ES2241478B1 - PHARMACEUTICAL PREPARATION FOR THE SUSTAINED RELEASE OF A PHARMACEUTICALLY ACTIVE PRINCIPLE. - Google Patents

Abstract

Pharmaceutical preparation for sustained release of a pharmaceutically active principle (s), wherein the preparation is formed by particles with internal core (1) and a first coating (2) thereon, wherein said coating ( 2) contains a mixture of: (a) between 50% and 95% by weight of a copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride in a molar ratio between the three acrylates of 1: 1.8-2, 2: 0.08-0.12, preferably 1: 2: 0.1, (b) between 2% and 30% by weight of a copolymer of ethylacrylate and methacrylic acid in a molar ratio of 1: 0, 8-1.2, preferably 1: 1, and (c) between 1% and 40% by weight of the pharmaceutically active principle.

Description

Pharmaceutical preparation for release sustained from a pharmaceutically active principle.

Field of the invention

The present invention relates to a Pharmaceutical preparation for the sustained release of a pharmaceutically active principle.

Technical background

For many applications it is desirable use an oral preparation with release properties modified to control the release over time, the place of release of the drug in the gastrointestinal tract or the Temporary release profile of a drug.

One of the modified release preparations most common is one in which the active substance or the Pharmaceutical product presents a coating of material enteric, that is, resistant to gastric juice and insoluble in the acidic medium of the stomach (pH 1-3 approx.) but it dissolves in the stretch of the duodenum, which is weakly acidic to weakly alkaline (pH> 5.5). This type of preparation allows control the release zone based on the pH of the tract gastrointestinal and also allows a delayed release (it is say, after going through the acidic medium). These particles are use, p. e.g., to protect the gastric lining against certain compounds or to protect active ingredients that are unstable in acidic environment versus strongly gastric medium acid that would produce its immediate inactivation.

This type of modified release preparation It can also be developed so that it has a pH of optimal release equivalent to that normally found in certain sections of the intestinal tract. This way you can get more differentiated control of the release zone for the pharmaceutically active principle.

Many of these release preparations modified are formed by multilayer particles, in which the active substance is normally located near the center, optionally on or within a neutral particle that, to It is then coated with a material that dissolves in a defined section of the intestine. Another layer can be formed by a enteric coating, that is, a juice resistant material gastric. This type of preparation is exemplified in EP 0 720 473, where budesonide particles with a profile of controlled release consisting, from the inside to the outside, of: (a) a neutral particle, (b) a layer of active substance formed by micronized budesonide and one or more soluble auxiliary agents in water, (c) a first layer of insoluble lacquers in the juice gastric and soluble or insoluble in intestinal juice and (d) a second layer of insoluble lacquers in gastric juice and intestinal.

Other preparations basically produce a release of the active substance from a preparation Galenic that is maintained over time and constitute the so-called sustained release preparations. This may be necessary, for  example, when active ingredients are used with a brief plasma half-life but to achieve the therapeutic effect They must act for a long time. The preparations of Sustained release prevents repeated dosing, which power human errors and is uncomfortable for the patient.

These sustained release preparations they can include, for example, a spongy polymer matrix to the that the active compound is incorporated. Diffusion and erosion mechanical and chemical matrix during the gastrointestinal passage produces a release of the active substance by the matrix for a prolonged period.

You can also get a release sustained with preparations composed of particles (also called microgranules, particles, grains, microcompressed or granules) with different polymeric coatings. The coatings of the different particles may differ in that to its solubility. The solubility of the coating layers can be adjusted to the local pH of the digestive tract, as has been previously mentioned. Thus, in the finished medication (e.g., hard gelatin capsules) a mixture of laminated particles that release the active substance in different stretches of the digestive tract. This type of preparation allows control the zone and the moment of release from the beginning active.

You can also modify the properties of release protecting the active substance with a layer of coating of a certain thickness and solubility pH dependent. When the thick layer slowly degrades in the intestinal environment, degradation is not uniform throughout the particle surface. At some points they can form cracks or pores that allow the start of the release of the active principle. As the coating layer degrades, an increasing amount of layer of the principle is exposed active that dissolves.

Particularly in the case of drugs very assets should favor a slow and very controlled release to prevent temporary "elevations" of the plasma concentrations With the release preparations sustained in which the active ingredient layer is covered by a layer of a polymer of certain solubility may not be achieved the desired level of reproducibility and control of the release.

Obviously, for many active ingredients it is beneficial to be able to control the tract section gastrointestinal and the time of release. exist preparations that combine layers with release properties delayed, p. eg, using polymers with a solubility pH dependent, and layers with release properties sustained, p. eg, using insoluble polymer matrices in water with a certain permeability of the active substance.

For these coating layers mentioned previously, Eudragit® polymers are frequently used. Eudragit® L100 is a copolymer of methacrylic acid and methyl methacrylate combined in a given ratio that results insoluble in an acidic environment such as the stomach and form a highly waterproof protective layer known as enteric coating Eudragit® L100-55 is a copolymer of methacrylic acid and ethyl acrylate, in which the ratio of the monomers is chosen so that it is insoluble to a pH below 5.5 but soluble at a pH above this value.

Other widely used polymers are Eudragit®RS (low permeability) or Eudragit®RL (high permeability). These polymers are insoluble in water and form membranes of different permeability regardless of pH. The RS / RL mixing ratio and layer thickness define the permeability properties of the resulting preparation.

In addition, polymer blends with a solubility pH dependent, such as Eudragit®L and forming polymers water insoluble diffusion barriers, such as Eudragit®RL or RS, are known by the state of the art.

EP 0 377 517 exemplifies preparations with coating layers formed by insoluble polymer blends and others with a pH dependent solubility. In said patent describes a sustained release pharmaceutical preparation formed by a core particle that includes a compound of theophylline and a coating thereon formed by (i) a polymeric matrix practically insoluble regardless of pH, (ii) an enteric polymer whose solubility depends on pH and (iii) a component at least partially soluble in water.

A different type of mixed layer is exemplified in US 5,175,003, which describes a galenic preparation formed by particles with a mixed layer of a polymer with a pH dependent solubility, an active pharmaceutical component e hydroxyethyl cellulose or hydroxypropyl cellulose or shellac or mixtures thereof.

