NZ223228A

NZ223228A - Lactone derivatives as carriers in controlled and delayed release oral pharmaceutical compositions

Info

Publication number: NZ223228A
Application number: NZ223228A
Authority: NZ
Inventors: Bernd Zierenberg; Bernhard Freund; Dieter Bendix; Gunther Entenmann
Original assignee: Boehringer Ingelheim Int
Priority date: 1987-01-21
Filing date: 1988-01-19
Publication date: 1990-12-21
Also published as: NO880230L; EP0275961B1; DK23588D0; FI93425C; FI93425B; AU1065388A; EP0275961A2; IL85144A; MX10146A; DE3889933D1; DK23588A; KR880008806A; NO175352C; ATE106718T1; NO880230D0; NO175352B; EP0275961A3; CA1329767C; ZA88358B; FI880210A0

Abstract

The medicinal preparation having controlled continuous release of active compound is prepared from an excipient based on biologically degradable cyclic carboxylic acid esters, oligomers derived therefrom and/or polymers.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £23228 V, -«"r 4 V. C NO DRAWINGS Priority Date{s): .. Complete Specification Filed: Clasa: i Sty' 2*V DEC *19*90 Publication Date: P.O. Journal. No: . )3sa.-. 22 32 2 8 o\ Patents Form No. 5 NEW ZEALAND ^9JANV$& PATENTS ACT 1953 COMPLETE SPECIFICATION /Tn Controlled and delayed release oral pharmaceutical composition tf/We, BOEHRINGER INGELHEIM INTERNATIONAL GMBH a body corporate organised under the laws of the Federal Republic of Germany of D-6507 Ingelheim am Rhein, Federal Republic of Germanyt hereby declare the invention, for which %/vie pray that a patent may be granted to ij^/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by Page la) O '■V"v^ . _ ■■ . . ' ... . ; ...... . 223228 I - la - NI 52-472 CONTROLLED AND DELAYED RELEASE ORAL PHARMACEUTICAL COMPOSITION The present invention relates to controlled and delayed release oral pharmaceutical compositions. ! Oral pharmaceutical compositions having a polymeric ! O 5 carrier for the active substance and including | some such compositions which provide delayed release of the active substance, have been described in a number of patent specifications. The polymeric I carriers that have been used include, for example, ! 10 polymers based on acrylic acids and celluloses, \ 1 inter alia. A disadvantage is that the majority | of carrier materials are non-physiological substances, f | that is to say substances which do not occur naturally 3 in the body, and thus have to undergo stringent 1 15 tests for toxicological safety. However, polymers I (including oligomers and copolymers) of lower hydroxy- I carboxylic acids, particularly glycolic and lactic \ acids, are broken down in the body by the natural A _ | rn metabolic cycle and are toxicologically harmless. 20 Stitches and implants based on these polymers have f been successfully used in surgery for some time. Parenteral pharmaceutical compositions made using copolymers of lactic and glycolic acid have been 25 disclosed, for example, in US-A-4273920 and also in GB-A-1325209. These two publications describe pharmaceutical compositions comprising these polymers, which compositions have the property of releasing the active substance over a lengthy period of time, 30 i.e. between 14 days and a year. This is desirable in the case of parenteral delayed-release compos itiorw^pr-©^: however due to the slow rate of active substance /r ■I 1#^" f (followed by page 2f\ 1 n r* c. V v.. 223228 * 5 10 15 20 C 25 c 30 release, polymers of lactic and glycolic acid would appear to be totally unsuitable for use in oral pharmaceutical compositions. It is an objective of the present invention to provide an oral pharmacuetical composition capable of permitting controlled delayed release of an active substance by the use of a physiologically acceptable (e.g. toxicologically safe) polymeric carrier material. By "active substance" is meant a pharmaceutical^ acceptable substance which has a physiological effect. In one aspect the present invention provides an oral