As in Example 3, the release profile of each dissolution test was plotted and the release profiles are shown in FIG. 2.

From the release profiles in FIG. 2 shows that the presence of the HPMC coating significantly improves the release of cyclosporine compared to the uncoated core. Not only is the cyclosporin released more quickly during the first 2 hours, but the presence of the HPMC coating also keeps the cyclosporin in solution in the water dissolution medium.

Example 5 Preparation of a minigranule with a first hydroxypropylmethylcellulose coating and a second ethylcellulose/pectin coating.

The core was prepared and then coated with Opadry with a first coating (also called inner coating) according to the procedure of example 1. The minigranule obtained using the procedure of example 1 was then additionally coated with a second coating (also called outer coating) of a mixture of Surelease® (ethyl cellulose dispersions) and pectin.

The outer coating of Surelease®/pectin was applied using the following procedure. Pectin was added to purified water in a stainless steel tank and mixed to form a solution. Surelease® was slowly added to the tank while maintaining mixing to ensure the required concentration of pectin in Surelease® for the outer coating. The resulting coating slurry was then applied to the surface of the internally coated minigranules using a coating method similar to that described for the Opadry coating in Example 1 until the desired Surelease®/pectin weight gain was achieved. The outer coated minigranules were then dried in a coater for one hour at 40-45°C.

Received a number of minigranules with different levels of Opadry and different levels of Surelease®/pectin. In table. 5 shows the percent weight gain with Opadry and the percent weight gain with Surelease®/pectin for the resulting minigranules.

- 70 040614

Table 5

% weight gain due to Opadry % Weight Gain with Surelease/Pectin Example 5a no data 9% Example 5b 2.7% eleven% Example 5c 6.3% eleven% Example 5d 10% eleven% Example 5e no data 5% Example 5f 2.6% 4.6% 5g example 11.9% 5.4% Example 5h no data 21.3% Example 51 10.6% 23.3% Example 5j 15.5% 23.1%

Examples 5a, 5e and 5h lack the Opadry coating. They provide coating of the core described in example 1, using Surelease®/pectin, described above.

Minigranules of examples 5a-5j have the compositions shown in table. 6.

Table 6

Component Example 5a Example 5d Example 5s Example 5b Example 5h Example 51 Example % mass/mass Cyclosporine A 9, 9 8.8 9, 2 9.5 8.9 7.9 7, 6 Miglyol 810 N 4.2 3, 8 3, 9 4.0 3, 8 3.4 3.2 Transcutol HP 15, 1 13.4 13, 9 14.4 13.5 12.0 11.5 Kolliphor EL 8.4 7, 6 7.8 θ, 1 7, 6 6, 8 6, 5 SDS 3, 7 3.3 3.4 3, 5 3.3 thirty 2, 8 Sorbitol 5, 2 4.7 4.8 50 4.7 4.2 4.0 Gelatin 45.2 40.3 41.8 43.2 40.6 36, 1 34.6 Opadry No data 8.2 5, 3 2.4 No data 7.8 10, 9 Surelease (contents solid substances) 8, 1 9, 7 9, 7 9, 7 17.2 18.4 18.5 Pectin 0.2 0.2 0.2 0.2 0.4 0.4 0.4

- 71 040614

Table 6 (continued)

Component Example 5e Example 5 f % w/w 5g example Cyclosporin A 10.3 10.1 9, 2 Miglyol 810N 4.4 4.3 3, 9 Transcutol HP 15, 6 15, 3 13, 9 Kolliphor EL 8, 8 8, 6 7.8 SDS 3, 8 3.7 3.4 Sorbitol 5, 4 5, 3 4.8 Gelatin 46.9 45.9 41.8 Opadry no data 2.4 10.1 Surelease (contents solids) 4.7 4.3 50 Pectin 0, 1 0, 1 0, 1

Example 6 In vitro dissolution profile of the minigranules of examples 5a-5d.

In vitro dissolution profiles of a sample of the minigranules prepared in Examples 5a-5d were measured using the following two step dissolution test. Dissolution testing was performed according to USP <711> Dissolution using Apparatus II (paddle apparatus) operated at a paddle speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C. In the first stage of the test, the dissolution medium was 750 ml of 0.1 N HCl with imitation of the pH of the intragastric medium. At the beginning of the test (t=0), the sample was placed in the dissolution medium. After 2 hours, an aliquot of the medium was taken for subsequent analysis and immediately began (preferably within 5 minutes) the second stage of the dissolution test. In the second step, 250 ml of 0.2M tribasic sodium phosphate containing 2% sodium dodecyl sulfate (SDS) was added to the dissolution medium and the pH was adjusted to 6.8±0.05 using 2N NaOH or 2N HCl as needed.

