CA1225596A - Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content - Google Patents

Abstract

ABSTRACT

A process for the preparation of sustained release tablets having an active ingredient content of at least 80% and possessing a structure which loosens in aqueous medium but does not disintegrate to discrete particles within 4 hours, in which the particles of the active ingredient are coated in a liquid medium with a water-insoluble polymer -preferably ethylcellulose-and then mixing the coated particles with at least one disinteg-rant which is capable swelling in aqueous medium, and then pressing the mixture into tablets.

Description

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PROCESS FOR THE PREPARATION OF SUSTAINED RELEASE
PHARMACEUTICA~ COMPOSITIONS HAVING A HIGH ACTIVE
INGREDIENT CONTENT
Field of the invention This invention relates to a process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content. The process of the present invention can be widely used in the pharmaceutical industry for the preparation of sustained release tablets.
The advantage of the proess of the present invention is that it is generally applicable to a wide range of active ingredients and provides sustained release tablets having a high active ingredient content above 80%.

Background of the invention The advantages of sustained release pharmaceutical compositions are well known and their use is becoming more and more widespread. The methods used in this field of pharmaceutical industry are continuously developing.
However, the requirements for sustained release compositions are considerably higher and more stringent than those required from conventional pharmaceutical compositions. For this reason there is no known process which can be applied to any active ingredient and which meets all re~uirements. The preparation of sustained release pharmaceutical compositions from active ingredients having a relatively high therapeu-tical dose is particularly fraught with difficulties because the solid oral pharmaceutical compositions are of a limited size (the weight of a single dosage unit can generally he not more than 0.8-1.0 g) and for this reason the known methods whexein the sustained release e~fect ~as achieved with the 122~ii5~, aid of a relatively higher amount of auxiliary agents (the amount of the said auxiliary agent being approximately the same as that of the active ingredient) were not applicable or applicable only to a very limited extent.
Sustained relase pharmaceutical compositions corresponding to a relatively high single dosage unit of 100-500 mg can be prepared first of all in the form of matrix tablets. This is due to the fact that pharmaceutical compositions which have the lowest specific volume and may be hence most easily swallowed, can be manufactured by pressing.
According to U.S. Patent No. 2,895,881 waxes or fatty substances or hydrogenated castor oil can be used as release retarding agent in the preparation of matrix tablets. For this purpose glycerol monostearate (U.S. Patent No. 2,993,839), a mixture of stearic acid and castor oil (U.S. Patent No. 2,736,628), waxes, a mixture of waxes and water insoluble substances and mixture of waxes and hydrophylic polymers (U.S. Patents Nos. 4,132,753, 3,402,240, 3,459,850 and 3,487,138) can also be applied. According to U.S. Patents Nos. 2,987,445 and 3,317,394 water insoluble polymers, polyethylene and polymethyl methacrylate and polyvinyl chloride can be used as release retarding agent.
It is also known that a mixture of waxes and water insoluble polymers (U.S. Patent No. 3,965,256), mixtures of polymers which readily swell in water and form a gel (U.S.
Patent No. 3,065,143), polymers forming complex with each other in water (carbopol; an acrylic acid polymerisate) and polyvinyl pyrrolidone (U.S. Patent No. 3,458,622) and a mixture of carbopol and polyoxyethylene glycol (U.S. Patent No. 3,634,584) can also be used as release retarding agent.
British Patent No. 935,672 discloses the USQ of protein 122~s~

derivatives, while in U.S. Patent No. 3,062,720 the use of water insoluble substances (e.g. talc, calcium sulfate, calcium hydrogen phosphate, etc.) is reported. According to .S. Patent No. 3,905,508 a mixture of talc, ethyl cellulose and a metal stearate is used.
The matrix tablets disclosed in the aforementioned references comprise 10-70% of active ingredient. Sustained release tablets having a higher active ingredient content than the above value can only be prepared from active ingredients that are poorly soluble in aqueous medium (less than 1%).
According to the above references, matrix tablets are prepared by means of conventional granulating methods (by wet or dry granulation) or in the case of fatty substances by melting the release-retarding ingredients and incorporating the active ingredient into the liquid matrix material.

