WO2007091059A1

WO2007091059A1 - Preparation and composition of a solid dosage form containing tacrolimus and/or sirolimus

Info

Publication number: WO2007091059A1
Application number: PCT/GB2007/000422
Authority: WO
Inventors: Ales Franc; Borek Zaludek; Roman Gonec; Ales Cirkva; Sabina Malovana; Anna Petrovicova
Original assignee: Pliva Hrvatska D.O.O.; Mcleish, Nicholas, Alistair, Maxwell
Priority date: 2006-02-08
Filing date: 2007-02-06
Publication date: 2007-08-16
Also published as: GB0602632D0

Abstract

A method is provided for preparing a solid dosage form comprising a water-insoluble medicinally active substance selected from tacrolimus and sirolimus, whereby the medicinally active substance is dissolved in an organic solvent, a mixture comprising at least one pharmaceutically acceptable carrier with swelling ability is then coated with the solvent containing the medicinally active substance, the solvent is evaporated, and the mixture is processed into a suitable solid dosage form.

Description

Preparation and Composition of a Solid Dosage Form Containing Tacrolimus and/or Sirolimus

The present invention relates to a method for preparing a solid dosage form comprising a water-insoluble medicinally active substance selected from tacrolimus and sirolimus. Furthermore, a solid dosage form comprising a water-insoluble medicinally active substance selected from tacrolimus and sirolimus is provided.

Tacrolimus (also known as tacrolim) and sirolimus (also known as sirolim) are highly effective immunosuppressives of macrolides group being isolated from Bacterium Streptomyces tsukubaensis. They are bonded to FKBP-12 immunofillin in T lymphocytes. The complex mentioned blocks calcineurin and thus inhibits a signal necessary for transcription of information for interleukin 2 formation. It inhibits IL-2 formation and thus hinders activation of T lymphocytes. Tacrolimus resorption after oral administration is rather variable; its concentration (C_max) in blood culminates within 1 - 3 hours in average. When administered orally (0.3 mg/kg/day) to patients after liver transplantation, the steady-state concentration was reached 3 days later in most of them. Tacrolimus is bonded to erythrocytes in blood. The ratio of 20:1 was established when plasma:whole blood binding ratio was determined. Erythrocytes: plasma distribution ratio is heavily dependant on hematocrit values, tacrolimus concentration and temperature. Tacrolimus in plasma is bonded to plasmatic proteins from 98.8%; it is largely distributed in a human organism. It is metabolized mostly in liver in which it shows high affinity to P450 3A liver cytochromal system, and particularly to the cytochrome P450 3A4. The elimination process is long and variable. Tacrolimus is eliminated from the organism particularly via faeces. Tacrolimus

It is a white crystalline powder from the physical-chemical point of view. Preferability it is used in the form of a monohydrate in the dosage forms. Chemical name: 15,19- Epoxy-3H-pyrido[2, 1-c][1 , 4]oxaazacyclotricosine-1 , 7,20,21 (4H.23H)- tetrone, 5,6,8,11 , 12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19- dihydroxy-3-[(1 E)-2-[(1 R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1- methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-, (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-(9CI) As tacrolimus and sirolimus are practically insoluble in water, it cannot be prepared in the solid dosage form without previous processing. The methods intended for the preparation of dosage forms aimed at increasing bioavailability of the medicinal substance from the dosage form, for example, formation of the solid dispersions, micelar solubilization or preparation of the soluble complexes with cyclodextrins, are therefore described in the technical and patent publications. The procedures mentioned are used for the preparation of various dosage forms of which oral capsules, ointments and injections are commercially available.

EP 240773 relates to a preparation of a solid dosage form containing tacrolimus with increased solubility in water whereby the solid dispersion contains tacrolimus and HPMC polymer soluble in water, at the ratio between 1 :0.5 and 1 :5, advantageously 1 :1. Tacrolimus is dissolved in an organic solvent; a polymer soluble in water is then added and, if necessary, a thickening agent in the form of a suspension which is then evaporated. A number of excipients are used.

EP 0943327 relates to the preparation of a solid dosage form containing tacrolimus with increased solubility in water in a mixture with a surfactant and a solid carrier. According to this procedure tacrolimus is dissolved in an organic solvent together with a surfactant and a polymer and, if necessary, thickened using the additive of other, hydrophilic polymers, after which the solvent is evaporated. The mixture mentioned is then processed using, for example, milling to obtain the suitable oral dosage form featuring with higher solubility in water and thus also with higher bioavailability. A number of surfactants, such as Tween, Cremophor, Sefsol, Miglyol, Pluronic, bile acids and sodium lauryl sulfate are mentioned as well as HPMC, HPC, HEC, MC, CMC, PVP, PEG as polymers and various saccharides.