Samples of the dissolution medium were taken at the following time points during the second stage of the test: 4, 6, 12 and 24 hours after the start of the test (ie from t=0 at the beginning of the first stage).

A sample taken at the end of the first step (2 hours) and samples from the second step were analyzed for cyclosporin A using reverse phase HPLC with ultraviolet detection at 210 nm.

The amount of dissolved cyclosporine A in the dissolution medium is expressed as a percentage based on the initial content of cyclosporine in the test formulation (percent release). The percent release values represent the release profile when plotted against time, and the release profile for each of the minigranule samples from Examples 5a-5d is shown in FIG. 3.

From the release profiles in FIG. 3, it is clear that the presence of the HPMC inner coating improves the release profile compared to the uncoated minibead of example 5a. Minibeads containing an internal coating of HPMC, give a higher percentage of release of cyclosporine from minibeads than from uncoated minibeads. The same relationship between percent release of cyclosporine from inner coated and uncoated minigranules can be seen in the release profiles in FIG. 4.

Example 7 In vitro dissolution profile of the minigranules of examples 5e-5g.

Following the procedure described in Example 6, a release profile was created for each of the minibeads of Examples 5e-5g. These release profiles are shown in FIG. 4. In FIG. 4 shows that the effect seen in FIG. 3 also occurs when using an inner-coated pellet with a lower level of Surelease/pectin.

Example 8 In vitro dissolution profile of the minigranules of examples 5h-5j.

Following the procedure described in Example 6, a release profile was created for each of the minibeads of Examples 5h-5j. These release profiles are shown in FIG. 5. In FIG. 5 shows that the effect seen in FIG. 3 and 4 also occurs when using an internally coated pellet with a higher level of Surelease/pectin.

Example 9 Preparation of additional minigranules with a first coating of hydroxypropylmethylcellulose and a second coating of ethylcellulose/pectin.

Example 5 describes the use of Opadry White to provide a hydroxypropyl methylcellulose interior coating. Next will be described the preparation of additional hydroxypropyl methyl cellulose first coated and ethyl cellulose/pectin second coated minigranules using Methocel E5 (available from Colorcon Limited) as hydroxypropyl methyl cellulose.

Minigranules were prepared in the same way as in Example 5, except that Methocel E5 was used for the first coating (inner coating) instead of Opadry White.

Received a number of minigranules with different levels of Methocel E5 and different levels of Surelease®/pectin. In table. 7 shows the percent weight gain with Methocel E5 and the percent weight gain with Surelease®/Pectin for the resulting minigranules.

Table 7

% weight gain due to Methocel E5 % Weight Gain with Surelease/Pectin Example 9a no data 9% Example 9b 3% eleven% Example 9c 5.3% eleven%

Example 9a lacks the Methocel E5 coating. It provides coating of the core described in example 1 with Surelease®/pectin described above.

Minigranules of examples 9a-9c have the compositions shown in table. 8.

Table 8

Component Example 9a Example 9b Example 9c % mass/mass Cyclosporin A 9, 9 9, 4 9, 2 Miglyol 810 N 4.2 4.0 4.0 Transcutol HP 15, 1 14.4 14.1 Kolliphor EL 8.4 8, 1 7.9 SDS 3.7 3, 5 3.4 Sorbitol 5, 2 50 4, 9 Gelatin 45.2 43, 1 42, 1 Methocel E5 no data 2, 6 4.5 Surelease (solids content) 8.1 9, 7 9, 7 Pectin 0.2 0.2 0.2

Example 10 In vitro dissolution profile of the minigranules of examples 9a-9c.

In vitro dissolution profiles of a sample of the minibeads prepared in Examples 9a-9c were measured using the dissolution test method described in Example 6. The release profile for each of the minibeads of Examples 9a-9c is shown in FIG. 6.

In FIG. 6 shows that when using Methocel as an internal coating, the same result was obtained as when using Opadry as an internal coating.

Example 11 Comparison of in vitro dissolution profiles of examples 5a-5d and examples 9b-9c.

In FIG. 7 shows the release profile of each of Examples 5a-5d and 9b-9c. As mentioned above, in FIG. 6 shows that with the Methocel inner coated minigranules, the same effect is observed as with the Opadry inner coated minigranules. In addition, if the release profiles obtained with the Methocel inner-coated minigranules were plotted against the release profile of the Opadry inner-coated beads as in FIG. 7, it can be seen that the Methocel inner-coated minigranules and the Opadry inner-coated minigranules give exactly matched release profiles.

Example 12 Preparation of mesalamine-containing minigranules with a first coating of hydroxypropylmethylcellulose and a second coating of ethylcellulose/pectin.

Mesalamine-containing minigranules were prepared as described in Example 5, except that the cores were prepared by hand instead of passing the mixture through a vibratory nozzle. In addition, cyclosporine was replaced by mesalamine, and the oil phase formed during the process of obtaining the core (described in example 1) did not form a solution, mesalamine remained in suspension.