pharmaceutical composition adapted for the controlled delayed release of an active substance and comprising said active substance and a carrier or coating material, wherein said carrier or coating material comprises a material selected from biodegradable cyclic carboxylic acid esters, polymers thereof, and mixtures of said esters or polymers. The oral composition of the invention conveniently may be in the form of a tablet, a powder, granules, a capsule or a pellet and preferably is adapted to permit continuous release of active substance within a period of 24 hours. The polymers of the biodegradable cyclic carboxylic acid esters, useful as carrier or coating materials include the oligomers, co-oligomers, homopolymers and copolymers thereof. Suitable carrier or coating materials for this purpose include l,3-dioxan-2-ones of formula I R 1 > r- " \ - - 3 - 1,4-dioxan-2-ones of formula II lactides of formula III 10 (,"■ RJ R* 22 3 2 2 8 15 and lactones of formula IV 20 'icrVi' n ^ In formulae I,II,III and IV 25 R*, R^, R^, R^, R"* and R®, which may be the same or different, each represents a hydrogen atom, 30 a C^_g cycloalkyl or C^_^2 (preferably C^_4) branched or unbranched alkyl, alkenyl or alkynyl group optionally substituted by a halogen atom or by a hydroxy, a branched or unbranched alkoxy, a C^_g acyl, a carboxyl, an amino, or an alkylamino-, dialkylamino-35 or quaternary amino group (which alkylamino-, dialkylamino-. o "W j I ^ I -'IW"1 ■ s ■> m 22 3 2 2 8 - 4 - or quaternary amino group preferably has 1 to 4 carbon atoms), a acyl group with 1 to 5 carbon atoms, a branched 5 or unbranched alkoxy)carbonyl group or an optionally substituted arvl or heteroaryl group having 6 to 12 carbon atoms in the ring system; and n represents any one of the integers from 2 10 to 10. Useful as halogen atoms in the compounds of formulae I to IV are fluorine, chlorine, bromine and iodine atoms and unless stated otherwise the preferred 15 alkyl moieties in these compounds and their polymers are preferably methyl, ethyl, propyl, isopropyl, butyl, or tert.-butyl groups, and aryl moieties are preferably phenyl or substituted phenyl groups. 20 The above-mentioned lactones (i.e. the compounds of formulae I to IV) and their polymers, e.g. the oligomers and co-oligomers thereof having number average molecular weights of up to 3000 and the polymers and copolymers thereof having number average 25 molecular weights of up to 1.2 million, are particularly suitable for use as the carrier or coating material in the compositions of the invention. Other suitable carrier and coating materials include mixtures of the above-mentioned lactones, the oligomers 30 and co-oligomers, polymers and co-polymers thereof. Also suitable as carrier or coating materials are mixtures of the lactones described above or polymers thereof with other polymers such as for example 35 polyacrylates, polymethacrylates, polyesters, polyamides, celluloses and starches. A • •" v,. 22 3 2 2 8 s - Some of the lactones described above and the polymers prepared therefrom have centres of asymmetry. The starting materials for preparing the carrier f*} or coating materials may be the dextrorotatory 5 forms, the laevorotatory forms, the optically inactive racemic forms, the optically inactive meso forms and any desired mixtures of these individual forms. Co-oligomers and copolymers of the lactones described 10 may, if desired, be prepared so that the different monomer units occur randomly distributed or in blocks of different lengths in the polymer chain. Both random co-oligomers and copolymers and also block co-oligomers and copolymers are suitable 15 carrier materials. The oligomers, co-oligomers, polymers and copolymers may be prepared by various methods. A number of patent specifications describe methods based on 20 the condensation of hydroxycarboxylic acids, whilst other patent specifications describe methods based on the ring-opening