The mixture of the active substance with a certain type Polymer is also known by the prior art. In EP 1 060 743 exemplifies a pharmaceutical form of cisapride of sustained release This pharmaceutical form comprises a layer in where a single type of an enteric polymer with a solubility pH dependent, such as p. eg, Eudragit®L, mixed with Cisapride

Insoluble or partially soluble polymers used in the prior art are relatively expensive and its thickness cannot be reduced beyond a certain limit for guarantee a sustained release after passing through the stomach. In addition, the degree of sustained release that the layers of Coating of a certain thickness is inappropriate for some Applications. On the other hand, the degree of dependent solubility pH is inappropriate for some applications.

Therefore, it is desirable to have a galenic preparation that has well defined properties of both delayed and sustained release, a better profile of sustained release (i.e. a slower release of active ingredients), a better pH-dependent solubility and, at at the same time, require a minimum use of expensive excipients such as Eudragit® polymers.

Summary of the Invention

The present invention allows solving these problems offering a pharmaceutical preparation with a sustained release of a pharmaceutically active substance, in where said preparation is formed by particles that have a inner core (1) and a first coating (2) on it, said coating (2) being formed by a mixture of:

(a) between 50% and 95% by weight of a copolymer, preferably between 60% and 90% by weight of ethyl acrylate, methyl methacrylate and trimethylammonioethyl chloride methacrylate in a molar relationship between the three acrylates of 1: 1.8-2.2: 0.08-0.12, preferably 1: 2: 0.1, (Eudragit ® RS) and

(b) between 2% and 30% by weight, preferably between 5% and 20% by weight of an ethyl acrylate copolymer and methacrylic acid in a molar ratio of 1: 0.8-1.2, preferably 1: 1, (Eudragit ® L 100-55) and

(c) between 1% and 40% by weight, preferably between 5% and 15% by weight of the principle pharmaceutically active; where the percentages of the components (a), (b) and (c) only refer to the coating (2);

and optionally a second enteric type coating (3) on the first. Said second coating (3) is especially preferable when acid-sensitive active ingredients or active ingredients that can irritate the gastric mucosa are used. Furthermore, said second coating (3) is preferably used to minimize the in-vivo variability of drug administration, since gastric release of the drug is avoided.

Surprisingly, when using a Pharmaceutical preparation according to the present invention, formed by a mixed layer of components (a), (b) and (c) on a core internal, a more sustained release profile can be obtained than with the preparations included in the state of the art.

In addition, the present preparation presents a surprisingly high and reliable sensitivity to variations pH This means that sustained release can be adjusted very accurately at wider pH intervals than it was possible with the preparations included in the state of the art. Therefore, the release of the drug according to the pH conditions present in the tract gastrointestinal, with a physiological range of pH included approximately 1.5 to 8.

A particular advantage of the present invention it is the surprising fact that a smaller amount can be used of insoluble or partially soluble polymers than in Sustained release preparations included in the state of the technique but maintaining a similar sustained release profile to these.

Another advantage of the present invention is that the Pharmaceutical preparation production process consists of a smaller number of stages and, therefore, is shorter and simpler than perform and therefore economically preferable. This advantage is due to the use of a single layer of active ingredient / polymer, while that a principle layer is used in the state of the art active and a separate polymer layer (in addition to other possible layers).

Brief description of the drawings

Figure 1: Schematic cross section of particles of the present invention (A) and of different particles included in the prior art (B) and (C). The particles included in the state of the art are prepared with the same basic components and the same quantities as (A), that is, a insoluble copolymer (a) and a copolymer (b) with a solubility pH dependent (e.g., Eudragit® RS and Eudragit® L 100-55, respectively) and a principle pharmaceutically active (c) but containing layers with different Compositions of said components.

Figure 2: Release profiles (% of dissolution over time) of particles and reference particles at pH = 6. a) 0.4 mg particles of Tamsulosin according to Example 1 and Reference Example 1, b) 0.4 mg particles of Diltiazem from according to Example 2 and Reference Example 2, c) particles of 1 mg of Diltiazem according to Example 3 and the Example of reference 3, d) 0.6 mg particles of Tamsulosin according to Example 4 and Reference Example 4 and e) 0.6 mg particles of Tamsulosin according to Example 5 and the Example of reference 5.

Figure 3: Release profiles (% of dissolution over time) of particles of 0.4 mg Tamsulosin according to Example 1 and Reference Example 1 at two pH values environmental (pH = 6.0 and 6.8).

Figure 4: Release profiles (% of dissolution over time) of 0.4 mg particles of Diltiazem according to (a) Example 2 and (b) Reference Example 6 to three values of environmental pH

Figure 5: Release profiles (% of dissolution over time) of Tamsulosin particles according to the Example 6 to four ambient pH values (pH = 5.5, 6.0, 6.8, and 7.2).

Figure 6: Release profiles (% of dissolution over time) of three different batches A, B and C of particles of according to Example 9 containing 0.4 mg of Tamsulosin and different amounts of copolymers (a) and (b) in layer (2) at pH environmental = 6.8.

Figure 7: Release profiles (% of dissolution over time) of two different batches of Tamsulosin particles according to Example 6 and Example 10 at two pH values environmental ((a) pH = 6.0 and (b) pH = 6.8).

Figure 8: Release profiles (% of dissolution over time) of Tamsulosin particles according to the Example 6 at two speed stirring blades.

Detailed description of the invention

The term "sustained release" in the The present invention refers to any release maintained in the time of an active substance contained in a galenic preparation. This means that, applying physical or chemical measures related to the active substance and / or other excipients, agents filler, coatings or other elements of the preparation Galenic, a more sustained release is achieved than in absence of said physical or chemical measures.

The term "particle" herein invention refers to any type of particle that can form part of or constitute a galenic preparation. Between these particles are found, although not exclusively, microgranules, granules, powder, grains, seeds, tablets or capsules and may be formed by a homogeneous material or include differentiated layers or components. Particles too they can be composite particles that contain, in turn, other smaller particles This type of composite particles can be tablets or capsules, although not exclusively. The Composite particles can be formed by one or several smaller particle types, being able to understand each type of particle, in turn, different layers and substances. The particles compounds can be made up of smaller particles with a enteric coating that can also be found applied on the entire composite particle instead of over the most particles small that make it up.