This procedure generated three samples of minibeads with different levels of Opadry and

- 73 040614 different levels of Surelease®/neKTUHa. In table. 9 shows the percent weight gain with Opadry and the percent weight gain with Surelease®/pectin for the resulting minigranules.

Table 9

% weight gain due to Opadry % Weight Gain with Surelease/Pectin Example 12a no data 10.5% Example 12b 5% 12% Example 12c 12% 11.5%

Example 12a lacks the Opadry coating. It provides for coating the core described in example 1 with Surelease®/pectin as described above.

Minigranules of examples 12a-12c have the compositions shown in table. 10.

Table 10

Component Example 12a Example 12b Example 12c % mass/mass Mesalamine 9.0 8.4 7, 9 Miglyol 810 N 4.7 4.4 4.2 Transcutol HP 13.7 12, 9 12.1 Kolliphor EL 7.5 7.0 6, 6 SDS 3.5 3.3 3, 1 Sorbitol 50 4.7 4.4 Gelatin 47.2 44.4 41.8 Opadry no data 4.3 9, 6 Surelease (solids content) 9.2 10, 4 10.1 Pectin 0.2 0.2 0.2

Example 13 In vitro dissolution profile of the minigranules of examples 12a-12c.

In vitro dissolution profiles of a sample of the minigranules prepared in Examples 12a-12c were measured using the dissolution test method described below: 0.05 M pH 7.5 phosphate buffer prepared by dissolving 6.8 g potassium dihydrogen phosphate and 1 g sodium hydroxide in water to make a 1000 ml solution and adjust with 10N sodium hydroxide to pH 7.5±0.05, 900 ml were used.

Apparatus 2 USP with paddle speed 75 rpm.

The temperature of the dissolution medium: 37±0.5°C.

The release profile for each of the minibeads of Examples 12a-12c is shown in FIG. 8.

Example 14 Preparation of Hydralazine HCl containing minigranules with a first coating of hydroxypropylmethylcellulose and a second coating of ethylcellulose/pectin.

Coated minigranules containing hydralazine HCl were prepared by coating a core containing hydralazine HCl. Hydralazine HCl is a hydrophilic API, its solubility in water is approximately 8 g/l (ie 0.8%), however, it was found that the API was completely dissolved in the aqueous phase of the composition when heated at 60-70°C.

Core manufacturing.

Cores in the form of whole mini-granules were prepared manually as follows.

The aqueous phase was prepared by adding sodium dodecyl sulfate (SDS) and D-sorbitol to purified water with constant stirring until a solution was obtained. Hydralazine HCl and gelatin were then added to this solution and heating to approximately 60-70° C. was carefully applied to achieve complete melting of the gelatin. Stirring was continued until a clear solution was obtained.

The composition of the aqueous phase is shown in table. eleven.

- 74 040614

Table 11

The oil phase was prepared by mixing together 2-(2-ethoxyethoxy)ethanol (Transcutol HP), polyethoxylated castor oil (Kolliphor EL) and capric/caprylic acid triglyceride (Miglyol 810) with stirring at room temperature until a solution was formed. The composition of the oil phase is given in table. 12.

The oil phase was emulsified with the heated water phase in a ratio of approximately 1:12 (oil phase:water phase). The resulting mixture was stirred at 60-70° C. until homogeneous. The composition of the emulsion is shown in table. 13.

The resulting mixture was then manually pushed through the hole into a medium chain triglyceride (Miglyol 810) cooling oil cooling chamber at a temperature of 4-10°C. The minigranules were removed from the cooling oil and dried at room temperature for 24 h.

The composition of the nuclei is shown in table. 14.

Table 14

Components % mass/mass Hydralazine HC1 10.4 Transcutol HP 13.7 Miglyol 810N 3.7 Kolliphor EL 7.4 Gelatin 54.8 D-sorbitol 6.0 SDS 4.0

The cores obtained using the procedure described in this example were covered with Opadry White 20A28380 (supplied by Colorcon) in the same way as described in example 1, if necessary. Cores were coated directly or coated with Opadry cores were coated with Surelease/pectin as needed, as described in Example 5. Six sets of mini-beads with different levels of Opadry and different levels of Surelease®/pectinα were prepared according to this procedure. In table. 15 shows the percent weight gain with Opadry and the percent weight gain with Surelease®/pectinα for the resulting minigranules.

- 75 040614

Table 15

% weight gain due to Opadry % Weight Gain with Surelease/Pectin Example 14a no data eleven% Example 14b 6.4% 10.8% Example 14c 11.5% 11.1% Example 14d no data 17.7% Example 14e 6.4% 17.9% Example 14f 11.5% 16.6%

Examples 14a and 14d lack the Opadry coating. They provide coating of the core described in example 1, using Surelease®/pectin, described above.