Detailed disclosure of invention The object of the present invention is to overcome the above drawbacks of the known methods and to provide a process for the preparation of sustained release pharmaceutical compositions, which is applicable to any active ingredient and ensures a high active ingredient content.
The sustained release solid pharmaceutical compositions of this invention have a high active ingredient content of more than 80%, prepared by compressing a composition that is a mixture of particles wherein the particles of the active ingredient are coated with a film that is insoluble in aquQous medium, and at least one 12~i59~, , disintegrating agent capable of swelling in aqueous medium.
The pharmaceutical compositions may also contain further auxiliary agents (e.g. fillers, lubricants, friction reducing agents, etc.). It is an essential feature of the present invention that the particles of the active ingredient be coated in a li~uid phase by microencapsulation. The release of the active ingredient from the solid pharmaceutical composition is slowed down by the "barrier" effect of the water insoluble matrix structure formed during compressing the microencapsulated material. A substance that is capable of swelling in water acts as a disintegrant which loosens the structure of the matrix and enables the penetration of the solvent medium into the inner layers of the compressed matrix. Thus, the release of the active ingredient takes place over about 8 hours which is optimal for oral absorption. If desired, the release rate can be changed by modifying the chemical composition. The amounts of the film forming agent and of the disintegrating agent and can be adjusted to a value that is optimal for a given therapeutical application.
It has been found that the release rate can be appropriately decreased and release can be retarded also in the case of active ingredients that are readily soluble in water. This can be accomplished by applying onto the particles of the active ingredient a water insoluble coating by means of microencapsulation in li~uid phase and then pressing tablets from the microcapsules thus prepared. The tablets also contain at least one disintegrating agent capable of swelling in water that is used in a sufficiently low concentraticn which only loosens the structure of the tablet in the aqueous medium but causes no disintegration thereof to discrete particles.

122~i596 The use of microencapsulation methods for the preparation of sustained release pharmaceutical compositions is known per se. However, according to the known processes in most cases a relatively high wall thickness was required to retard the release of the active ingredient. According to U.s. Patent No. 3,557,279 a triple of normal amount of ethyl cellulose is used in the preparation of microcapsules containing indomethacin and having a suitable release rate.
According to Pharmazie 10, 721-723 (1976) and J. of Pharmacy and Pharmacology 912-914 (1976) the release of chloramphenicol and sodium phenobarbital is retarded by preparing microcapsules in which the ratio of active ingredient and ethyl cellulose encapsulating wall material is 1:2, 1:1 and 2:1, respectively. According to U.S. Patent No.
3,909,444 the active ingredient is first granulated with a polymer that is insoluble in acidic medium and the granules thus obtained that have a matrix structure, are thereafter coated with ethyl cellulose.
Microcapsules are generally used either filled into hard gelatin capsules or in suspension to protect the walls of the microcapsules from damage. Special safety measures have to be taken when such microcapsules are pressed into tablets to maintain the release rate of the active ingredients at the original level. According to U.S. Patent No. 3,922,338 microcapsules diluted with a large, such as 1 to 1.5 fold amount of filling material, are introduced into the middle layer of sandwich structure tablets having three layers. In the case of ~ctylsalicylic acid active, the use of crystals of suitable particle size (0.15-1.8 mm) and of suitable form (the ratio of the size of the edges of crystal partiales is 1:2:4) protects the microcapsulQs from damag~

during pressing and provides a disintegration time o~ less than 1 minute (within an hour the relase of the activeingredient is below 70% -U.S. patent specification No.
3,488,418 and 3,524,910). In this particular case, the special and favorable properties of acetylsalicylic acid enable the preparation of pharmaceutical compositions exhibiting a sustained therapeutical effect for about 8 hours in spite of the relatively rapid (not longer than 4 hours) release.
Microencapsulation of acetylsalicylic acid is discussed in several U.S. patent specifications (e.g. U.S.
Patent Nos. 3,341,416, 3,155,590, 3,703,576, 3,951,851 and 3,891,570). According to these patents, the ratio of core material to wall material is 1:50-1:1 but these patents are entirely silent respecting any data about the changes that occur in microcapsules during pressing. In the afore-mentioned U.S. patents, the use of several polymers is mentioned (e.g. cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcelluloseacetate-phthalate;
various ethyl cellulose derivatives).
With the only exception of acetylsalicylic acid, no process is known for the preparation by microencapsulation of sustained release pharmaceutical compositions having an active ingredient content above 80%.
When studying the release of the active ingredient from tablets pressed ~rom microencapsulated active ingredi-ents, it has been found that when rapidly disintegrating tablets are prepared the release becomes rapid as a result of the damage of the wall of the microcapsules caused during pressing. This release rate is substantially the same as that of conventional tablets, i.e. within an hour a 100%
release is obtained. On the other hand, i~ microcapsules are pressed into tablets by themselves or by the addition of ~3 .