polymerisation of lactones, for example: 25 ? -H,0 r i fn ^.0. H0-C-C00H 30 £i T Lr1 o^o-r • R" 35 The method of manufacture of the above-mentioned oligomers, co-oligomers, polymers and copolymers 223228 - 6 - is generally not critical £or their use as carrier or coating material for the pharmaceutical compositions of the invention. The oligomers, co-oligomers, polymers and copolymers can all be used according 5 to the invention, irrespective of whether they are prepared by condensation from hydroxy acids and their derivatives or by polymerisation from lactones. In the interests of simplicity, the oligomers, co-oligomers, polymers and copolymers 10 of the lactones, may be referred to herein as polymers without thereby referring to the method of production, degree of polymerisation or other properties. Preferred as carrier or coating materials are polymers 15 (homo- and copolymers) of glycolide, L-lactide, D,L-lactide, D-lactide, 1,4-dioxanone and caprolactone. The copolymers may be synthesised from two or more comonomers. The amount of each comonomer may conveniently vary between 1 and 99%. 20 Particularly preferred lactones are glycolide, L-lactide, D-lactide, 25 D,L-lactide (racemate), and meso-lactide. Particularly preferred polymers are poly-L-lactide, 30 poly-D-lactide, poly-D,L-lactide, poly (L-lactide-co-glycolide) with not more than 55 mol-% glycolide, and poly (D,L-lactide-co-glycolide) with not more than 35 55 mol-% glycolide. >:x / : ' .'ii m 22 3 2 2 8 By suitable selection of the coating or carrier material, desired rates of active substance release from the pharmaceutical composition of the invention may be achieved. The biodegradable carrier or 5 coating material used in the preparation of the compositions may thus allow active substance release rates to be varied within a wide range. in order to achieve the desired rate of active 10 substance release, the pharmaceutical compositions according to the invention may, for example, be prepared by the following processes which themselves represent further aspects of the invention. 15 Thus in another aspect the present invention provides a process for the preparation of an oral pharmaceutical composition according to the invention, which process comprises dissolving or suspending a said carrier or coating material and a said active substance 20 in a volatile solvent, drying a film of the solution or suspension thereby obtained, grinding the dried film thereby obtained to a particle size of 10 to 500 micrometers, and formulating the granulate obtained thereby, optionally together with one 25 or more pharmaceutical carriers or excipients, into oral dosage units, e.g. by filling into capsules or by compressing into tablets. In this process, the carrier or coatinq material, 30 e.g. a polymer or copolymer as defined hereinbefore is dissolved or suspended in a volatile solvent, such as dichloromethane, and mixed with the active substance. In this process therefore the polymers or copolymers and the volatile solvent used will 35 suitably be such that the selected polymer or copolymer dissolves or adeouately swells in the selected solvent. Tt may be noted that the solubility of v. v 22 3 2 2 8 - 8 - a copolymer of glycolide and lactide is reduced as its glycolide content increases. Copolymers containing more than 55?, of glycolide do not generally dissolve in the volatile solvents in Question. 5 The solution or suspension obtained by this process may be poured out to form a film from which the solvent is eliminated. The film thus formed is then ground to a screened particle size in the range from 10 to 500, e.g. 50 to 500, micrometers conveniently ~~ 10 at a temperature below the glass temperature of the polymer in auestion. The rate of release of active substance from the final product can be varied by varying the particle size. The powder thus obtained may be compressed directly to form 15 tablets or packed into capsules. The ratio of polymer to active substance is non-critical within wide limits and the active substance may conveniently be present at between 0.1 and 20%, preferably between 0.5 and 5% by weight relative to the weight of 20 the carrier or coating material. If desired, adjuvants conventionally used in pharmaceuticals, such as corn starch, lactose and the like, may be added ^) during the production of the pharmaceutical composition, e.g. during the cold grinding or the tablet compression. 