The term "physiologically excipient acceptable "in the present invention refers to any excipient used in pharmaceutical preparations for oral administration generally known by the state of the technique. These excipients can be, although not in form excluding, talc, sucrose, corn starch, hydrolysed starch, sugar, lactose, microcrystalline cellulose, mannitol, dextrose, triethyl citrate, polymers of methacrylic acid, cellulose derivatives, plasticizers, lubricants and / or agents release and optionally also colored pigments and / or Silicone defoamers.

The term "pharmaceutically principle active "in the present invention refers to any active substance that is suitable for oral administration or that can become suitable for oral administration by an appropriate galenic preparation. Among these principles assets are found, although not exclusively, Amlodipine, Budesonide, Candesartan, Cisapride, Diclofenac, Diltiazem, Donepezil, Fentanyl, Glimepiride, Mebeverin, Memantine, Nicardipine, Olanzapine, Omeprazole, Ondansetron, Oxybutynin, Pramipexole, Ramipril, Risperidone, Rivastigmine, Tamsulosin, Theophylline, Tibolone, Tolterodine, Topiramate or Trandolapril.

Other active ingredients that can be administered orally they are, for example, acidic compounds such as, e.g. eg the acetylsalicylic acid and Diclofenac (acid o-2,6-dichloroanilin phenylacetic). Since these substances have side effects that irritate or damage the stomach lining when used for a while Prolonged, often included in release preparations modified

Modified Release Preparations they are also used to protect unstable active ingredients in acidic medium versus strongly acidic gastric medium, which It would result in immediate inactivation. Among these compounds acid sensitive are found, e.g. eg, derivatives of benzimidazole used as inhibitors of H + / K + -ATPase for treatment of ulcers, Omeprazole (5-methoxy-2 (((4-methoxy-3,5-dimethyl-2-pyridyl) methyl) -sulfinyl) -1H-benzimidazole), lansoprazole (2 - (((3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl) -sulfinyl) -1H-benzimidazole)  and pantoprazole (5-Difluoromethoxy-2 - ((3,4-dimethoxy-2-pyridyl) methyl) -sulfinyl) -1H-benzimidazole) which act as potent acid secretion inhibitors gastric. Omeprazole has been credited in the treatment of ulcers of the duodenum, gastric ulcers, reflux esophagitis and syndrome Zollinger-Ellision. In this context they are used parenteral and solid oral administration medications. Omeprazole, for example, has a half-life of less than 10 minutes in aqueous solution at pH values below 4. both solid medications for oral use (tablets, microcapsules, granules) of Omeprazole or its derivatives must be fully protected against gastric juice during its passage to through the stomach

Other typical active ingredients for modified release preparations, and in particular for Sustained release preparations are those that present a brief plasma half-life Release preparations sustained can reduce the frequency of administration of the dose.

The particles of the present invention can include one or more active ingredients, which, in turn, may be contained in one or several layers of the particle.

The present invention relates to a Pharmaceutical preparation for the sustained release of a pharmaceutically active principle composed of particles with layers of different components. These particles may consist of an inner core, manufactured with physiologically excipients acceptable, preferably, but not exclusively, sucrose, corn starch, starch hydrolysates, sugar, lactose, microcrystalline cellulose, mannitol or dextrose. This inner core It is also called an inert nucleus. The particles can also be formed by an inner core that contains a principle pharmaceutically active So this type of core is called active core

The size of the inner core is not limited in the present invention, provided that it is suitable for Desired pharmaceutical preparation. The subject matter expert is familiar with the size and type of internal cores used for particles composed of pharmaceutical preparations. He inert core diameter can vary between about 0.1 and 2 mm In a preferred embodiment, the inner core has a diameter between 0.4 and 0.8 mm, more preferably 0.5 mm This kernel seed can have a diameter such that it allows obtain a final particle with a diameter between approximately 0.3 and 2.5 mm. Core seeds can present between approximately 5% and 95% by weight, preferably between 50% and 90% by weight with respect to weight Total finished particles. For reference, in forward said core element will be mentioned with the number (one).

On the inner core (1) is applied a mixed layer formed by at least one mixed active ingredient with copolymers and / or excipients and / or fillers (2) that according to the present invention it comprises:

- between 50% and 95% by weight of a copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl chloride methacrylate in a molar relationship between the three acrylates of 1: 1.8-2.2: 0.08-0.12, preferably 1: 2: 0.1, component mentioned hereafter as component (to),

- between 2% and 30% by weight of a copolymer of ethylacrylate and methacrylic acid in a molar ratio of 1: 0.8-1.2, preferably 1: 1, component hereinafter referred to as component (b), and

- between 1% and 40% by weight of the principle pharmaceutically active, component mentioned hereinafter as pharmaceutical component (s) (c), and

- plasticizers / lubricants / excipients, component mentioned hereinafter as component (d).

In a preferred embodiment, the layer (2) understands:

- component (a) with 60-90% by weight of a copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride in a molar ratio between  the three acrylates of 1: 1.8-2.2: 0.08-0.12, preferably 1: 2: 0.1,

- component (b) with 5% -20% by weight of a copolymer of ethylacrylate and methacrylic acid in a ratio 1: 0.8-1.2 molar, preferably 1: 1, and

- the pharmaceutical component (s) (c) with 5% -15% by weight of the pharmaceutically active substance,
Y

- component (d) with plasticizers / lubricants / excipients.

In an especially preferred embodiment of the invention the layer (2) consists of:

- component (a) with 50-85% by weight of a copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride in a molar ratio between  the three acrylates of 1: 1.8-2.2: 0.08-0.12, preferably 1: 2: 0.1,

- component (b) with 10-30% by weight of a copolymer of ethylacrylate and methacrylic acid in a 1: 0.8-1.2 molar ratio, preferably of 1: 1,

- the pharmaceutical component (s) (c) with 5-40% by weight of the pharmaceutically active principle (s)
you and

- component (d) with plasticizers / lubricants / excipients.

In another preferred embodiment they may be present layers with or without pharmaceutically active compounds. In a particularly preferred embodiment this other layer is a enteric coating In another preferred embodiment, this other layer is a layer of lacquer.