Another way to prepare a solid dosage form containing tacrolimus is described in WO 00/53177. A preparation of liposomes is disclosed that contains pipecoline acid and its derivatives without the need to use cholesterol for the stabilization. The solution may be used for the injection and other - e.g., oral - administration. A further application, JP 7-242535, describes the preparation of a composition intended for oral administration in the form of solid gelatine capsules. The medicinal product is dissolved in propylene glycol and an additive enhancing absorption. The internal surface of the capsule is coated with the substance insoluble in propylene glycol, e.g. cellulose derivatives or, if necessary, acrylic acid derivatives. JP 6 - 183970 discloses the preparation of an OΛ/V (oil in water) type emulsion intended for injection, oral and other administration. The emulsion contains pharmaceutically acceptable solvents, as ethanol, propylene glycol, glycerine, etc., together with an oil- in-water type tenside. Isopropylmyristate, maize oil, sesame oil, soybean oil, etc. form the oily or hydrophobic constituent. The concentration of the active substance here is 0.01-10 mg/ml.

In the JP 2-310833 an aqueous solution is described in which the active substance is dissolved with a hydrotropic addition and tensids. The mixture of hydrogenated castor oil, glycerine monooleate, sodium salt of taurocholic acid and D- mannitol is then used in the final dosage form.

Further, studies are known from the literature (Hidetoshi A., et al., JPET, Vol. 297, Issue 2, 547-555, May 2001) where the increased solubility is reached via the formation of complexes with dimethyl-betacyclodextrines that dissolve tacrolimus and, in addition, ease the transport through intestinal carriers.

US 2004/254210 A1 relates to a formulation comprising tacrolimus whereby all ingredients are mixed after which the solvent is evaporated. In US 2004/198645 A1 a process for producing a pharmaceutical formulation is described whereby the drug is mixed with a surfactant in an organic solvent after which this mixture is spray-dried on to lactose. The US 2003/215496 discloses a formulation comprising tacrolimus or sirolimus, whereby the drug is sprayed on to beads or sugar particles. The WO 2005/004848 A1 relates to a formulation comprising tacrolimus, whereby tacrolimus is mixed into a solvent with a surfactant and then sprayed on to an additive without the function of a carrier, such as anhydrous dibasic calcium phosphate. According to the WO 02/38126 A1 a composition comprising an active ingredient is sprayed on to cores of glass.

The physical-chemical parameters of tacrolimus and sirolimus, particularly insolubility in water and low wettability, do not enable the formation of a solid dosage form that allows for the rapid release of tacrolimus or sirolimus. It is not easy to achieve a dosage form featuring a satisfactory rate of dissolution sufficient bioavailability without using special pharmaceutical technology, techniques that result in its solubilization or cosolubilization of tacrolimus and/or sirolimus.

The known methods used for the preparation of a formulation comprising tacrolimus consist in that tacrolimus is dissolved in an organic solution containing a hydrophilic polymer, if necessary, with the addition of a suitable surfactant accompanied with thickening compounds, most often polymers or saccharides. This organic solution moreover contains environmentally unacceptable, toxic dichloromethane for dissolving the polymer (HPMC). This is followed by expensive and time-consuming drying, then crushing or milling, which is expensive from the energetic point of view, and further mixing. Alternative methods such as the preparation of inclusive components or liposomes are very expensive, elaborate and time-consuming. In addition, tacrolimus and sirolimus need special handling as they are toxic substances.

It is therefore necessary to provide a formulation comprising tacrolimus and/or sirolimus which fulfils all the pharmaceutical requirements, in particular which has sufficient dissolution properties in order to ensure acceptable bioavailability. At the same time this formulation should be produced by a method which is easy to carry out, with as little steps as possible, efficient, cost saving and without the need of special equipment.

The above aim is solved by a method for preparing a solid dosage form comprising a water-insoluble medicinally active substance selected from tacrolimus and sirolimus and a combination thereof, whereby

- the medicinally active substance is dissolved in an organic solvent,

- a mixture comprising at least one pharmaceutically acceptable carrier with swelling ability is then coated with the solvent containing the medicinally active substance,

- the solvent is evaporated, and

- the mixture is processed into a suitable solid dosage form.