25 During the cold grinding, the mass ratio of polymer containing the active substance to excipient may vary within wide limits and may conveniently be from about 10:1 to 1:4. 30 A preferred polymer for use in this process is a poly-D,L-lactide with a degree of polymerisation of between 4 and 6. Other preferred polymers are poly-L-lactide with a number average molecular weight of about 2000, poly-L-lactide (number average 35 molecular weight of about 43,000), poly-D,L-lactide (number average molecular weight about 363,000), copolymer D,L-lactide/glycolide 50/50 (number average 22 3 2 2 8 - 9 molecular weight about 8000) and a copolymer of D,L-lactide/glycolide 75/25 with a number average molecular weight of about 19,000. 5 In the case of an oral pharmaceutical composition prepared by this process in tablet form, virtually no drug is released during the retention time in the stomach, even though the tablet very rapidly breaks up into individual particles in the stomach. 10 The active substance is only released during the passage through the intestines, i.e. in a neutral medium, and there it is released continuously over a period of 3 to 12 hours. The properties described open up the possibility of achieving a pH-dependent j 15 release of active substance, i.e. a release which ! will increase as the pH rises, such as, for example, a controlled release of active substance in the intestinal tract. One possible application is -j a delayed-release tablet which is resistant to | 20 gastric juices. Low molecular weight poly-D,L-lactide has particularly ^ high rates of active substance release. The release rate may be slowed down to any desired extent by 25 the addition of higher molecular weight polymers and also copolymers, lactides and glycolides. On the other hand, by the addition of other polymers, D e.g. polyacrylates (for example Eudragit NE 30 D) the release rate may be increased to a desired 30 extent. It is therefore possible to adapt the pharmaceutical composition of the invention to the individual active substance and the particular requirements of therapy. 35 The pharmaceutical composition of the invention can alternatively be prepared in the form of a matrix-type tablet. 223228 - 10 - Thus in a further aspect the invention provides a process for the preparation of an oral pharmaceutical composition according to the invention, which process comprises compressing into tablet form a mixture of a said carrier or coating material and a said 5 active substance, after optionally granulating said mixture or one or more of the components thereof, said mixture optionally further containing one or more pharmaceutical carriers or excipients. 10 To prepare a matrix tablet, the active substance is conveniently mixed with a polymer or copolymer or mixture thereof as hereinbefore described, optionally including small amounts of excipients conventional in pharmaceutical preparations, such as magnesium 15 stearate, Aerosil and the like, the mixture conveniently being prepared and compressed by known methods, e.g. using granules formed by moist granulation, or by direct compression of polymer material and active substance. 