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only a lubricant, the release rate slows down to a great extent and a 100% release can be achieved within as long as 8-10 hours. In the latter case, the retarding of the release is attributable to the crosslinked matrix structure formed between the walls of the microcapsules during pressing. It has been surprisingly found that such crosslinked matrix structure brings about a very significant release retarding effect, even when present in a relatively small amount, such as 2-18% by weight. The release rate can be controlled by modifying the amount of matrix material (i.e. that of the wall material of the microcapsules) and the pressing strength. It has been found, however, that the release rate of the compositions cannot be optionally modified just by varying the said two parameters. The release is either too rapid or so slow that complete release of the active ingredient does not take place even within 8-10 hours.
It has been found that the release of the active ingredient can be modified within very broad limits in a highly reproducible manner when a disintegrating agent capable of swelling in water is added to microcapsules from which tablets passing overly slow release properties can be prepared by pressing. This can be done when the disintegrant is added in such an amount which does not cause disintegra-tion of the tablets to discrete particles having a particle size smaller than 1 mm but merely loosens the structure of the matrix in the aqueous medium. Any suitable disintegra-ting agent used generally for this purpose in the manufacture of tablets can be employed, such as starch and derivatives thereof, carboxymethyl starch, carboxymethyl cellulose, formaldehyde caseine, crosslinked polyvinyl pyrrolidone, etc.

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Practically any film forming polymer material that is insoluble in aqueous medium can be used for the preparation of microcapsules, such as cellulose acetate, polyvinyl acetate, polyvinyl butyral. Ethyl cellulose is particularly suitable. Microencapsulation can be carried out with the aid of any suitable microencapsulating process known ~er se, which is capable of forming an uniform continuous coating on the surface of the particles of the active ingredient. In the case of ethyl ~.ellulose, suitably a process carried out in a cyclohexane medium can be used as disclosed in U.S. Patent No. 3,531,418 and British Patent No.

2,002,318. The solvent evaporating methods can be carried out with other polymers as described in U.S. Patents Nos.

3,891,570 and 3,951,851.
The particle size of the active ingredient used for microencapsulation is not critical. It is preferred to grind crystalline active substances to a particle size below 50 /um to form a continuous coating on the surface of the particles. The quality of the coating can be checked in a simple manner by a polarizing microscope.
The in vitro release of active ingredient particles (microcapsules) coated with a uniform layer was studied by microscopic measurements. It has been found that even if the amount of the coating substance is 10-18%, the release rate is too large, about 90-100% within an hour.
This means that the microcapsules are not suitable for the preparation of sustained release pharmaceutical compositions not by themselves and also not when filled into hard gelatin capsules. It is therefore indispensable to convert the microcapsules to matrix tablets by pressing.
According to the present invention, a process for the preparation of sustained release solid pharmaceutical " ~2~i5;~1Si compositions is provided, the compositions having an active ingredient content of at least 80~ and having a structure which loosens in aqueous medium but does not disintegrate to discrete particles within 4 hours, which comprises coating the particles of the active ingredient in a liquid medium with a water ins~luble polymer, suitably with an ethyl cellulose polymer film, and thereafter admixing the coated active particles with at least one disintegrating agent that is capable of swelling in aqueous medium, *nd pressing the mix~ure into tablets.
According to the process of the present invention, sustained release tablets can be prepared, comprising at least 80% of the active ingredient. In the first step of the process of the present invention, the particles of the active ingredient are subjected to microencapsulation. This may be particularly advantageously carried out by microencapsulation with ethyl cellu~ose in cyclohexane solvent medium. The crystal particles of the active ingredient and 2-18% based on the active ingredient of ethyl cellulose such as sold by Hercules, Inc. under the trade name N-100, are dispersed in so much cyclohexane that the athyl cellulose concentration should amount to 2-5%. The system is warmed to 80C, kept at this temperature for an hour and cooled slowly to room temperature. Polyisobutylene may be added to the system or the particles of the active ingredient are ground to a particle size below 50 /um to improve the uniform character of the coating of the microcapsule. The microcapsules are filtered off fro~ tne ~ooled system. rnen they are dried, sieved, mixed with a suitable disintegrating agent and optionally with lubricants and finally pressed into tablets of high solidity.
_g_ ~2~559~i In the case of certain active ingredients, the parameters which ensure optimal release rate, such as starting particle size o~ the active ingredient, amount of ethyl cellulose, character and amount of the disintegrating agent etc. have to be determined by routine experimentation which can be easily performed.
Further details of the present invention are disclosed in the following Examples without intending to limit the scope of protection to the said Examples.