This inventive procedure eliminates complicated and costly handling; it is time undemanding, efficient and the active substance needs no substantial handling during the preparation: There is no need for environmentally unacceptable or toxic components. There is no milling since the solvent is applied onto carrier particles of required size after which the particles can be sieved. Furthermore, the drying is carried out under less harsh and aggressive conditions compared to the prior art methods since only the necessary amount of solvent is coated onto the carrier particles compared to mixing the carrier in liquid with the solvent. There are only a minimum steps necessary according to this process and no liposomes or other expensive additives are used compared to some prior art methods. The mixture shows excellent flow properties and may be used without any further processing. Furthermore it has been surprisingly shown that the formulation produced by this new method has unexpectedly a higher dissolution rate of the active substance compared to the known methods produced by conventional mixing in liquid phase.

In a first step the active substance is dissolved in an organic solvent. This organic solvent can be any suitable solvent well known to the person skilled in the art, preferably ethanol. It is important to dissolve the active substance homogeneously in order to be able to apply the active substance onto the carrier in a homogeneous way. Therefore, sufficient dissolution and mixing is advantageous.

The coating of the mixture comprising the carrier with the solvent can be carried out in any suitable way well known to the person skilled in the art. The main point is to apply the solvent in a homogeneous way without using liquid phase mixing. The coating may be carried out by spraying or enveloping, by using mist or fog chambers. The person skilled in the art will be able to select the appropriate method. None of the prior art documents mention the coating of a carrier with swelling ability with the active substance dissolved in an organic substance.

Preferably, the solvent is evaporated by increasing the temperature. The person skilled in the art will select the suitable method depending on the solvent. The evaporation is carried out in order to produce a dry product which is then further processed into a suitable dosage form. Drying temperature for carrying out this process is about 40 - 7O⁰C.

The suitable dosage form into which the mixture is processed is for example a tablet, capsule, bag, whereby the processing can be filling, pressing, and others. These methods are carried out according to conventional methods.

The inventive dosage form preferably comprises either tacrolimus or sirolimus or both together. However, it can also comprise one or more additional active substances.

The carrier used is one with swelling ability which means that the volume of the carrier is increased, e.g. the surface of the carrier increases thereby enhancing solubility. Preferably, the pharmaceutically acceptable carrier increases its volume when in contact with a liquid, preferably a liquid with a pH of under 7, still preferred with a pH from 1 to 5. An example of such a liquid is 0,1 M HCL with a pH of about 1. This carrier is advantageous since it will increase its volume once the solid dosage form reaches a liquid, in particular the gastric juice, and through this increase of volume of the carrier the active substance will be released from the surface of the carrier. Two advantages are achieved: first, the active substance is set free at the place where it will be active, e.g. the gastric region and second, a maximum amount of active substance is released immediately thereby increasing the dissolution rate of the active substance. With respect to the granule size, preferably 90% of the carrier has a particle size of lower than 300 microns (50 US mesh). Such carriers are well known to the person skilled in the art.

Preferably the solvent is continually evaporated during the coating of the mixture. This achieves a particularly homogeneous covering of the carrier with the active substance. Evaporation can be carried out by increasing the temperature during coating. One possibility is coating in a fluid bed.

Advantageously, the pharmaceutically acceptable carrier is crosscarboxymethylcellulose, ultraamylopectin and/or crosspolyvinylpyrrolidone. The mixture can comprise one, two, all of these carriers or even more. These carriers have the above requirement that their volume is increased when in contact with a liquid, in particular gastric juice and they have shown to be particularly useful for the inventive method and formulation.

According to a preferred embodiment the mixture comprises at least one further inert substance, in particular a filling agent, saccharide, lubricant and/or disintegrator. These inert substances facilitate the process for producing the solid dosage form and/or improve the characteristics of the form. Of course also two or more filling agents, two or more saccharides, two or more lubricants, and/or two or more disintegrators can be used. The saccharide is for example lactose, mannitol, sorbitol, fructose and/or saccharose, the preferred one being lactose. As lubricants preferably magnesium stearat, aluminium stearate, zinc stearat and/or talc are used. The preferred disintegrators are crosscarboxymethylcellulose, ultraamylopectin and/or crosspolyvinylpyrrolidone, preferably the sodium salt of crosscarboxymethylcellulose. Preferably, the filling agent is a mixture of saccharide, for example lactose, and a disintegrator, e.g. a disintegrating agent.

Advantageously the solvent comprises at least one adhesive, preferably a polymer, still preferred dimethyl aminoethyl methacrylate, PVA, PVP, HPC and/or HPMC, most preferred dimethyl aminoethyl methacrylate. Then at least one adhesive is added in order to facilitate that the active substance adheres to the carrier after it is applied thereto, thereby the method of producing the dosage form and the form itself are improved. If the adhesive is a pH-dependant polymer, it will change its adhesive characteristics when a change in pH occurs in a way that when the pH decreases, for example when the dosage form is in contact with gastric juice, also the adhesive properties will decrease and thereby release the active substance. The preferred (pH dependent) adhesive is Eudragit E, which is dimethyl aminoethyl methacrylate.