20 The following are some examples of polymers and copolymers which are particularly suitable for the manufacture of matrix-type tablets: 25 poly (L-lactide), poly (L-lactide), 30 poly (D,L-lactide) molecular weight of between 1000 and 5000 (determined by terminal group titration) inherent viscosity between 0.5 and 1.5 dl/g inherent viscosity between 1.5 and 2.5 dl/g 35 poly (D,L-lactide-co-glycolide) 50:50, inherent viscosity between 0.2 and 1.0^|r/g l1 v c M 7 r\ ? c C vV' 223228 poly (D,L-lactide-co-glycolide) 75:25, inherent viscosity between 0.2 and 1.0 dl/g 5 The following polymers and copolymers are particularly preferred: poly-L-lactic acid (molecular weight of 2000) poly-L-lactide 'Mvis = 43»000) 10 poly-D,L-lactide *Mvis = 363,000) copolymer [poly(D,L-lactide-co-glycolide)] 50:50 copolymer [poly(D,L-lactide-co-glycolide)] 75:25 The selection of preferred polymers listed above 15 is also useful in the preparation of the other pharmaceutical forms described herein. This list is given by way of example, without restricting the invention to the use of the polymers or molecular weights or inherent viscosities specified. 20 The matrix tablet of the invention conveniently has a very high content of active substance, which may be up to 90% by weight relative to the total weight of the composition depending on the active substance. A content of 40% by weight of active 25 substance is generally regarded as the lower limit. In the case of highly active pharmaceutical active substances it is sometimes necessary to incorporate into a matrix tablet smaller quantities of active 30 substance than those referred to above; in such a case it is highly advantageous to add a readily soluble excipient, e.g. lactose, or even some excipients which are less soluble or insoluble in water, to ensure a release of active substance within 24 35 hours. < ■» r- > "V\ \u 22 3 2 2 8 - 12 - In contrast to the rapidly decomposing delayed release tablets described previously, the matrix tablet of the invention allows release of active substance into the stomach. The release characteristics 5 are determined not only by the polymer composition but also by the form of the matrix tablet. An increase in molecular weight of the polymer slows down the rate of release. 10 A further embodiment of the pharmaceutical composition of the invention consists of forms for oral administration having a retardant coating of a carrier or coating material as hereinbefore described, e.g. of a homopolymer or copolymer of the compounds of formulae I, II, 15 III and IV hereinbefore described, preferably of a lactide/glycolide homopolymer or copolymer, optionally combined with other polymers such as water soluble polymers, e.g. polyethylene glycol, or water-swellable polymers such as Eudragit NE 30 D. 20 Thus in a still further aspect the invention provides a process for the preparation of an oral pharmaceutical ^ composition according to the invention, which process comprises applying to granules or pellets comprising 25 a said active substance a retardant coating comprising a said carrier or coating material whereby to yield coated granules or pellets of which the retardant coating constitutes from 3 to 30% of the total ' weight. 30 The method used to produce retardant coatings is well known to those skilled in the art and requires no special explanation. Thus, for example, the active substance in the form of pellets (e.g. about 35 1.0 to 1.6 mm pellets) may be coated in a fluidised bed granulator with a polymer dissolved in a suitable solvent. Coatings may also be applied using the 22 3 2 2 8 - 13 - coating pan method. In qeneral, the quantity of retardant coating amounts to 3 to 30% ^y weight, preferably 5 to 20, more particularly 5 to 10% ^ by weight relative to the total weight of the composition. 