Although pharmaceutical preparations that include components (a), (b) and the (the) pharmaceutical component (s) (c) are well known by the state of the art, however, the fact is not known of mixing the three components in a single layer. The state of the technique knows the mixture of components (a) and (b) that is applied as a separate layer on the layer formed by the pharmaceutical component (s) (c), or the existence of a layer formed by a mixture of component (b) and component (s) pharmacist (s) (c) and another layer separated with the component (to).

Surprisingly, the mixture of the three elements (components (a) and (b) and the (the) pharmaceutical component (s) (c)) improves properties of the pharmaceutical preparation with respect to the Sustained release, sensitivity to pH variations and the quantity of the substances necessary to obtain the profile of desired release.

When release properties are compared of the particles of the present invention with those of particles included in the prior art containing the same quantity of each component but where the pharmaceutical component (s) (c) constitutes a layer separated covered by a layer formed by components (a) and (b), the particles of the present invention show better release properties, in the sense that the active compound it is released more slowly, that is, the release by The particles of the present invention are more sustained. This result is unexpected because, in the particles included in the prior art, the mixed layer with the components (a) and (b) covering the separate layer of the component (s) Pharmacist (s) (c) must first be eroded at least partially so that the component (s) Pharmacist (s) (c) can be released. Conversely, one might think that in the present invention the (the) pharmaceutical component (s) (c) is released as soon as the mixed layer begins to erode or is exposed to The liquids of the medium. Surprisingly, this is not the case.

Another advantage of a pharmaceutical composition according to the present invention is that while in the state of the technique two separate layers are used (e.g., the (the) pharmaceutical component (s) (c) in one layer and the components (a) and (b) in another separate layer; or the pharmaceutical component (s) (c) and component (b) in one layer and the component (a) in another separate layer), in the invention only one layer is used (components (a) and (b) and pharmaceutical component (s) (c) mixed in one single layer) In the first case, each layer is applied successively during production and, therefore, the processing time and additional requirements of handling. However, reducing the absolute number of layers needed to obtain the desired release profile assumes shorter and less complex production processes, with corresponding economic advantages.

In addition, the composition according to the present invention has a surprising effect in terms of pH sensitivity of active compound release. This can be observed in particles that contain the same total amount of components of the layers in a microgranule although with a Different composition in each layer. So, if the particles of the The present invention presents a mixed layer with the three elements (components (a), (b) and active substance (c)), the microgranules included in the state of the art have two separate layers, prepared with different mixtures of these three elements (see also Figure 1 A (particles of the invention), B and C (particles included in the state of the art)).

In the particles included in the state of the technique, the release of the active substance is sensitive to small variations of the environmental pH, which gives rise to different profiles of release of the active principle in time. So, p. eg, to a Ambient pH = 6 less active substance is released than at a pH environmental = 6.8. These differences in the amount of principle released asset can be observed at different points temporary, thus obtaining different profiles of time release.

Surprisingly, in the particles of the present invention this sensitivity against small pH variations in terms of the amount of active substance released was more marked than in the particles included in the state of the art This means that the release of the principle active was much more affected for a longer period of time prolonged than in the case of the microgranules included in the state of the art Therefore, at the time points where particles included in the state of the art did not have a variation of the amount of active ingredient released to different pH values (eg, after 300 min. of dissolution at pH = 6 and pH = 6.8), the particles of the present invention still they showed a different release of the active substance to these two pH values Also, the release at these pH values was seen affected more markedly in the case of particles of the invention that in that of the particles included in the state of the technique. This means that the release profiles at different pH values showed a greater difference in the case of particles of the invention. In other words, the difference of active substance released at two different pH values in a certain time point in the particles of the invention was greater than the difference observed at the same pH values and in the same time point in the particles included in the state of The technique.

In addition, the pH sensitivity of the particles included in the prior art is limited to an interval of more restricted pH. This means that the differences pH dependent on release profiles can only be observed, p. e.g., at an ambient pH between 6 and 6.8, but not below or above this value. Therefore, the release profiles, p. eg, at pH = 6.8 or pH = 7.2 results indiscernible for the particles included in the state of the technique, while the particles of the invention are obtained different release profiles for a wider range of pH values Therefore, the release profile at an ambient pH D.E.P. eg, 7.2 is different from that of, e.g. eg, pH = 6.8.

Also, the pH sensitivity of the particles of the present invention presents a homogeneous gradation in a wide pH range, e.g. eg, between pH = 5.5 and pH = 7.2. This means that the difference between release profiles to ambient pH values such as, e.g. e.g., 5.5 and 6.0, is similar to the difference between the release profiles that are obtained at pH values as, e.g. eg, 6.8 and 7.2. In other words, the differences in the amount of active substance released in any time point at different ambient pH values are similar (e.g., between pH 5.5 and pH 6.0 or between pH 6.8 and pH 7.2).

A reliable and predictable response to different pH values is a prerequisite to get a control precise time and zone of drug release in the gastrointestinal tract.

Another advantage of the particles of the present invention is that smaller amounts of the components (a) and (b) to obtain a specific profile of release. Therefore, using in the particles of the invention the same amounts of components (a) and (b) as in the particles included in the state of the art, a more sustained or slower release. On the contrary, if in particles of the present invention the amount of components (a) and (b), a release profile similar to of the particles included in the state of the art with higher amounts of components (a) and (b).

The layer (2) can also be coated with one or More additional layers. In a preferred embodiment, this layer additional is an enteric coating, indicated hereinafter with the number 3). The term "enteric coating" in this context means that the coating prevents or reduces the release of the active substance (s) by the particle and / or prevents or reduces the penetration of substances from the gastrointestinal tract to the beginning assets). Preferably, the enteric coatings are designed to fulfill these functions at certain pH values environmental and stop performing its barrier function to other values of Typical pH of certain sections of the gastrointestinal tract. A preferred example of enteric coating is one resistant to gastric juice. Enteric coatings include preferably substances such as polymers of methacrylic acid, cellulose derivatives, plasticizers, lubricants and / or agents release and optionally colored pigments and / or a Silicone defoamers.