Minigranules of examples 14a-14f have the compositions shown in table. 16.

Table 16

Component Example 14a Example 14b Example 14s Example 14d Example 14th Example 14f % mass/mass Hydralazine 9, 4 8.8 8.4 8.8 8.3 8.0 Miglyol 810 N 3, 4 11, 6 11.1 11.7 10, 9 10.5 Transcutol HP 12.3 3, 1 thirty 3, 1 thirty 2.9 Kolliphor EL 6, 7 6, 3 6.0 6, 3 5, 9 5, 7 SDS 3, 6 46.5 44.2 46.6 43.7 42, 1 Sorbitol 5, 4 5, 1 4.8 5, 1 4.8 4, 6 Gelatin 49.4 3.4 3.2 3.4 3.2 3, 1 Opadry No data 5, 4 9, 3 No data 5, 1 8.9 Surelease (solid content) 9, 9 9, 8 100 15.0 15, 1 14.2

Example 15 In Vitro Dissolution Profile of the Minibeads of Examples 14a-14f.

In vitro dissolution profiles of a sample of the minibeads prepared in Examples 14a-14f were measured using the dissolution testing method described in Example 13. The release profile for each of the minibeads of Examples 14a-14f is shown in FIG. 9.

The release profile in FIG. 9 shows the same effect as seen in the previous examples - increased percent release of hydralazine active ingredient from HPMC inner coated minigranules compared to uncoated minigranules with comparable levels of Surelease/pectin. For example, a comparison between non-inner coated example 14a and inner coated example 14c demonstrates the effect of a higher release percentage with an HPMC inner coating. The same can be said about comparing example 14d with example 14f.

Example 16 Preparation of celecoxib containing minigranules with a first coating of hydroxypropylmethylcellulose and a second coating of ethylcellulose/pectin.

Coated minigranules containing celecoxib were prepared by coating a core containing celecoxib. Celecoxib is a hydrophobic API.

Core manufacturing.

Cores in the form of whole mini-pellets were obtained manually, as described below.

The aqueous phase was prepared by adding sodium dodecyl sulfate (SDS) and D-sorbitol to purified water with constant stirring until a solution was obtained. Then gelatin was added to this solution and

- 76 040614 carefully applied heating to approximately 60-70°C to achieve complete melting of the gelatin. Stirring was continued until a clear solution was obtained.

The oil phase was prepared by mixing macrogol hydroxystearate (Kolliphor HS-15) together with celecoxib. The mixture was stirred at room temperature to form a solution.

The oil phase was emulsified with the heated aqueous phase in a ratio of approximately 1:3 (oil phase:water phase). The resulting mixture was stirred at 60-70° C. until homogeneous.

Then the resulting mixture was manually pushed through the hole into the cooling chamber of the cooling oil with medium chain triglyceride (Miglyol 810) at a temperature of 10°C. The minigranules were removed from the cooling oil and dried at room temperature for 24 h.

Cores obtained using the procedure described in this example were coated with Opadry White 20A28380 (available from Colorcon) in the same way as described in example 1, and then coated with Surelease as described in example 5. The cores were also coated directly (t .e. in the absence of a coating of Opadry) using Surelease in a manner similar to that described in example 5. In table. 17 shows the composition of the mini-beads coated with 27% weight gain with Surelease® without inner coating from Opadry (un-coated mini-beads). In table. 18 shows the composition of mini-beads coated with 10% Opadry internal coating and 27% weight gain with Surelease® (internal coated mini-granules).

Table 17

27% increase masses of Surelease compound (without internal coating) Component % mass/mass Celecoxib 4.8 Kolliphor HS-15 43.0 Gelatin 24.9 SDS 3.3 D-sorbitol 2.8 Surelease 21.2

Table 18

27% increase weight of Surelease compound (10% Opadry internal coating) Component % mass/mass Celecoxib 4.4 Kolliphor HS-15 39, 8 Gelatin 23, 1 SDS 3.1 D-sorbitol 2.5 Opadry 7.3 Surelease 19, 7

Example 17 In Vitro Dissolution Profile of the Minibeads of Examples 16

The in vitro dissolution profiles of a sample of the minigranules prepared in Example 16 were measured using the dissolution testing method described below.

In vitro release was measured using a two step in vitro dissolution test in which the formulation was subjected to 0.1 N HCl for 2 h to mimic intragastric pH and then subjected to pH 6.8 for twenty 2 h (by adding enough 0 .2 M tribasic sodium phosphate solution with or without 0.05% sodium dodecyl sulfate (SDS) to mimic pH in the small intestine and lower gastrointestinal tract. An in vitro test using Apparatus II (apparatus with a paddle) was performed with a paddle speed of 75 rpm and with a dissolution medium at a temperature of 37±0.5°C. Aliquots of media were taken for analysis at 1, 2, 4, 6, 12 and 18 hours. Aliquots were analyzed for celecoxib using a high performance liquid chromatography (HPLC) method. From the area under the curve (according to the HPLC method), the percentage of drug release at specific time points was calculated.