5 Spray solutions used in this process will generally have a polymer content of 5 to 10? by weight. As previously described in connection with the matrix tablet, the release of the active substance 10 starts in the stomach and may be varied over a lengthy period of time by chanqing the molecular weight of the coating material, "be rates of release may additionally be varied by coxMning the coating material with other water-soluble polymers, e.g. 15 polyethylene glycols ffor example polyethylene glycol 60001. In a yet further aspect the invention provides a process for the preparation of an oral pharmaceutical 20 composition according to the invention, which process comprises admixing a said active substance and a said carrier or coating material, optionally f~}. together with one or more pharmaceutical carriers or excipients, and extruding the mixture obtained. 25 In this process, the carrier or coating material is preferably a finely divided polymer material. This is mixed with the active substance and optional excipients such as lactose and is then extruded. 30 The extruded shapes, e.g. small rods containing the active substance may then be further processed to form suitable galenic preparations. The pharmaceuticals produced by the so-called extrusion method have the advantage that there is no need for any solvent 35 in their manufacture. •V"" • v rv -t 22 3 - 14 - The pharmaceutical preparations according to the invention are also suitable for stabilising certain active substances in pharmaceuticals. Some pharmaceutically active substances from the 5 group comprising the sympathicomimetics of the phenylethylamine type have a tendency to undergo oxidative changes on storage: in particular, on exposure to moisture sliqhtly or more seriously discoloured products may form. Experience has 10 shown that such changes take place more readily in a neutral or alkaline pH, than in an acidic medium. The addition of acid to pharmaceuticals of this 15 kind is not the ideal remedy in every case. However, polymers of lactic acid, which are hydrolytically broken down to the monomer in the presence of water, may act as a latent acid reservoir releasing acid as required. 20 A granulated tablet material containing 7.5% of 1 O m-proterenol sulphate (trade mark: Alupent) discolours w within 48 hours, if kept at about 60°C sealed up in the presence of the moisture of the granules. 25 Similar granules to which 5% of poly (L-lactic acid) having a molecular weight of 2000 has been added show no discolouration under identical conditions. The Examples which follow are intended to illustrate 30 the invention without restricting its scope in anyway. Unless otherwise stated, all ratios and percentages with the exception of comonomer contents of copolymers 35 herein are by weight and molecular weights given herein are number average molecular weights. Comonomer contents of copolymers are, unless otherwise stated, expressed as mole ratios or mole %. 22 3 2 r> - 15 - Example 1 Poly-D,L-lactide (degree of polymerisation 4 to 6) is taken up in methylene chloride and mixed with 1% by weight of clonidine base. The solvent is then removed and the film produced is ground 5 up cold. The ground material obtained is adjusted by screening to a log-normal distribution, e.g. with the parameters (dz = 80 micrometers, O" = 0.23) (dz is the average diameter of the particles,C is standard deviation) and the release of the clonidine 10 is measured by HPLC in a USP tester XVII. When the rate of release of the clonidine from this oligomeric poly-lactide is determined, it can be seen that virtually no drug is released in the gastric juice phase (pH 1.2; retention time lh); 15 the drug is only released as it passes into the intestinal juice. Table 1 shows the percentage release data for clonidine over an observation period of 6 hours. 20 Table Is Release data for the batch We T 66 in a modified USP tester XVII 25 30 0.25 h 0.6 % of active 1 h 0.8 released 2 h 29.8 4 h 55.6 6 h 70.8 Example 2; Matrix tablets Theophylline-polymer granules were obtained by moist granulation with an organic solvent. From the granulate matrix tablets were prepared using an eccentric press EKO with a 12 flat facetted 35 convex punch. 