Example 1 Preparation of Sustained Release Tablets comprising L-~ methyl-dopa (L-~ - methyl-3,4-dihydroxy-phenylalanine) as active ingredient 200 g of L-oC-methyl dopa (particle size below 50 um) and 20 g of ethyl cellulose (quality: N-100, ethoxy content: 47.5-49%, viscosity 100 mPa measured at 25C in a 5% by weight 80:20 toluene ethanol mixture) and 10000 ml of cyclohexane are introduced into a 2 round-bottomed flask eguipped with a reflux condenser and a stirrer.
The powder is suspended under constant rate of stirring -about ~00-250 r.p.m.- and the mass is warmed to 80C with the aid o~ a water bath. The mixture is refluxed under stirring at this temperature for 30 minutes and allowed to cool to 40C within about an hour under constant stirring. On cooling, the particles become coated with ethyl cellulose. The resulting material is cooled with cold water below 20C, the microcapsules are isolated by filtration and dried at room temperatura on a tray. ~n sieving, the product thus obtainQd on a 1 mm sieve, free flowing, ~2t2~59~

nonsticking and nonadhering granules are obtained. Under microscope it is observed that the product consists predominantly of almost isodiametrical agglomerates of 100-300 /um which do not show any crystalline character under polarized light. If L ~ -methyl-dopa having a particle size larger than 100 um is used for microencapsulation, the peaks of the crystal particles are not coated by ethyl cellulose.
In a double-conical mixing apparatus the following powder mixtures are prepared from the above microcapsules by homogenizing for 20 minutes.

Amount in the mixture (g) Component I II III IV

L- ~ -methyl-dopa microcapsule~ 88.7 88.7 88.7 88.7 Microcrystalline cellulose 10.3 6.3 6.3 9.4 Potato starch -- -- 4.0 --Sodium carboxy-methyl cellulose (Nymcel) -- 4.0 -- 0.9 Magnesium stearate1.0 1.0 1.0 1.0 100.O 100.O 100.O 100.O

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The powder mixture thus contained is pressed into ta~lets comprising 500 mg of L-c~-methyl-dopa, having a diameter of 12 mm and a breaking strength of 100-120 kN.
The release of the active ingredient is determined by the "half-change" stress method by using a disintegration testing apparatus according to USP XX. Dissolution is started in the first hour with artificial gastric fluid and the half of that solvent medium is replaced in each hour with artificial intestinal fluid.
The composition of artificial gastric fluid is as follows:
Sodium chloride 2 g N hydrochloric acid 80 ml Distilled water to 1000 ml The composition of the artificial intestinal fluid is as follows:
Disodium hydrogen phosphate 8.05 g Sodium dihydrogen phosphate 1.56 g Distilled water to 1000 ml During the test, 6 tablets are placed into each container of the apparatus and the containers are moved in a beaker maintained by thermostat at 37C and comprising 800 ml of dissolving medium, vertically with an amplitude of 2.5 cm and a speed of 0 cm/sec. After the half of the dissolving medium has been replaced, the L-~C-methyl-dopa concentration of the residual liquid is spectrophoto-metrically determined.

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The results of the release experiment are summarized in the following table:

Amount of released active Release time ingredient, %
(in hours) I II III IV

1 26.5 98.3 44.5 44.0 2 -- 55.8 55.9 3 66.8 71.1

4 36.6 -- 75.7 92.9 39.6 -- 82.9 92.9 6 42.8 -- 89.0 99.4 7 46.4 -- -- 102.2 8 50.0 -~

.

On the basis of the above in vitro release tests, compositions III and IV of the present invention were determined to meet the requirements of sustained release compositions. The release rate of composition I containing no disintegrating agent is too slow while that of composition II containing a large amount of Nymcel disintegrant is too rapid, because the tablet disintegrates within 5 minutes. On decreasing the amount of Nymcel, the desired release rate can be adjusted.