Preferably, the mixture comprising the at least one carrier is coated by spraying the solvent onto it. This is an easy and effective, well known method of applying the necessary amount of solvent comprising active substance on the carrier whereby it will be evenly coated and thereby provide a homogenous distribution of active substance on the carrier.

Still preferred, after evaporating the solvent, at least one further inert substance is added to the mixture, preferably a filling agent, disintegrator, lubricant and/or saccharide. Thereby, the exact features of the dosage form can be changed according to the required physico-chemical characteristics and adapted to the type of patient, the amount of active substance, etc. The preferred filling agent, disintegrator, lubricant and saccharide are the ones already mentioned above. Of course also two or more filling agents, two or more disintegrators, two or more lubricants and/or two or more saccharides can be used. In particular if the disintegrator also increases its volume when in contact with a liquid, preferably a liquid with low pH as for the carrier mentioned above, the dosage form will disintegrate as soon as it reaches the gastric region thereby optimising release of the active substance as mentioned above.

According to a particularly advantageous method the mass ratio of the pharmaceutically acceptable carrier with swelling ability to the medicinally active substance which is applied thereto is from 0.5 : 1 to 20 : 1., preferably from 1 : 1 to 10:1 , still preferred from 3 : 1 to 5 : 1. This mass ratio allows for an optimal amount of active substance to be applied to the carrier and at the same time to optimize the dissolution rate of active substance from the carrier.

Preferably, the mass ratio of the adhesive to the active substance is from 1 : 0.5 to 1 : 2, preferably 1 : 1. The exact ratio will of course depend on the strength of the adhesive. However, this range can be applied in general, particularly with Eudragit E, whereby a sufficient adherence of the active substance to the carrier is achieved while the release of the active substance when in contact with the liquid occurs as required.

Still preferred, the mass ratio of the carrier to the further inert substance which it is mixed to before applying the solvent is from 1 : 1 to 1 : 50, preferably 1 : 5 to 1 : 25, still preferred 1 : 7 to 1 : 10. With this ratio a sufficient amount of inert substance, in particular a filling agent, saccharide, lubricant and/or disintegrator is mixed with the carrier in order to achieve optimal physico-chemical properties.

According to a further aspect of the present invention, a solid dosage form comprising a water insoluble medicinally active substance selected from tacrolimus and sirolimus is provided, which is producible according to the above mentioned inventive method. For this aspect the above described preferred embodiments also apply.

The resulting dosage form preferably comprises lubricant at the mass ratio to the carrier of between 1 : 10 and 1 : 250, still preferred between 1 : 50 and 1 : 150, most preferred of 1 : 80 and 1 : 120.

Advantageously, the solid dosage form comprises between 0.1 and 20 wt%, preferably between 0.5 and 10 wt%, most preferred between 1 and 5 wt% tacrolimus and/or sirolimus.

A preferred amount of carrier in the solid dosage form is between 0.5 and 50 wt%, still preferred between 5 and 35 wt%, most preferred between 10 and 25 wt%.

Preferably, the solid dosage form comprises one or more saccharides in an amount of 10 to 80 wt%, still preferred 20 to 75 wt%, most preferred 40 to 70 wt%.

Examples

The method of how to prepare the solid dosage form according to the present invention is illustrated using the following examples of the preferred embodiment and the figure, without any limitation of the scope of the invention. The weights in the examples are given in the mass parts. The figure shows the comparison in dissolution rate of a capsule according to the present invention and a prior art capsule.

Example 1

Production of Capsule 1

Composition of the dosage form, in mass parts:

1. Weigh tacrolimus (1) and dissolve it in ethanol (3).

2. Dissolve Eudragit E (2) in the resulting solution.

3. Weigh the components (4, 5), mix then in a suitable mixer and put it in a fluid drier.

4. Apply (spray) tacrolimus solution onto the solid composition under the suitable conditions.

5. Dry the resulting mixture in a fluid way at the temperature between 50 ⁰C and 70 ⁰C until the humidity of 2% - 4% is reached.

6. Weigh the components (6, 7) and sieve it using a sieve with 0.8-mm meshes.

7. Mix the dried mixture with the components being already sieved in the suitable mixer.

8. Fill the resulting mixture into gelatine capsules.

Example 2

Production of Capsule 2

Alternatively, the base granulate may be prepared and, after being reconstituted, three strengths may be obtained.