Both inner-coated and non-inner coated mini-beads were tested using the SDS-free dissolution test described above and the mini-beads with

- 77 040614 internal coating was also tested using a dissolution test with 0.05% SDS. The release profile for each of the example 16 minigranules is shown in FIG. 10.

The release profile in FIG. 10 demonstrates the same effect as seen in the previous examples, an increased final percent release of celecoxib active ingredient from HPMC inner coated minibeads compared to uncoated minibeads with comparable Surelease levels.

Example 18 In vitro dissolution profile of minigranules from different lots.

Minibead cores were prepared according to the procedure described in Example 1. From these cores, three sets of minibeads coated with both an inner coat of Opadry and an outer coat of Surelease/pectin were made, and three sets of Surelease/pectin coated minibeads were made. Three samples with both Opadry inner coating and Surelease/pectin outer coating had the amount of coating corresponding to 5% weight gain with Opadry and 11.5% weight gain with Surelease/pectin. Three samples coated with Surelease/pectin only had an amount of coverage corresponding to a 9% weight gain due to Surelease/pectin. Compositions of minigranules coated with Opadry and without inner coating with Opadry are shown in Table 1. 19.

Table 19

Component with internal coating (%) without internal coating (%) Cyclosporin A 9, 2 9, 9 Miglyol 810 N 3, 9 4.2 Transcutol HP 14.0 15, 1 Kolliphor EL 7.9 8.4 SDS 3.4 3.7 Sorbitol 4.9 5, 2 Gelatin 42.1 45.2 Opadry 4.3 no data Surelease (solid content) 10.1 8.1 Pectin 0.2 0.2

The dissolution profile of these six samples of minibeads was tested using the dissolution test protocol of Example 6 to obtain the dissolution profile shown in FIG. eleven.

In FIG. 11 shows the wide variation in release profiles for samples of uncoated HPMC minibeads, with percentage release after 12 hours ranging from 48 to 63% and after 24 hours they range from 61 to 83%. In contrast to the results obtained for the non-HPMC inner-coated mini-beads, the HPMC inner-coated mini-beads show very little variation in percentage release between batches.

Example 19 Coating thickness measurement.

The minibead obtained according to the procedure disclosed herein was examined under a scanning electron microscope (SEM). The minigranule had a first coat of Opadry with a 10% weight gain and a second coat of Surelease/Pectin (98:2 ratio) with a 11% weight gain. The mini-bead was cut in half through the widest point of the mini-bead. The cross-sectional surface of the pellet was then examined under SEM. In FIG. 12 shows a cross-sectional SEM image of a minibead, and FIG. 13 is an enlarged version of the image of FIG. 12. In FIG. 13 clearly shows the difference between the first coating and the second coating. From the SEM image, it can be determined that the thickness of the first coating was 41 µm and the thickness of the second coating was 40 µm.

Example 20 Minigranule Compositions

Minigranules with the compositions shown in table. 21 was obtained using a method similar to that described in example 1 called Making the core, except that the ratio of the oil phase to the aqueous phase was 1:5 in the compositions of table. 21. Mixing the oil phase and the aqueous phase resulted in a liquid mixture with the composition shown in table. 20. Surfactant table. 20 was one of the surfactants shown in table. 22. Minigranules with the composition of table. 21 received with all surfactants table. 22 with the exception of labrafil M 1944 CS. It is contemplated that the minigranules can be formulated with a liquid composition containing LabrafilM 1944 CS by varying the ratio of oil to water phase or by increasing the viscosity of the liquid composition.

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Claims (53)