22 3 2 2 8 - 16 - The rate of active substance release was measured using a USP 21 tester, paddle model, 100 and 150 rpm, buffer pH 1.2 (artificial gastric juice, 0.06N hydrochloric acid), PH 6.5 (artificial intestinal juice, 0.06N hydrochloric acid, PH adjusted to PH6.5 with tri-sodium phosphate). Table 2 shows the percentage release data for theophylline over an observation period of 7 hours. 22 32 2 * Table 2 - 17 - Release data for theophylline a) Composition A Release Theophylline 80% lh 18.5% Poly (r>,L-lactide) 20% 3h 31.3% 5h 40.1% Mg stearate 0.3% 7h 47.1% Aerosil 0.3% Dichloromethane 40ml Remarks: Tablets look the same after release , very hard. Measurements were carried out at 100 rpm b) Composition (Theophylline granulate) Release Theophylline 80% lh 21.1% Poly(D,L-lactide-co- 3h 36.0% glycolide) 50:50 20% 5h 46.6% 7h 55.4% external phase: Mg stearate 0.3% Aerosil 0.3% Dichloromethane 20ml Remarks: After the release, the tablets look the same, very hard. Measurements carried out at 100 rpm Release c) Composition (Theophylline granulate (0.8-1.0mm) Theophylline 80% Poly(D,L-lactide-co-glycolide) 75:25 20% external phase: Mq stearate 1.0% Aerosil 0.3% Dichloromethane 50ml Measurements were carried out at 150 rpm. d) Composition (Theophylline granulate) less than 0.3mm) Theophylline 80% Poly(D,L-lactide) 20% Dichloromethane 40ml Ethanol 10ml lh 24.3% 3h 42.8% 5h 54.9% 7h 64.3% Release lh 23.8% 3h 40.7% 5h 52.3% 7h 61.2% Remarks: The tablets were still stable after the release. Measurements were carried out at 150 rpm. 22 3 2 2 8 - 18 - e) Composition (Theophylline granulate 100% (less than 0.3)) Release Theophylline Poly-L-lact i de, Molecular weight about 2000 Dichloromethane 80% 20% 20ml A B lh 25.3% 21.1% 3h 63.0% 44.3% 5h 86.2% 61.5% 7h 95.6% 74.8% Remarks; The tablets are unaltered after the release. Measurements were carried out at 150 rpm. A = Hardness 140 KN B = Hardness 150 KN J . 22 3 2 - 19 - Example 3 : Coated compositions Coated compositions for oral administration were prepared using theophylline as the active substance and using various polymeric coating materials which comprised polylactides alone or in combination with 5 other polymers such as Polyethylene glycol 6000, and D Eudragit NE 30 D. The coated compositions were prepared in the form of rounded pellets of about 1.0-16 mm size and containing about 80% active substance. 10 The coating process was performed under the following parameters: spraying/apparatus: solvent: 15 batch size: spray solution: WST 1 methylene chloride about 1.2 kg 5% polymer in each case (unless otherwise stated) rr The rate of release of the active substance was measured 20 in vitro using a USP21 tester (paddle) 150 rpm, buffer pH 1.2/pH 6.5 Table 3 shows the percentage release data for theophylline over an observation period of 7 hours. (% contents 25 referred to in this Example are on a dry weight basis and MW stands for molecular weight). 223228 - 20 - Table 3 Polymer coating composition 1-0.Poly-L-lactide, (MW about 2000) 100% lh 3h 5h 7h Release for 5% 10% Coatings 43.8% 91.7% 97.5% 98.5% 1.1.Poly-L-lact ide, (MW about 2000) 75% Eudragit NE30D 25% lh 12.5% 22.8% 3h 33.5% 44.2% 5h 52.5% 56.6% 7h 68.4% 65.7% 1.2.Poly-L-lact ide (MW about 2000) 50% Eudragit NE30D 50% 1.3.Poly-L-lactide (MW about 2000) 75% Polyethylene glycol 6000 25% 1.4.Poly-L-lactide 50% Polyethylene glycol 6000 50% 2.0.Poly-L-lact ide (inherent viscosity 0.9 dl/g) 100% lh 10.3% 16.5% 3h 30.1% 37.9% 5h 51.2% 51.9% 7h 66.3% 61.8% lh 100.0% 3h 5h 7h lh 100.0% 3h 5h 7h lh 55.6% 3h 87.6% 5h 94.5% 7h 96.8% 2.1.Poly-L-lact ide (inherent viscosity 0.9 dl/g) 94% Eudragit NE30D 6% lh 1.1% 0.9% 3h 2.9% 2.3% 5h 4.8% 1.9% 7h 6.5% 3.7% 2.2.Poly-L-lactide (inherent viscosity 0.9 dl/g) 88% Eudragit NE30D 12% lh 3.7% 0.7% 3h 7.9% 1.9% 5h 11.9% 3.2% 7h 15.5% 4.6% 2.3.Poly-L-lact ide (inherent viscosity 0.9 dl/g) 75% Eudragit NE30D 25% lh 3h 5h 7h 1.3% 3.0% 4.7% 6.3% 1.3% 2.3% 3.2% 4.0% Remarks: a 4% lacquer solution was used for coating.. </div>