Composition of dosage form, in mass parts Basic granulate

Mixing with basic granulate

1. Weigh the active substance (1) and dissolve it in ethanol (3).

2. Dilute Eudragit E (2) in the resulting solution.

3. Weigh the compounds (4, 5), mix them in a suitable mixer and put them into a fluid drier.

4. Spray tacrolimus solution onto the solid compound under the suitable conditions.

5. Dry the resulting mixture in a fluid way at the temperature between 50 ⁰C and 70 ⁰C until humidity of 2% - 4% is reached. This is the base granulate (6

6. Weigh the specified quantity of the base granulate (6).

7. Weigh the compounds (7, 8, 9) and sieve in using the sieve with 0.8-mm mesh.

8. Mix the appropriate part of the base granulate (6) with the sieved compounds in the suitable mixer.

9. Fill the resulting mixture into gelatine capsules.

Example 3

Production of Capsule 3

The basic granulate is produced by fluid-bed granulation. The dispersion of the active ingredient and HPMC in alcohol 96% is sprayed onto the mixture lactose DCL 11 with Ac-Di-SoI during fluidisation. Wet granulate is dried in a fluid-bed dryer and re- granulated.

Tacrolimus 5 mg: The basic granulate is mixed with disintegrant and lubricant. The final mixture is then filled into the hard gelatinous capsules No. 4. Tacrolimus 0.5, 1 mg: The basic granulate is diluted with lactose to achieve appropriate concentration and then the disintegrant and lubricant are admixed. The final mixture is then filled into the hard gelatinous capsules No. 5

Example 4 Dissolution Profile

The dissolution profile of capsule 1 produced according to above example 1 ("240805A") was compared to the dissolution profile of a capsule produced according to prior art, a generic standard for peroral tacrolimus whereby tacrolimus is dissolved in a solvent after which the solvent and the carrier are mixed in liquid phase ("Prograf 5C8134E"). The dissolution test carried out was the paddle test, rotation: 50 rpm, volume 900 ml; medium: 0.1 M HCI, 0.1 % sodium larylsulfuricum.

As can be seen in the following table and in the figure, the capsule 1 according to the present invention shows a higher dissolution rate than the capsule according to the prior art., e.g. the tacrolimus in the inventive capsule is dissolved quicker than the tacrolimus in the prior art capsule.

Claims

1. A method for preparing a solid dosage form comprising a water-insoluble medicinally active substance selected from tacrolimus and sirolimus and a combination thereof, characterized in that

- the medicinally active substance is dissolved in an organic solvent,

- a mixture comprising at least one pharmaceutically acceptable carrier with swelling ability is then coated with the solvent containing the medicinally active substance ,

- the solvent is evaporated, and

- the mixture is processed into a suitable solid dosage form.

2. The method according to claim 1 characterized in that the solvent is continually evaporated during the coating of the mixture.

3. The method according to claims 1 or 2, characterized in that the pharmaceutically acceptable carrier is crosscarboxymethylcellulose, ultraamylopectin and/or crosspolyvinylpyrrolidone.

4. The method according to any one of claims 1 to 3, characterized in that the mixture comprises at least one further inert substance, in particular a filling agent, saccharide, lubricant and/or disintegrator.

5. The method according to any one of claims 1 to 4, characterized in that the solvent comprises at least one adhesive, preferably a polymer, still preferred dimethyl aminoethyl methacrylate, PVA, PVP, HPC and/or HPMC, most preferred dimethyl aminoethyl methacrylate.

6. The method according to any one of claims 1 to 5, characterized in that the mixture comprising the at least one carrier is coated by spraying the solvent onto it.

7. The method according to any one of claims 1 to 6, characterized in that after evaporating the solvent, at least one further inert substance is added to the mixture, preferably a filling agent, disintegrator, lubricant and/or saccharide.

8. The method according to any one of claims 1 to 7, characterized in that the mass ratio of the pharmaceutically acceptable carrier with swelling ability to the medicinally active substance which is applied thereto is from 0.5 : 1 to 20 : 1., preferably from 1 : 1 to 10:1 , still preferred from 3 : 1 to 5 : 1.

9. The method according to any one of claims 1 to 8, characterized in that the mass ratio of the adhesive to the active substance is from 1 : 0.5 to 1 : 2, preferably 1 : 1.

10. The method according to any one of claims 1 to 9, characterized in that the mass ratio of the carrier to the further inert substance which it is mixed to before applying the solvent is from 1 : 1 to 1 : 50, preferably 1 : 5 to 1 : 25, still preferred 1 : 7 to 1 : 10.

11. A solid dosage form comprising a water insoluble medicinally active substance selected from tacrolimus and sirolimus, characterized in that it is producible according to a method according to any one of claims 1 to 10.