Table 20 Component % mass/mass Cyclosporine 4, 1 Transcutol HP 6, 2 Surface-active substance* 4.3 Miglyol 810 2, 1 Gelatin type A 14.3 Sorbitol 1.7 SDS eleven Purified water 66.2 Table 21 Component % mass/mass Cyclosporine 12.1 Transcutol HP 18.3 Surface-active substance* 12, 9 Miglyol 810 6, 2 Gelatin type A 42.3 Sorbitol 50 SDS 3.2 In table. 22 shows the surfactants of the compositions of table. 20 and 21. The table also shows the results of a crystallization test performed on liquid compositions containing each of the surfactants. Crystallization test. Emulsions were obtained with the composition disclosed in table. 20, for each of the surfactants listed in table. 22, with agitation at 250-350 rpm. Emulsion samples were taken at 30 minute intervals and viewed under a microscope at 50x or 100x magnification. The time of occurrence of crystals in the sample is shown in table. 22. Table 22 Surface-active substance HLB Crystallization period (hours) Span 85* 1.8 3 LabrafilM 1944 CS 4 1 span 40* 6, 7 1.5 Plurol Oleique SS 497 6 1 LabrafilM 2130 CS 4 0.5 Cremophor EL 14 0.5 CLAIM 1. A pharmaceutical composition containing a core and a first coating, where the core is in the form of a solid colloid containing a continuous phase and a dispersed phase, while the continuous phase contains a hydrogel-forming polymer matrix and the pharmaceutically active ingredient is in solution or suspended in the dispersed phase, and the forming the hydrogel polymer matrix contains a thermoreversible hydrogel-forming polymer, where the coating contains a water-soluble cellulose ether and the coating is present in an amount corresponding to an increase in weight due to the coating by 1-15% of the core weight and has a thickness of 1 to 500 microns. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a second coating containing a delayed release polymer. - 79 040614 3. Pharmaceutical composition according to claim 2, wherein the first coating is in contact with the core. 4. The pharmaceutical composition of claim 2 wherein the second coating is on top of the first coating. 5. A pharmaceutical composition according to any one of claims 2 to 4, wherein the delayed release polymer is selected from an enteric soluble polymer, a pH independent polymer, a pH dependent polymer, and a polymer particularly susceptible to degradation by bacterial enzymes in the gastrointestinal tract, or a combination of the two. or more such polymers. 6. A pharmaceutical composition according to any one of claims 2 to 5, wherein the delayed release polymer is water-soluble or water-permeable in an aqueous medium with a pH greater than 6.5. 7. Pharmaceutical composition according to claims 2 to 6, wherein the delayed release polymer contains a pH-independent polymer, such as ethyl cellulose. 8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the water-soluble cellulose ether is selected from any one or combination of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, and hydroxypropylmethylcellulose. 9. The pharmaceutical composition of claim 8, wherein the water-soluble cellulose ether is hydroxypropyl methylcellulose. 10. The pharmaceutical composition according to claims 1 to 9, wherein the pharmaceutically active ingredient is a hydrophobic pharmaceutically active ingredient or a hydrophilic pharmaceutically active ingredient. 11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the hydrogel-forming polymer matrix contains a hydrocolloid selected from carrageenan, gelatin, agar and pectin or a combination thereof, preferably selected from gelatin and agar or a combination thereof, more preferably a hydrogel-forming polymer matrix. matrix, is or contains gelatin. 12. The pharmaceutical composition of claim 10 or 11, wherein the hydrogel-forming polymer further comprises a plasticizer such as a plasticizer selected from glycerol, a polyhydric alcohol such as sorbitol, polyethylene glycol and triethyl citrate, or mixtures thereof, preferably sorbitol. 13. A pharmaceutical composition according to any one of claims 1 to 12, wherein the active ingredient is encapsulated in a hydrogel-forming polymer matrix. 14. Pharmaceutical composition according to claim 1, where the dispersed phase contains a hydrophobic phase. 15. Pharmaceutical composition according to claim 1, where the dispersed phase contains a liquid lipid and optionally miscible solvent. 16. The pharmaceutical composition of claim 14, wherein the dispersed phase comprises a glyceride composition, wherein optionally the dispersed phase is or contains a monoglyceride, diglyceride, or fatty acid triglyceride, or a combination thereof, or the dispersed phase contains a caprylic/capric acid triglyceride composition. 17. Pharmaceutical composition according to any one of claims 1 and 14, 15, where the dispersed phase contains an oil selected from vegetable oil and oil derived from petroleum. 18. Pharmaceutical composition according to any one of claims 1 and 14, 15, wherein the dispersed phase contains a polyunsaturated fatty acid selected from ω-3 oils, such as eicosapentaenoic acid, docosahexaenoic acid, α-linoleic acid and conjugated linoleic acid. 19. Pharmaceutical composition according to any one of claims 1 and 14, 15, where the dispersed phase contains an oil selected from olive oil, sesame oil, coconut oil, palm kernel oil and margosa seed oil. 20. A pharmaceutical composition according to any one of claims 1 and 14, 15, wherein the dispersed phase comprises an oil phase selected from caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride, caprylic/capric/succinic triglyceride and propylene glycol dicaprylate/dicaprinate. 