Claims

1. 22 32 - 21 - ,4.Poly-L-lactide (inherent viscosity lh 1.5% 1.1%

0.9 dl/g) 50% 3h 3.5% 2.4% Eudragit NE30D 50% 5h 5.5% 3.6% 7h 7.7% 5.0% Remarks: 3% lacquer solutions were used for coating

2.5.Poly-L-lactide (inherent viscosity lh 78.1% 20.9%

0.9 dl/g) 75% 3h 94.3% 48.4% Polyethylene glycol 5h 97.5% 64.9% 6000 25% 7h 98.5% 75.6%

2.6.Poly-L-lactide (inherent viscosity lh 100.0%

0.9 dl/g) 100% 3h 5h 7h All the percentages given refer to the total content actually found. Example 3 illustrates the release rates for 5 and 10% coatings. The polymer contents listed total 100%. v *;_ 22 - 22.5228;WHAT WE CLAIM IS:;o;G;C;10;15;20;25;1. An oral pharmaceutical composition capable of controlled delayed release of a pharmaceutically active substance capable of exerting its activity after oral administration and comprising said active substance and a carrier or coating material, wherein said carrier or coating material comprises a material selected from biodegradable cyclic carboxylic acid esters, polymers thereof, and mixture of said esters or polymers.;2. A composition as claimed in claim 1 wherein said carrier or coating material comprises a material selected from oligomers, co-oligomers and co-polymers of said biodegradable cyclic carboxylic acid esters.;3. A composition as claimed in either one of claims 1 and 2, wherein said carrier or coating material comprises a material selected from the group comprising cyclic carboxylic acid esters of formulae I, II, III and IV;R1;R3l;>v°;R;7S-°;r';r A;R5 R;I;.1;R R;R;R;R;/-0;.0;0;^0-7;RJ;ii in;30;IV;35;1 2;(wherein R , R ,;c £;R and R ,;which iha; c;the same or different, each represents , - qi>^ \990;10;22,^228;- 23 -;a hydrogen atom,;a C^_g cycloalkyl or C-^-^ branched or unbranched alkyl, alkenyl or alkynyl group optionally substituted by a halogen atom or by a hydroxy, a branched or unbranched alkoxy, a acyl, a carboxyl,;an amino, or an alkylamino-, dialkylamino- or quaternary amino group,;a ci_5 acyl group with 1 to 5 carbon atoms, a branched or unbranched (C1-5 alkoxy)carbonyl group or an optionally substituted aryl or heteroaryl group having 6 to 12 carbon atoms in the ring system,;15 and n may represent any one of the integers from 2 to 10) ,;polymers thereof and mixtures of said esters and/or said polymers.;20;4. A composition as claimed in claim 1,;wherein said carrier coating material comprises a material selected from glycolide, lactide, oligomers and co-oligomers thereof with molecular weights 25 of up to 3000, polymers and co-polymers thereof with molecular weights of up to 1.2 million, and mixtures of two or more of the said materials.;^ -'w';5. A composition as claimed in either of claims 30 1 and 2, wherein said carrier coating material is selected from the group comprising glycolide, L-lactide, D-lactide, D,L-lactide, meso-lactide, poly-L-lactide, poly-D-lactide, poly-D,L-lactide, poly(L-lactide-co-glycolide), poly(D,L-lactide-35 co-glycolide) and combinations thereof.;N.z. pate,~:t;17 OCT;223228;- 24 -;6. A composition as claimed in any one of claims 1 to 5 further containing one or more pharmaceutical carriers or excipients.;5

7. A composition as claimed in claim 6 containing a water-soluble additive or excipient.;

8. A composition as claimed in any one of claims 1 to 7, additionally comprising a water-swellable;10 or water-soluble polymer or copolymer.;

9. A composition as claimed in any one of claims 1 to 8 in the form of a tablet, a capsule, a pellet or granules.;15;

10. A process for the preparation of an oral pharmaceutical composition as claimed in claim;1, which process comprises dissolving or suspending a said carrier or coating material and a said active 20 substance in a volatile solvent, drying a film of the solution or suspension thereby obtained,;grinding the dried film thereby obtained to a particle size of 10 to 500 micrometers, and formulating the granulate obtained thereby, optionally together 25 with one or more pharmaceutical carriers or excipients,;into oral dosage units.;

11. A process as claimed in claim 10 wherein the quantity of said active substance dissolved;30 or suspended in said solvent is 0.1 to 20% by weight of said carrier or coating material dissolved or suspended in said solvent.;

12. A process for the preparation of an oral 35 pharmaceutical composition as claimed in claim;1, which process comprises compressing into tablet form a mixture of a said carrier or coating material;■ • -VI ^ „;'v;> r * i 223228 and a said active substance, after optionally granulating said mixture or one or more of the components thereof, said mixture optionally further containing one or more pharmaceutical carriers . . ( or excipients. 5

13. A process as claimed in claim 12 wherein from 40 to 90% by weight of said mixture is comprised of said active substance. 10

14. A process for the preparation of an oral pharmaceutical composition as claimed in claim 1, which process comprises applying to granules or pellets comprising a said active substance a retardant coating comprising a said carrier or 15 coating material whereby to yield coated granules or pellets of which the retardant coating constitutes from 3 to 30% of the total weight.

15. A process for the preparation of an oral 20 pharmaceutical composition as claimed in claim 1, which process comprises admixing a said active substance and a said carrier or coating material, f"7\ optionally together with one or more pharmaceutical carriers or excipients, and extruding the mixture 25 obtained.

16. A process as claimed in claim 15 wherein as said carrier or coating material is used a finely divided polymer material.

17. Controlled and delayed release oral pharmaceutical compositions substantially as herein disclosed in any one of the Examples. BOEHRINGER INGELHEIM INTERNATIONAL GMBH 1 ■J r r\Attorneys SON & CAREY