|Title of Invention||
"A PROCESS FOR THE PREPARATION OF A COPOLYMER"
|Abstract||Copolymers consisting of ethylenically unsaturated, radically polymerisable monomers having a carboxyl group, and alkyl esters of such monomers, synthesised from A) 10 to 25 wt.% of methacrylic acid, B) 40 to 70 wt.% of methyl acrylate C) 20 to 40 wt.% of methyl methacrylate, are suitable as coating and binding substances for pharmaceutical compositions which enable a release of the active substance at pH 6.5 to 7 and dissolve at pH 7.5, especially when the copolymer is present as a latex dispersion in an aqueous phase.|
|Full Text||The present invention relates to the process for the preparation of a copolymer of ethylenically unsaturated, radically porymerizable monomers with a carboxyl group and alkyl esters of such monomers. Said copolymers are preferably present as latex dispersions in an aqueous phase. The copolymer may be used as coating and binding agent for pharmaceutical compositions.
Coating substances for pharmaceutical compositions having the above-mentioned composition are known from DE-C 2 135 073 in the form of an aqueous dispersion. They contain emulsion polymers which are synthesized, as a rule, from 50 wt.% of methacrylic acid and 50 wt. % of methyl or ethyl acrylate. A binding agent of this kind is available commercially under the trade name EUDRAGIT L30D (Trademark of Rohm GmbH, Darmstadt).
Coatings for pharmaceutical compositions prepared from this substance are insoluble in the acid medium of the gastric juices. They only dissolve in the intestinal juices at pH value of 5.5 and above leading to release of the core which contains the active substance so that it may dissolve. Different release characteristics are required for different active substances. Some pharmaceutical compositions are intended to release the active substance as soon as the composition enters the duodenal or the upper intestinal regions at pH values of about 5 to 6. Other compositions only do so when they reach the lower intestinal regions up to the colon, at pH values of about 6 to 7.5. For this purpose, a
sufficiently wide range of coating substances is required having different pH release values, in order to control the release of the active substances in these intestinal regions.
The release characteristics of coatings of pharmaceutical substances in vitro are usually tested using artificial gastric juice (0.1 n HC1) and artificial intestinal juice (pH 6.8) using USP. In order to measure the gradual dissolution of the coatings in the intestinal region, it has proved advantageous to determine the rate at which a water-soluble substance contained in the pharmaceutical composition is released, initially into artificial gastric juice over two hours and then into buffer solutions, starting at pH 5.0, and then changing the buffer solution every sixty minutes, and increasing the pH value by 0.5 each time.
Aqueous coating substances which also permit the preparation of pharmaceutical compositions with a pH release value of 7 to 7.5 are already known from EP-B 152 038. For this, however, the mixing of at least two dispersions of coating substances is necessary, of which one is responsible for the pH control and the other for the adjustment of the elasticity of the coat. This latter neutral polymer component, however, is insoluble in intestinal juice and its presence frequently results in an undesirable delay in the dissolution even when the desired pH value has been reached.
We have now prepared a coating substance which may be used in the form of an aqueous dispersion. It produces coatings which dissolve in the lower intestinal regions or in the colon and, when the above-mentioned testing method is used, only permits the release of the active substance from the coated pharmaceutical compositions at pH 6.5 to 7.0 and at the latest, by the time pH 7.5 is reached, within a period of up to 120 minutes. Here, it
is desirable to retain the advantageous applicational characteristics of the known aqueous coating substances. When drying the coating, which contains not more than 10 wt. % of plasticizer based on the emulsion polymer, film formation is intended to take place below 30°C.
With a commercially available coating substance based on a copolymer consisting of methacrylic acids and ethyl acrylate in a ratio of 50:50, the desired release characteristics cannot be achieved by reducing the methacrylic content in the copolymer. Such a reduction only results in delayed dissolution, i.e. in a flatter release curve, but not in an increase of the pH value at which release commences. The release starts at pH 5 to 6 when the methacrylic content is only 10%. The use of comonomers which reduce the hydrophilic behaviour of the coating substance, such as butyl- or 2- ethylhexylesters of acrylic- or methacrylic acid, have not been successful either, since here too there is a delay in dissolution, but not an increase in the pH values at which dissolution commences.