21. Pharmaceutical composition according to any one of claims 1 and 14, 15, where the dispersed phase contains an oil phase selected from linoleyl macrogol glycerides (polyoxyl glycerides) and caprylocaproyl macrogol glycerides. 22. Pharmaceutical composition according to any one of claims 1 and 14-21, where the dispersed phase contains an oil phase with an HLB value from 0 to 10. 23. Pharmaceutical composition according to any one of claims 1 and 14-21, where the dispersed phase further comprises a solvent, where the solvent is miscible with the dispersed phase and water, where preferably the solvent is selected from 2-(2-ethoxyethoxy)ethanol and polyethylene glycol, more preferably the solvent is 2-(2-ethoxyethoxy)ethanol. 24. The pharmaceutical formulation of claim 23 wherein the solvent comprises a poly(ethylene glycol) selected from a PEG with an average molecular weight of about 200 to about 400, such as PEG 200 or PEG 400. 25. Pharmaceutical composition according to any one of claims 1 and 14-24, wherein the dispersed phase contains an oil phase which constitutes 10-85%, preferably 20-30%, of the dry weight of the core. 26. The pharmaceutical composition according to claim 1, where the dispersed phase contains an oil phase containing - 80 040614 medium chain triglyceride, polyethoxylated castor oil and 2-(ethoxyethoxy)ethanol. 27. The pharmaceutical composition according to claim 1, where the active ingredient is a hydrophobic active ingredient and is in solution in the dispersed phase; or is a hydrophilic active ingredient and is suspended in the discontinuous phase. 28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the core further comprises a surfactant, such as an anionic surfactant, preferably selected from alkyl sulfates, carboxylates, or phospholipids, or a nonionic surfactant, preferably selected from sorbitan surfactants, PEG fatty acids or glyceryl fatty acids, or poloxamers, or combinations thereof. 29. The pharmaceutical composition according to any one of claims 1 and 14-28, wherein the core further comprises a surfactant present at least in the continuous phase, the surfactant having an HLB value of at least 10, preferably more than 20. 30. The pharmaceutical composition of claim 29 wherein the surfactant in the continuous phase is an anionic surfactant such as at least one surfactant selected from fatty acid salts and bile salts, preferably an alkyl sulfate such as sodium dodecyl sulfate. 31. Pharmaceutical composition according to any one of claims 1 and 14-30, wherein the dispersed phase contains a non-ionic surfactant. 32. Pharmaceutical composition according to any one of claims 1 and 14-31, where the dispersed phase additionally contains a surfactant with an HLB value in the range of 1-20, preferably 1-15, 110, 10-20, 10-15, 1- 5. 33. The pharmaceutical composition according to any one of claims 1 and 14-31, wherein the continuous phase contains a hydrogel-forming polymer matrix and the dispersed phase contains an oil phase containing an oil and a surfactant, where the oil and surfactant are both characterized by an HLB value of range 0-10. 34. The pharmaceutical composition of claim 33 wherein the oil has an HLB value in the range of 1-5 and the surfactant has an HLB value in the range of 2-8, preferably 3-7, 2-6 or 3-4. 35. The composition according to any one of claims 31-34, wherein the surfactant comprises a surfactant selected from fatty acid glycerides, polyethylene glycol fatty acid esters, propylene glycol fatty acid esters, fatty acid lactic acid ester , sucrose fatty acid esters, sorbitan fatty acid esters, polyethylene glycol fatty alcohol esters, block copolymers of ethylene oxide, propylene oxide and polyoxyethylene ethers; preferably the surfactant comprises a surfactant selected from fatty acid glycerides, polyethylene glycol fatty acid esters, propylene glycol fatty acid esters, fatty acid lactic acid esters or sucrose fatty acid esters; or where the surfactant comprises a surfactant selected from fatty acid glycerides, polyethylene glycol fatty acid esters, propylene glycol fatty acid esters, and fatty acid lactic acid esters; or where the surfactant contains a fatty acid glyceride; where the surfactant contains an ester of sorbitan and a fatty acid, such as a mono-, di - or triester of sorbitan and a fatty acid. 36. The composition according to any one of claims 31 to 34, wherein the surfactant is selected from oleoyl macrogol glyceride, lyenoyl macrogol glyceride, lauroyl macrogol glyceride, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monoheptanoate, propylene glycol monocaprylate, propylene glycol dicaprylocaprate; polyethylene glycol cetyl ether, polyethylene glycol stearyl ether, polyethylene glycol oleoyl ether, polyethylene glycol lauryl ether and polyoxyethylene octylphenyl ether; sorbitan trioleate, sorbitan monopalmitate, sorbitan laurate, sorbitan palmitate, sorbitan stearate, sorbitan oleate, sorbitan anisstearate, and sodium stearoyl-2-lactylate. 