The particles of the present invention also can be processed to obtain typical pharmaceutical forms for oral administration Preferred examples are the capsules, the tablets or granules. In the state of the art they are known multitude of pharmaceutical forms that are available for the expert in the field and meet the specific requirements of a certain drug or a certain application.

The present invention also relates to a process to manufacture a pharmaceutical release preparation sustained composed of a mixed layer (2) according to the present invention. In this production process, components (a) and (b) and the pharmaceutical component (s) (c) are dissolve, partially dissolve, disperse or suspend in suitable solvents to finally obtain a single mixture homogeneous These solvents can be water or solvents organic such as ethanol, methanol or acetone. Other solvents organic, including halogenated, may also result adequate. Mixtures of solvents can also be used. For those skilled in the art are known solvents that result suitable for the active substances and substances contained in the layer (2) of the invention.

The mixture of solvents and substances is applied to then as a coating layer on a particle of nucleus, which can be an inert nucleus. The core particle can Include several layers of different composition. The methods of application of the mixture on the particles are well known for the state of the art and include, but not exclusively, spraying with a Wurster device of a Glatt device.

Optionally, the production process according to the The present invention may also include the addition of others. coatings on the layer (2). These coatings can be enteric coatings, coatings with active substances or other known coatings for galenic preparations, used alone or in combination.

The invention is described below in more detail using as reference the examples included in continuation.

Examples

The following examples compare the multilayer particles according to the present invention (Examples 1 to 6, see Figure 1 A) with the particles included in the state of the technique (Reference Examples 1 to 6, see Figure 1B and C) in regarding their release profiles at different values of environmental pH

All particles of the present invention and the reference examples have an internal core (1) with a diameter between 0.5 and 0.7 mm and contain between 60% and 90% by weight of sugar and between 10% and 40% by weight of starch of corn

The particles of the present invention have a first coating (2), wherein said coating (2) It contains a mixture of:

- component (a): between 50% and 95% in weight of a copolymer, preferably between 60% and 90% by weight of ethyl acrylate, methyl methacrylate and trimethylammonioethyl chloride methacrylate with a molar relationship between the three acrylates of 1: 1.8-2.2: 0.08-0.12, preferably 1: 2: 0.1, (Eudragit® RS), and

- component (b): between 2% and 30% by weight, preferably between 5% and 20% by weight of a copolymer of ethyl acrylate and methacrylic acid with a molar ratio of 1: 0.8-1.2, preferably 1: 1, (Eudragit® L 100-55), and

- pharmaceutical component (s) (c): between 1% and 40% by weight, preferably between 5% and 15% by weight of the principle (s) pharmaceutically active (s) and

- excipients (d). In a preferred embodiment an enteric coating (3) is also applied.

The particles of the reference examples 1-5 contain mixed layers (2 ') with the same total amount of the components of the layer (2) of the invention. However, the layers (2 ') are two separate layers, one that Contains the active principle (s) (c) and another with modified release agents (components (a) and (b)). Optionally you can also include a coating layer enteric resistant to gastric juice (3) (see Figure 1 B). In reference example 6, the particles have a core inert (1) and layers (2``), which also contain the same amount of the same components of the layer (2) of the invention, although divided into a layer that contains the active substance (s) (c), a release agent modified with a pH dependent solubility, component (b) and another layer with an independent modified release agent of pH, component (a). Optionally you can also include a layer enteric coating (3) (see Figure 1 C).

Table 1 summarizes the proportions of components (a) and (b) and of the pharmaceutical component (s).
(c) of the layer (2) of Examples 1-6 and the layers of reference examples 1-6.

Example 1 0.4 mg particles of Tamsulosin hydrochloride with enteric coating Layer (2), (components (a) and (b) and component (s) pharmacist (s) (c))

1.4 g of Tamsulosin HCl, 19 g of Eudragit® RS (Rohm Pharma, Germany), 2 g of Eudragit® L 100-55 (Rohm Pharma, Germany) and 2 g of triethyl citrate were dissolved in a mixture consisting of 400 ml of ethanol (96%) and 200 ml of acetone. As an adjuvant in the process, 53 g of talc was dispersed. 650 g of inert core particles were loaded into a Wurster device of a Glatt apparatus equipped with a 1.2 mm spray nozzle. The inlet air temperature was maintained at 40 ° C. The particles were coated with the solution of the
mixture.

Layer (3), component (b)

An enteric coating layer was prepared dispersing 200 g of Eudragit® L-30D 55 (Rohm Pharma, Germany), 5 g of triethyl citrate and 58 g of talc in water to obtain a solid content dispersion of 24.6%. He Enteric coating was applied with a Wurster device equipped with a 0.8 mm spray nozzle.

After the operation, the particles in an oven at 40 ° C for 24 hours.

As for the weight, the finished particles were composed of an inert core of 180 mg, a layer (2) of 22 mg and a layer (3) of 39 mg, with a final particle weight of 241 mg All finished particles from the following examples They presented a similar composition.

Reference Example one

0.4 mg particles of Tamsulosin hydrochloride with enteric coating Layer (2 '), pharmaceutical component (s) (c)

1.4 g of Tamsulosin were completely dissolved HCl and 21 g of polyvinyl pyrrolidone (PVP) in 400 g of ethanol (96%). 35 g of talc was dispersed as an adjuvant in the process. This suspension was applied to 650 g of charged core particles in a Wurster device of a Glatt device equipped with a nozzle 1.2 mm spray. The intake air temperature is kept at 40 ° C.

Layer (2 '), (components (a) and (b))

19 g of Eudragit® RS (Rohm Pharma, Germany), 2 g of Eudragit® L 100-55 (Rohm Pharma, Germany) and 2 g of triethyl citrate in a mixture of 400 ml of ethanol (96%) and 200 ml of acetone. 18 g of talc was dispersed as adjuvant in the process. This suspension was applied to the particles previously loaded in a Wurster device of a Glatt device equipped with a 1.2 mm spray nozzle. Temperature of the inlet air was maintained at 40 ° C.

Layer (3), component (b)

An enteric coating layer was prepared and It was applied as in Example 1.

The finished particles were dried in a stove at 40 ° C for 24 hours.

Example 2 0.4 mg Diltiazem hydrochloride coated particles enteric Layer (2), (components (a) and (b) and component (s) pharmacist (s) (c))

This layer was prepared and applied to the particles of inert nucleus as in Example 1, but instead of Tamsulosin HCl, 1.4 g of Diltiazem HCl was used as the principle active.