In accordance with the present invention, there is provided a process for the preparation of a copolymer of ethylenically unsaturated, radically polymerizable monomers having a carboxyl group and alkyl esters of such monomers, said process comprising copolyrnerizing in any known manner such as herein described 10 to 25 wt. % of methacrylic acid (A), 40 to 70 wt. % of methyl acrylate (B), and 20 to 40 wt. % of methyl methacrylate (C).
The coating and binding agent for pharmaceutical compositions comprising the copolymer so prepared is novel and it is found to be giving the desirable release characteristics.
Surprisingly, pharmaceutical preparations with a coating of this composition are resistant to gastric juice when the USP test is carried out and release virtually no active substance at pH 6.8, whereas complete release is achieved at pH 7.5 within 60 minutes. The advantageous release characteristics of the coating according to the invention are clearly apparent from Figure 1. For this, coating films have been applied onto glass beads in a normal layer thickness for pharmaceutical compositions, and the amount of polymer which dissolves at certain pH values has been determined by pH-stat-titration using alkali.
Figure 1 shows the dissolution curves for three coating substances according to the invention (Bl, B2 and B4, as listed in the Examples 1, 2 and 4), which have the following compositions (in wt.%)
These curves are compared with those of several coating substances (A, V1 to V4) which have the following compositions (in wt.%)
A corresponds to the commercial product EUDRAGIT L100. The preparation of V1 is described in Example 3. V2, V3 and V4 were prepared analogously using emulsion polymerisation. The curves for V2, V3 and V4 are almost
congruent and are jointly denoted by V2 in Figure 1. The advantageously steep path of the curves for the coating substances Bl, B2 and B4, according to the invention, which lie at higher pH values, could not be foreseen. Above pH 7.5, a complete dissolution of the coating substance is achieved.
A further advantage is the high elasticity and stretchability of the coating film. This is due to the comparatively low amount of solidifying monomer ingredients such as methyl methacrylate and methacrylic acid. However, it is surprising that by simply using methyl methacrylate, which produces the highest polymer hardness out of all the alkyl acrylates when used as a homopolymer, a stretchability is achieved which meets practical requirements. Therefore, plasticiser amounts of below 10 wt.% are generally sufficient, or plasticiser may even be dispensed with altogether. Any technical disadvantages which usually accompany the use of larger amounts of plasticisers are thus avoided.
The invention fills a gap in the galenic range of coating substances by providing coating substances with release curves at different pH values. Though coating substances have been available for the commencement of the release from pH 5.5 to 6.5, starting the release at pH 7 has not previously been possible in a satisfactory manner.
Preparing the coating substance
The coating substance according to the invention may be prepared in a manner known per se through radical emulsion polymerisation in an aqueous phase, in the presence of, preferably, anionic emulsifiers, using the method described in DE-C 2 135 073.
The monomer components denoted by A, B and C usually
form more than 80 wt.% and, preferably, 100 wt.% of the copolymer. The optionally remaining part may consist of other acrylic or methacrylic monomers, more particularly alkyl esters such as ethyl acrylate and methacrylate or butyl acrylate and methacrylate. The molecular weight is within the usual range, e.g. 50,000 to 300,000 Dalton.
The copolymer may be prepared by conventional methods of radical polymerisation in the presence of radical-forming initiators and, optionally, regulators for adjusting the molecular weight, in substance, solution or in emulsion. The use of emulsion polymerisation in aqueous phase, in the presence of water-soluble initiators and (preferably anionic) emulsifiers, is preferred. The emulsion polymer is, preferably, prepared and used in the form of a 10 to 50 wt.%, more preferably a 30 to 40 wt.%, aqueous dispersion. When used commercially, a solid content of 30 wt.% is preferable. For the purpose of further processing, the methacrylic acid units must be partly neutralised. A neutralisation of e.g. up to 5 or 10 mol % is possible if a thickening of the coating-substance dispersion is required. The weight average of the latex particle size is normally 40 to 100 nm, preferably 50 to 70 nm which ensures a viscosity of below 1,000 mPa s which is advantageous for the processing.