37. The composition according to any one of claims 31-34, where the surfactant is selected from sorbitan trioleate (Span 85), sorbitan monopalmitate (Span 40); polyglyceryl-3-dioleate (Plurol Oleique CC 497) and oleoylmacrogol-6-glycerides (Labrafil M1944CS); preferably the surfactant is selected from sorbitan trioleate (Span 85) and sorbitan monopalmitate (Span 40). 38. The composition according to any one of claims 33-37, wherein the oil phase contains a triglyceride selected from caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride and caprylic/capric/succinic triglyceride. 39. The pharmaceutical composition according to claim 1, where the dispersed phase contains an oil phase selected from - 81 040614 caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride, caprylic/capric/succinic triglyceride, propylene glycol dicaprylate/dicaprynate and polyethoxylated castor oil. 40. The pharmaceutical composition according to any one of claims 2-39, wherein the second coating further comprises a blowing agent. 41. The pharmaceutical composition of claim 1, wherein the discontinuous phase contains a pharmaceutically active ingredient such as cyclosporine, hydralazine or mesalamine; a medium chain mono-, di-, or triglyceride such as caprylic/capric triglyceride; a non-ionic surfactant such as polyethoxylated castor oil; and a solvent such as 2-(ethoxyethoxy)ethanol; and the continuous phase contains an anionic surfactant such as at least one surfactant selected from fatty acid salts, alkyl sulfates and bile salts, preferably an alkyl sulfate such as sodium dodecyl sulfate; a hydrogel-forming polymer matrix that contains a hydrocolloid selected from carrageenan, gelatin, agar and pectin or a combination thereof, preferably selected from gelatin and agar or a combination thereof, more preferably the hydrogel-forming polymer matrix polymer contains gelatin; and optionally a plasticizer such as a plasticizer selected from glycerol, a polyol such as sorbitol, polyethylene glycol and triethyl citrate, or a mixture thereof, preferably sorbitol. 42. Pharmaceutical composition according to any one of claims 1-40, where the core contains a hydrogel-forming polymer containing gelatin in an amount of 300-700 mg/g, and the core additionally contains mono-, dior triglycerides with an average chain length in an amount of 20-200 mg /g and the pharmaceutical composition additionally contains the following components: co-solvent in the amount of 150-250 mg/g; non-ionic surfactant in the amount of 80-200 mg/g; anionic surfactant in the amount of 15-50 mg/g. 43. A pharmaceutical composition according to any one of claims 1 to 42, wherein the composition is in the form of a mini-granule. 44. A pharmaceutical composition according to any one of claims 1-43, wherein the largest cross-sectional dimension of the core is from about 0.01 mm to about 5 mm. 45. A pharmaceutical composition containing a plurality of minigranules according to any one of claims 43, 44. 46. A pharmaceutical composition according to any one of claims 1 to 45, wherein the composition is for oral administration. 47. The pharmaceutical composition according to any one of claims 1 to 46, where the core is formed by mixing the dispersed phase with a continuous phase to obtain a colloid, where the continuous phase is an aqueous phase containing a hydrogel-forming polymer, and the dispersed phase is a hydrophobic phase, where pharmaceutically the active ingredient is in the dispersed phase where the colloid thickens to form a nucleus. 48. The pharmaceutical composition according to claim 47, where the core contains a hydrogel-forming polymer matrix and a hydrophobic phase dispersed in a hydrogel-forming polymer matrix, where the core contains gelatin, SDS, sorbitol, polyethoxylated castor oil, caprylic/capric triglyceride, 2-(ethoxyethoxy) ethanol; and where the aqueous phase (i) contains gelatin, sorbitol and SDS and the dispersed phase (ii) contains polyethoxylated castor oil, caprylic/capric triglyceride, 2-(ethoxyethoxy)ethanol and cyclosporin A. 49. The pharmaceutical composition according to any one of claims 1 to 48, formulated as a unit dosage form for oral administration containing from 0.1 to 1000 mg, from 1 to 500 mg, from 10 to 300 mg or from 25 to 250 mg, about 25 mg, about 35 mg, about 75 mg, about 180 mg, about 210 mg or about 250 mg of the active ingredient. 50. The pharmaceutical composition according to any one of claims 1 to 49, wherein the active ingredient is an immunosuppressant, a hydroxylase inhibitor or an anti-inflammatory agent, preferably the active ingredient is cyclosporin A, hydralazine or mesalazine or celecoxib. 51. The use of a pharmaceutical composition according to any one of claims 1 to 53 for treating a gastrointestinal condition, wherein the gastrointestinal condition is selected from inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, celiac disease, graft versus host disease, graft versus host disease of the gastrointestinal tract. intestinal tract, gastroenteritis, duodenitis, jeunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, pseudomembranous colitis, diverticulosis, diverticulitis, endometriosis, colorectal carcinoma and adenocarcinoma. 52. Use according to claim 51, wherein the gastrointestinal condition is ulcerative colitis. 53. The use of a pharmaceutical composition according to claim 1 for the treatment of conditions affecting the small intestine, such as celiac disease, GVHD or Crohn's disease. -