Example 2 Preparation of sustained release Trimethoprim tablats In this Example, the effect of the ethyl cellulose 122~;i59~;
content and disintegrating agant content of the microcapsules and that of the size of pressing strength on the release of active ingredient is demonstrated.
1000 ml cyclohexane are introduced into the apparatus according to Example 1, 10 g of polyisobutylene (Oppanol, molecular weight 90,000) are dissolved and to the solution thus obtained there are added 200 g of trimethoprim ~2,4-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine;
particle size below 200 um] and in three batches ethyl cellulose in three different amounts [lO g, 20 g and 30 g, respectively: quality as described in Example 1]. The mixture is stirred at a rate of 200 r.p.m. and worked up according to Example 1.
The microcapsules are homogenized with po~ato starch and magnesium stearate; the amounts of the components are shown in the following table. The mixture is pressed into tablets in an eccentric tablet-manufacturing machine equipped with a dynamometer comprising a strain gauge. The tablets contain 200 mg of trimethoprim and have a diameter of 10 mm.
Release tests are carried out in the apparatus described in Example 1 except that the artificial gastric fluid of the same composition is used throughout the entire experiment and samples of 10 ml.are taken every hour for spectrophotometrical analysis.
The composition of the powder mixture, the compressive strength and the release of the active ingredient from the tablets are shown in the following table.

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i-- ~ ~ ~ o ~225596 As it appears from the above table, the release of active from tablets prepared from microcapsules in which the ratio of ethyl cellulose to trimethoprim is 1:20, is too rapid even in the presence of as little as 1% of potato starch, while in the case of microcapsules which correspond to an ethyl cellulose to trimethoprim ratio of 2:20 more than 7% of potato starch are required to ensure complete release rate.
The above experimental results clearly show the effect of certain parameters on the release rate and the optimal composition can be determined by taking into consideration these effects.

Example 3 Preparation of sustained release potassium chloride tablets Potassium chloride is microencapsulated according to Example 1 by using 200 g of potassium chloride (particle size below 71 /um) and ~o g of ethyl cellulose (N 100).
A powder mixture having the following composition is prepared from the microcapsules having the following composition:
Potassium chloride microcapsule 98.0 g Potato starch 1.0 g Magnesium stearate 1.0 g Tablets having a diameter of 12 mm, a potassium chloride content of 500 mg and a breaking strength of 100-1~0 N are prepared from the homogenisate. The potassium chloride release of the resulting tablets is shown in the following table:

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Release time Released potassium (hours) chloride %

3 48.5 .

The release rate is determined in an Erweka type disintegration testing apparatus according to USP XX by using distilled water as dissolving medium and determining the amount of released potassium chloride by measuring conductivity.

Exam~le 4 Preparation of sustained release theophylline tablets Microencapsulation is carried out according to Example 2 by using 200 g of theophylline (particle size below 500 /um) as core material and 20 g of ethyl cellulose (type N 100) as coating material.
From the said microcapsules a powder mixture having the following composition is prepared:

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Theophylline microcapsules 275.0 g Nicrocrystalline cellulose 5.5 g Lactose (monohydrate) 18.0 g Magnesium stearate 1.5 g Total weight 300.0 g Tablets having a diameter of 10 mm, a breaking strength of 80 N, weighing 300 mg and comprising 250 mg of theophylline as active ingredient are pressed from the powder mixture. The release rate is determined according to Example 2 and the following results are obtained:

Release time Released theophylline (hours) %
19.1 2 29.5 3 39.0 4 52.9 68.4 6 82~7

Claims (9)

We claim:

1. A process for the preparation of sustained release tablets having an active ingredient content of at least 80% and possessing a structure which loosens in aqueous medium but does not disintegrate to discrete particles within 4 hours, which comprises coating the particles of the active ingredient in a liquid medium with a water insoluble polymer, thereafter admixing the coated active ingredient particles with at least one disin-tegrating agent being capable of swelling in aqueous medium, and pressing the mixture into tablets.

2. A process according to claim 1, wherein the water insoluble polymer is 2-18% by weight of ethyl ellulose.

3. A process according to claim 1 wherein 1-16% by weight of disintegrating agent is added.

4. A process according to any of claims 1-3 wherein the disintegrating agent is microcrystalline cellulose, potato starch, carboxymethyl cellulose, or a mixture of potato starch and microcrystalline cellulose.

5. A process according to any of claims 1-3 wherein L- methyl-3, 4-dihydroxy-phenyl alanine is the active ingredient.

6. A process according to any of claims 1-3 wherein 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl) pyrimidine is the active ingredient.

7. A process according to any of claims 1-3 wherein theophylline is the active ingredient.

8. A process according to any of claims 1-3 wherein potassium chloride is the active ingredient.

9. A sustained release tablet having an active ingredient content of at least 80% whenever prepared by the process according to any of claims 1-3.