Layer (3), component (b)

An enteric coating was applied as in the Example 1. The finished particles were dried in an oven as in Example 1.

       \ newpage
    

Reference Example 2

0.4 mg Diltiazem hydrochloride coated particles enteric

A reference particle was prepared as in the reference example 1, except that 1.4 g of Diltiazem HCl as active ingredient instead of the same amount of Tamsulosin.

Example 3 1 mg particles of coated Diltiazem hydrochloride enteric Layer (2), ((a) (b) and pharmaceutical component (c))

3.5 g of Diltiazem HCl, 19 g of Eudragit® RS (Rohm Pharma, Germany), 2 g of Eudragit® L 100-55 (Rohm Pharma, Germany) and 2 g of triethyl citrate were dissolved in a mixture formed by 400 ml of ethanol (96%) and 200 ml of acetone. 53 g of talc was dispersed as an adjuvant in the process. 650 g of inert core particles were loaded into a Wurster device of a Glatt apparatus equipped with a 1.2 mm spray nozzle. The inlet air temperature was maintained at 40 ° C. The particles were coated with the solution of the
mixture.

Layer (3), component (b)

The enteric coating layer was prepared dispersing in water 150 g of Eudragit® L-30D 55 (Rohm Pharma, Germany), 4 g of triethyl citrate and 58 g of talc to obtain a 24.6% dispersion of the solid content. He Enteric coating was applied with the Wurster device equipped with a 0.8 mm spray nozzle.

After the operation, the particles are dried in an oven at 40 ° C for 24 hours.

Reference Example 3

1 mg particles of coated Diltiazem hydrochloride enteric Layer (2 '), pharmaceutical component (c)

3.5 g of Diltiazem HCl were completely dissolved and 3.5 g of PVP in 400 g ethanol (96%). 35 g of talcum powder was dispersed as an adjuvant in the process. This suspension was applied to 650 g of inert core particles loaded into a Wurster device of a Glatt device equipped with a 1.2 spray nozzle mm The inlet air temperature was maintained at 40 ° C.

Layer (2 '), (components (a) and (b))

19 g of Eudragit® RS (Rohm Pharma, Germany), 2 g of Eudragit® L 100-55 (Rohm Pharma, Germany) and 2 g of triethyl citrate in a mixture consisting of 400 ml of ethanol (96%) and 200 ml of acetone. 18 g of talc was dispersed as an adjuvant in the process. This suspension was applied to previously loaded particles in a Wurster device of a Glatt device equipped with a 1.2 mm spray nozzle. The inlet air temperature was maintained at 40 ° C.

Layer (3), component (b)

An enteric coating layer was prepared and it was applied as in layer (3) of Example 3 and the particles Finished were dried as in Example 3.

Example 4 0.6 mg particles of Tamsulosin hydrochloride without enteric coating Layer (2), (components (a) and (b) and pharmaceutical component (C))

1.8 g of Tamsulosin HCl, 16 g of Eudragit® RS (Rohm Pharma, Germany), 5 g of Eudragit® L 100-55 (Rohm Pharma, Germany) and 2 g of triethyl citrate were dissolved in a mixture consisting of 400 ml of ethanol (96%) and 200 ml of acetone. 53 g of talc was dispersed as an adjuvant in the process. 540 g of inert core particles were loaded into a Wurster device of a Glatt apparatus equipped with a 1.2 mm spray nozzle. The inlet air temperature was maintained at 40 ° C. The particles were coated with the mixture solution.
cla.

After the operation, the particles are dried in a fluid bed at 40 ° C for 1 hour.

       \ newpage
    

Reference Example 4

0.6 mg particles of Tamsulosin hydrochloride without enteric coating Layer (2 '), pharmaceutical component (c)

1.8 g of Tamsulosin were completely dissolved HCl and 25 g of PVP in 450 g ethanol (96%). 35 g of dispersed talc as an adjuvant in the process. This suspension was applied to 650 g of inert core particles loaded in a Wurster device of a Glatt device equipped with a spray nozzle 1.2 mm The inlet air temperature was maintained at 40 ° C.

Layer (2 '), (components (a) and (b))

16 g of Eudragit® RS (Rohm Pharma, Germany), 5 g of Eudragit L 100-55 (Rohm Pharma, Germany) and 2 g of triethyl citrate in a mixture consisting of 400 ml of ethanol (96%) and 200 ml of acetone. 18 g of talc was dispersed as an adjuvant in the process. This suspension was applied to previous particles loaded into a Wurster device of a Glatt device equipped with a 1.2 mm spray nozzle. The inlet air temperature was maintained at 40 ° C.

The finished particles were dried as in the Example 4

Example 5 0.6 mg particles of Tamsulosin hydrochloride with enteric coating

The particles of Example 4 were coated also with an enteric coating.

Layer (3), component (b)

An enteric coating layer was prepared dispersing 120 g of Eudragit® L-30D 55 (Rohm Pharma, Germany), 3.5 g of triethyl citrate and 58 g of talc in water to obtain a 24.6% dispersion of the solid content. He Enteric coating was applied with the Wurster device over the particles obtained in Example 4. The air temperature input was maintained at 40 ° C and a nozzle of 0.8 mm spray.

After the operation, the particles are dried in an oven at 40 ° C for 24 hours.

Reference Example 5

0.6 mg particles of Tamsulosin hydrochloride with enteric coating

The particles of Reference Example 4 are coated with an additional enteric coating as described in Example 5 and the finished particles were dried as in the Example 5

Example 6 Large-scale production of particles containing 0.4 mg of Tamsulosin hydrochloride Layer (2), (components (a) and (b) and pharmaceutical component (C))

40 g of Tamsulosin HCl, 620 g of Eudragit® RS (Rohm Pharma, Germany), 57 g of Eudragit® L 100-55 (Rohm Pharma, Germany) and 68 g of triethyl citrate were dissolved in a mixture consisting of 14,000 ml of ethanol (96%) and 7,000 ml of acetone. The talc dispersed as an adjuvant in the process. 18,000 g of inert core particles were loaded into a Wurster device of a Glatt apparatus (GPCG 15) equipped with a 1.2 mm spray nozzle. The inlet air temperature was maintained at 40 ° C. The particles were coated with the solution of the
mixture.