The minimum film-forming temperature (MFT according to DIN 53 778) is between 0 and 25°C for most coating substances according to the invention, so that processing is possible at ambient temperature without the addition of a plasticiser. The break elongation of the films, measured according to DIN 53 455, is normally 50% or more if they contain a maximum of 10 wt.% of triethylcitrate.
The softening temperature of the polymer film produced
upon drying, which is determined by DSC measurement, is preferably within the range of 40 to 80°C, more preferably 45 to 70°C. The temperature stability of the emulsion polymers, determined by thermo-gravimetric analysis (TV0,1) is generally over 200°C, mostly within the range of from 200 to 240°C, which is surprisingly high for copolymers containing carboxyl groups. It is therefore also possible to process the emulsion polymers from the melt. Typical melting viscosities are as follows with e.g. emulsion polymers consisting of
60% MA, 20% MMA, 20% MAS of 8,000 Pa s at 160°C 60% MA, 25% MMA, 15% MAS of 4,000 Pa s at 150°C
(MA = methyl acrylate, MMA = methyl methacrylate, MAS = methacrylic acid, data in wt.%).
Processing of the coating substances to form pharmaceutical preparations
The new coating substances may be prepared in a similar way to other known aqueous coating substances based on acrylate. The most commonly used methods are the coating pan method and the fluid bed process. Standard amounts of the usual additives, e.g. plasticisers, pigments, fillers, thickening agents, defoaming agents and preservatives, may also be used. The coatings may be produced on plain and coated tablets, granules or crystals. It is also possible to produce matrix tablets or granules. The preferred processing temperatures are within the range of 30 to 60°C. Suitable film thicknesses are 10 to 80 micrometer.
It is also possible to utilize the pH control of the release of active substances through the coating film not only in the gastro-intestinal tract, but also in other body cavities, tissues, in the bloodstream and in the habitats of animals and plants in order to commence
the release of active substances there as the result of a change in pH value. This includes, for example, films which are introduced into the bloodstream by means of catheters, and implants of veterinary pharmaceutical agents and vaccines such as are added to fish food.
As with other aqueous coating substances, it is also possible to produce multi-layered coating systems. A core, for example, which contains alkaline or water-sensitive active substances may be provided with an insulating layer of another coating material such as cellulose ether, cellulose ester, cationic polymethacrylate (e.g. BUDRAGIT E100, -RL100, -RS100, all of Rohm GmbH), before the coating substance of the invention is applied. Likewise further coating layers, such as those which conceal the taste or have an attractive colour or sheen may subsequently be applied.
Example 1 - coating substance BI
297 g of an emulsion polymer consisting of 60 parts by weight of methyl acrylate, 25 parts by weight of methyl methacrylate and 15 parts by weight of methacrylic acid with 30% of dry substance (89 g of polymer substance) are diluted by adding 238 g of water.
1,000 g of round, slightly concave tablet cores, 7 mm in diameter, 3.3 mm in height and 140 mg in weight,
consisting of lactose (59.2 weight %) , Aerosil 200 (0.5 weight %), talc (3.0 weight %), microcrystalline cellulose Avicel pH 102 (30 weight %) magnesium stearate (0.3 weight %) Amijel (starch) (5.0 weight %) plus methylene blue (2.0 weight %) as an indicator, are heated to 30 C using hot air in a 25 cm diameter onion-shaped coating pan rotating at 40 rev./min. The dispersion is sprayed on at this temperature by means of an air pressure spray gun using 1 bar compressed air. The dispersion is continuously sprayed on for 140 minutes at a spraying rate of about 4 g of dispersion per minute. The coated tablets are then dried for 2 hours at 40 C in a drying
cupboard, stored uncovered overnight under ambient conditions, and then decomposition and dissolution behaviour is tested using DSP dissolution/ apparatus 2 (paddle). After having been in artificial gastric juice for 120 minutes followed by a further 60 minutes in buffer solution at pH 5,0, the coated tablets were recovered unchanged. When a buffer solution at pH 6.8 was used, all tablets disintegrated within 40 min.