Layer (3), component (b)

An enteric coating layer was prepared dispersing 6,500 g of Eudragit® L-30D 55 (Rohm Pharma, Germany), 200 g of triethyl citrate and talc in water for obtain a 24.6% dispersion of the solid content. He Enteric coating was applied with the Wurster device equipped with a 0.8 mm spray nozzle.

After the operation, the particles are dried in an oven at 40 ° C for 24 hours.

       \ newpage
    

Reference Example 6

Multilayer particles containing only Eudragit® L in the active ingredient layer Layer (2``), (pharmaceutical component (c), component (b))

This layer is equivalent to layer 2 of Example 2 although without Eudragit® RS. The auxiliary agents were adjusted correspondingly.

1.4 g of Diltiazem HCl, 2 g of Eudragit® L100-55 and 0.2 g of triethyl citrate in one mixture formed by 50 ml of ethanol (96%) and 25 ml of acetone. Be dispersed 5.5 g of talc as an adjuvant in the process. They charged 650 g of inert core particles in a Wurster device a Glatt device equipped with a 1.2 spray nozzle mm The inlet air temperature was maintained at 40 ° C. The particles were coated with the mixture solution.

Layer (2``), component (a)

Eudragit® RS was applied in a separate layer. Be dissolved 19 g of Eudragit® RS100 and 1.9 g of triethyl citrate in a mixture formed by 400 ml of ethanol (96%) and 200 ml of acetone. 47.5 g of talc was dispersed as an adjuvant in the process. This suspension was applied to previously charged particles in a Wurster device equipped with a spray nozzle 1.2 mm The inlet air temperature was maintained at 40 ° C.

Layer (3), component (b)

An enteric coating layer was prepared which It was applied and dried as in Example 1.

Example 7 Dissolution experiments at pH = 6

The finished particles of Examples 1-5 and Reference Examples 1-5 were subjected to dissolution experiments. The data obtained are summarized in Table 2 and in Figure 2. In vitro dissolution characteristics were determined using a vane stirrer of apparatus 2 according to F. Eur. This is a typical test used to obtain known galenic preparations. generally for the person skilled in the art and that allows to predict the release properties of an active ingredient in the gastrointestinal tract. The speed of rotation of the vanes was set at 50 rpm. The particles were dissolved in 500 ml of phosphate buffer (pH = 6). At regular intervals, triplicate samples were extracted to determine the content of active substance by HPLC. The average values are represented as a percentage of the dissolved active substance. The variation in time of the percentage of dissolution is also called the dissolution profile.

These data indicate that the particles of the The present invention (Examples 1-5) produces a more sustained release than particles included in the state of the technique (Reference Examples 1-5) both in presence (Examples 1-3, 5 and 6 and Examples of reference 1-3, 5 and 6) as in the absence (Example 4 and Reference example 4) of an enteric coating layer.

Example 8 Dissolution experiments at different pH values

Another technical effect of the particles of the present invention is the responsiveness of its solubility against different environmental pH values. Therefore in additional dissolution experiments according to the experimental procedure described in Example 7 (in addition to pH environmental) it was assessed to what extent the dissolution characteristics of the particles of the present invention by ambient pH. A comparison was made with the particles included in the state of the art.

Table 3 and Figure 3 show the comparison of particle dissolution behaviors of Example 1 and Reference Example 1 at pH = 6.0 and pH = 6.8. The particles of Example 1 had characteristics of pH dependent solution at all time points analyzed up to 300 min. On the contrary, the dissolution of particles included in the state of the art of the Example of reference 1 was only affected by the pH at the points 30 min temp. and 60 min.

Table 4 and Figure 4 compare the particles of Example 2 with the particles included in the state of the art of Reference Example 6. Buffer solution with three different pH values was used (6.0, 6.8 Y
7.2).

As can be seen in Figure 4, the particles of the invention had a better ability to pH response in terms of dissolution characteristics. This means that different environmental pH values produced profiles of release more differentiated than in the case of particles included in the state of the art. At pH = 6.0 and 6.8 the particles of the present invention presented profiles of different release, since at a higher pH it was released higher amount of active substance. On the contrary, the differences of amount of active substance released in the included particles in the state of the art at pH = 6.0 and pH = 6.8 were less marked. This means that in the analyzed time points the quantities of active substance released were more similar between yes that the quantities of active substance released in the case of The particles of the invention. In addition, the differences between release profiles at different pH values in the case of particles included in the state of the art were more irregular. This means that, p. For example, at pH 6.0 and pH 6.8 observed any difference in the amount released at the point 60 min time, while, on the contrary, it was observed a difference in subsequent time points. On the other hand, the particles of the present invention showed differences consistent in the release of active ingredients in all Time points analyzed.

In addition, the particles included in the state of the art showed no difference or an insignificant difference in the amount of active ingredient released by the particles at an environmental pH of 6.8 and 7.2. On the contrary, the particles of the invention showed clear differences in the amount of active ingredient released at the pH values analyzed (6.0, 6.8 and 7.2) at all time points of the experiments (t = 0 min.-300
min.)

This result is also confirmed by the data from Table 5 and Figure 5 demonstrating that the pH dependence of the amount of active substance released by part of the particles of the invention is uniformly different for different pH values between 5.5 and 7.2.

These results demonstrate that the behavior dissolution of the particles of the present invention is more sensitive to pH variations, which this sensitivity encompasses a wider range of ambient pH values and that profiles release are affected more consistently and predictably by the pH that in the case of the particles included in the state of technique

Example 9 Influence of the quantity of components (a) and (b) of the layer (2) on dissolution characteristics

To investigate the influence of the amount of polymer of the layer (2) on the dissolution characteristics is they manufactured three batches (lots A, B and C) of particles, each with the same amount (0.4 mg) of Tamsulosin HCl as component (c) but with different amounts of components (a) and (b). Followed practically the procedure of Example 1 although the amounts of components (a) and (b) were adjusted to the amounts of said components in the layer (2) of the finished particles, as indicated in Table 6. Therefore, the layer (2) of the particles of the Lot A contained a total of 8.42 mg of polymeric compounds (equivalent to 87.2% polymer with respect to the component pharmaceutical and plasticizer), layer (2) of Lot B contained a lower amount (5.31 mg) (85.1%) of polymer and the layer (2) of Lot C contained a slightly lower amount than the Lot B (5.03 mg) (84.8%) of polymer. The particles were subjected to dissolution experiments as described in Example 7 and the Results obtained are summarized in Table 6 and in Figure 6.

As can be easily seen in these experiments, the particles of Lot A, which contain the amount higher polymers, have dissolution characteristics which produce a more delayed release profile than lots B and  C, which contain a smaller amount of polymers. This means that the active substance is released more slowly in the Lot A particles. It can also be seen that B and C Lots they have similar release profiles, although the Profile of Lot C is slightly more delayed than that of Lot B. This is consistent with the amounts of polymers contained in these lots, since Lot B contains a slightly amount superior of polymers than Lot C.

These results clearly demonstrate that the relative amount of polymers in layer (2) affects predictable and reproducible to the release profile of a component pharmaceutical of a particle according to the present invention and that the realization of small variations in the amount of polymer allows to precisely adjust the release profiles of the drug.

Example 10 Reproducibility lot-to-lot

To assess the batch-to-batch reproducibility of the dissolution characteristics, a second batch of particles was manufactured according to Example 6 to compare the dissolution characteristics of the particles of the two batches at different pH values. Table 7 and Figure 7 show a high level of reproducibility of the amount of active substance released by the two batches of particles at pH = 6.0 and 6.8 over the entire period of time.
analyzed.

Example 11 Influence of the stirring speed on the solution

To assess the influence of other parameters different from ambient pH particles were dissolved according to Example 6 applying different stirring speeds. In the Table 8 and Figure 8 show a release profile slightly  delayed at 100 rpm versus 50 rpm.

The previous data show that particles of the invention have a more release profile held that the particles included in the state of the art. In addition, the relative amount of copolymers present in the particles reproducibly and predictably affects profiles of release. As a consequence, an amount can be used lower of the copolymers (a) and (b) to achieve the same profile of release in time than that obtained with the particles included in the state of the art.

In addition, the particles of the present invention they have greater sensitivity to the variation of the pH in their release profiles.

All these advantages allow you to adjust with precision drug release from the particles of the invention depending on the physiological conditions of the tract gastrointestinal.

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Table goes to page next)

one

2

3

4

Claims (13)

1. Pharmaceutical preparation for release sustained from a pharmaceutically active principle, wherein said preparation contains particles composed of an inner core (1) and a first coating (2) thereon, wherein said coating (2) contains a mixture of: (a) between 50% and 95% by weight of a copolymer of ethyl acrylate, methyl methacrylate and chloride trimethylaminoethyl methacrylate in a molar relationship between the three 1: 1.8-2.2 acrylates: 0.08-0.12, preferably 1: 2: 0.1, (b) between 2% and 30% by weight of a copolymer of ethylacrylate and methacrylic acid in a molar ratio of 1: 0.8-1.2, preferably 1: 1, (c) between 1% and 40% by weight of at least one pharmaceutically active principle and optionally (d) physiologically acceptable excipients; and, optionally, at least one other additional coating (3) on East. 2. The pharmaceutical preparation according to the claim 1, wherein said coating (2) contains a mix of: (a) between 50% and 95% by weight of said copolymer of ethyl acrylate, methyl methacrylate and chloride trimethylaminoethyl methacrylate in a molar relationship between the three 1: 2: 0.1 acrylates, (b) between 2% and 30% by weight of said copolymer of ethylacrylate and methacrylic acid in a ratio 1: 1 molar, (c) between 1% and 40% by weight of at least one pharmaceutically active component and optionally (d) physiologically acceptable excipients. 3. Pharmaceutical preparation according to the claim 1 or 2, wherein said coating (2) contains a mix of: (a) between 60% and 90% by weight of said copolymer of ethyl acrylate, methyl methacrylate and chloride trimethylaminoethyl methacrylate, (b) between 5% and 20% by weight of said copolymer of ethylacrylate and methacrylic acid, and (c) between 5% and 15% by weight of said principle (s) pharmaceutically assets). 4. Pharmaceutical preparation according to any one of claims 1 to 3, wherein at least a pharmacist principle (s) active (s) is selected from Amlodipine, Budesonide, Candesartan, Cisapride, Diclofenac, Diltiazem, Donepezil, Fentanyl, Glimepiride, Mebeverin, Memantine, Nicardipine, Olanzapine, Omeprazole, Ondansetron, Oxybutynin, Pramipexole, Ramipril, Risperidone, Rivastigmine, Tamsulosin, Theophylline, Tibolone, Tolterodine, Topiramate or Trandolapril. 5. Pharmaceutical preparation according to any one of claims 1 to 4, wherein the core Internal (1) contains a physiologically acceptable excipient. 6. Pharmaceutical preparation according to the claim 5, wherein at least one physiologically excipient Acceptable is selected from sucrose, glucose and starch. 7. Pharmaceutical preparation according to any of claims 1 to 6, wherein the inner core (1) has a diameter between 0.1 and 2.0 mm, preferably between 0.4 and 0.8 mm, especially of 0.5
mm 8. Pharmaceutical preparation according to any one of claims 1 to 7, wherein said additional coating (3) is at least one selected from enteric coatings and lacquer coatings. 9. Pharmaceutical preparation according to the claim 8, wherein said enteric coating is resistant to gastric juice. 10. Pharmaceutical preparation according to the claim 8 or 9, wherein the enteric coating contains at least one component selected from an acid polymer methacrylic, cellulose derivatives, plasticizers, lubricants, release agents, colored pigments or silicone antifoam. 11. Pharmaceutical preparation according to a any one of claims 1 to 10, prepared in the form of capsules, tablets or granules. 12. Process for manufacturing a preparation sustained release pharmaceutical according to any of claims 1 to 7, wherein the components (a), (b) and (c) they are dissolved in a mixture of solvents and applied on the inner core (1). 13. Process for manufacturing a preparation sustained release pharmaceutical according to any of claims 8 to 11 using the process of the claim 12, wherein at least one other coating is applied (3) on the first coating (2).