Example 2 - coating substance B2
Analogous to-Example 1, 297 g of an emulsion polymer consisting of 65 parts by weight of methyl acrylate 25 parts by weight of methyl methacrylate and 10 parts by weight of methacrylic acid containing 30% dry substance (corresponding to 39 g of polymer substance) were mixed with 22.3 g of talc and diluted with 238 g of water. The processing was carried as in Example 1 under the conditions described. The spraying rate was 4.5 g per minute and the spraying therefore lasted 124 minutes. The coated tablets were subsequently dried as in Example 1 and tested. Over two hours, they were resistant to gastric juice, they did not dissolve in buffer solutions at pH 5.0 and 6.8 after 60 minutes but they disintegrated in buffer solution at pH 7.5 within 50 minutes, as shown by the methylene blue dyestuff dissolving.
Example 3 - Comparison.polymer VI
As described in Example 1, an emulsion polymer consisting of 50 parts by weight of methyl acrylate, 20 parts by weight of methyl methacrylate and 30 parts by weight of methacrylic acid was processed .while adding 8.9 g of triethyl citrate as plasticiser. The coated tablets were resistant to gastric juice for 2 hours. They then remained unchanged for 60 minutes in a pH 5.0 buffer solution and disintegrated in a pH 6.5 buffer
solution within 1 hour.
Example 4 - Coating substance B4
In a fluidized bed apparatus GPC made by Glatt GmbH D-79589 Binzen, while rotating continuously, a mixture containing 417 g of a 30% emulsion polymer consisting of 70 parts by weight of methyl acrylate, 20 parts by weight of methyl methacrylate and 10 parts by weight of methacrylic acid, and an emulsion of 3.8 g of glycerol monostearate in 224 g of water were sprayed onto 1 kg of spherical particles with a diameter of 0.8 to 1.2 mm, containing 4.4 wt.% of bisacodyl as an active substance. The spraying rate was 10 g per min, while the spraying dispersion was supplied continuously to the spraying nozzle of the fluidized bed apparatus by means of an elastic hose pump. The resistance to gastric juice of the coated pellets and the dissolution speed thereof in a pH 6.8 buffer solution was then tested in a USP XXII Apparatus 2 (paddle). The release of bisacodyl from the pellets in gastric juice was less than 3% after 2 hours. After changing the test fluid to a pH 6.8 buffer solution the pellets gradually disintegrated and released more than 99% of the active substance contained therein within 45 minutes.
WE CLAIM: -
1. A process for the preparation of a copolymer of ethylenically
unsaturated, radically polymerizable monomers having a carboxyl
group and alkyl esters of such monomers, said process comprising
copolymerizing in any known manner such as herein described 10
to 25 wt. % of methacrylic acid (A), 40 to 70 wt. % of methyl
acrylate (B), and 20 to 40 wt. % of methyl methacrylate (C).
2. A process as claimed in claim 1, wherein the copolymer is
synthesized in an amount of more than 80 wt. % from the
ingredients (A), (B) and (C).
3. A process as claimed in claim 1 or 2 wherein the copolymer
comprises 10 to 20 wt. % of component (A).
4. A process as claimed in any one of claims 1 to 3, wherein the
copolymerization takes place in aqueous phase such that the
copolymer is present as a latex dispersion in an aqueous phase.
5. A process as claimed in claim 4, wherein the latex dispersion is a
10 to 50% aqueous dispersion
6. A process as claimed in claim 4 or 5, wherein the latex dispersion
is a 30 to 40% aqueous dispersion.
7. A process for the preparation of a copolymer substantially as
hereinbefore described and illustrated with reference to the
Examples 1 and 2.
|Indian Patent Application Number||1612/DEL/1995|
|PG Journal Number||31/2009|
|Date of Filing||30-Aug-1995|
|Name of Patentee||ROHM GMBH|
|Applicant Address||KIRSCHENALLEE, D-64293, DARMSTADT, GERMALNY.|
|PCT International Classification Number||C08F 10/00|
|PCT International Application Number||N/A|
|PCT International Filing date|