AU600712B2 - Pellet-containing pharmaceutical compositions - Google Patents

Abstract

The invention relates to a brick made of pellets with delayed and controlled release of the active ingredient in a meltable matrix consisting of a pharmacologically tolerated binder.

Description

600712 Australia Form PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: tnt. CI: Application Number: Lodged: 70q0/9~7 00 0 Complete Specification-Lodged: 0. 0 Accepted: 0 Lapsed: Published: ocum;'J)tilnft conlta1ins the L 171" 11~CI Ii tS maide under ,Sc ol49 and iscorrect for -pri I tIinIIg, Priority: 0 00Related Art: 0 0 00 000 Name of Applicant: 000 0 Address of Applicant: TO BE COMPLETED BY APPLICANT BOEHRINGER INGELHEIM INTERNATIONAL GMBH D-6507 Ingeiheim am Rhein, Federal Republic of Germany.

Bernhard FREUND and Erwin, THIES CAIJLINAN AND ASSOCIATES, Patent Attorneys, of Actual Inventors Address for Service: 48-50 Bridge Road, Richmond, State of Victoria, Australia.

Complete Specification for the invention entitled: P ELL ET -CO0N T AI NI NG PHA RM A CE UT I CA L

COMPOSITIONS"

The following statement is a full description of this invention, including the best method of performing it known to me:-* Note: The description Is to be typed In double spacing, pica typo face, In an area not exceeding 250 mm in depth and 160 mm in width, on tough white paper of good quality and it is to bo inserted inside this form, r rr-ri~ir~:r-;;C~II1~ZLt^~iUfii YO~L*Y;~~j-i I

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la- LF 51-490 Pellet-containing pharmaceutical compositions The present invention relates to pellet-containing pharmaceutical compositions.

Slow-release pellets containing an active substance are important in the area of orally administered medicaments. Usually, these pellets are introduced into gelatine push-fit capsules which the patient takes without opening. A major disadvantage of this way of administering an active substance is o o 10 that the dosage of the slow-release drug can only oo0 o be varied by an integral multiple of the dose contained 0. in a single push-fit capsule. Thus, it is not 00 0 possible for the patient to take a fraction of 0. a dose unit of the drug under controlled conditions, S0 15 i.e. to take a predeterminable and reproducible dose. There is also no guarantee that the remaining fraction of the dose unit will be kept together safely.

Furthermore, it may be noted that for reasons of drug safety, many push-fit capsules are provided with a safety seal which results in the capsule being destroyed if it is opened.

Moreover, many patients find it distinctly unpleasant to swallow a drug in the form of a commercial gelatine capsule, since the capsule produces the sensation of a foreign body on being swallowed. This sensation can be so pronounced that it completely stops the swallowing mechanism. Clearly, in such a case it would be advantageous to be able to dissolve the capsule in a small amount of water and to swallow the pellets thus released as an "aqueous suspension".

2 However, though this is hitherto not extensively known, commercial gelatine capsules will not dissolve in water at ambient temperature.

It is known to those skilled in the art that such pellets cannot be pressed to form tablets since the high pressure which has to be exerted in the press in order to achieve compaction leads to at least a partial destruction of the body of the pellets which may adversely affect active substance release behaviour of the pellet. The few attempts that have been made to develop a pellet which can withstand the high pressures required in tabletpressing have entailed drastic limitations in the choice of the coating materials and the size of the pellets (see DE-A-23 36 218) It is therefore an object of the present invention to provide a pharmaceutical or veterinary composition made from pellets, which is manufactured by a process during which the high press pressures usually required for tablet-pressing do not have to be exerted.

Thus, according to one aspect of the present invention, 25 we provide a delayed release pharmaceutical or o 00 veterinary composition comprising pellets which comprise an active substance and which are held in a fusible porous matrix comprising a physiologically acceptable binder, said binder being disintegrable.

30 in an aqueous medium o 00 In the composition the pellets are embedded in a fusible (sinterable) matrix, and the composition optionally comprises means such as, for example, 0 notches for easier subdivision.

0 9 4 The composition is preferably in the form of a Smoulding, more preferably in the form of a tablet I r Lr r-ill~iun;t; i-rxC ~-clrit ur~iuw--~-rar^

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0 00 00 0 0 .0 0 0 0 0 0 0 o oo 1o o S0 Q 00 0 0 00 0 0 o a o 0* oo 0 0 0 1 o Oa o0o0 3 or block of tablets, and preferably has a porous inner structure.

The terms fusible or sinterable matrix relate to a matrix which in the course of its manufacture is consolidated either by solidification of the melt or by sintering (brief heating) of a pulverulent material.

The term moulding, in the context of the present invention, encompasses not only tablet-like or capsule-like shapes but also all shapes which are suitable for oral administration or capable of division into forms suitable for oral administration.

For the composition of the invention pellets produced by conventional processes, such as dragee-making processes or coating processes, are suitable.

These include unretarded (that is to say directly 20 soluble) pellets, pellets which have a coating resistant to gastric juices, and slow-release pellets.

The matrix comprises binders and, if appropriate, additives such as are conventionally used in galenical preparations. To allow ready disintegration of the composition to release the active substance containing pellets from the matrix, the binder should preferably be water-soluble or at least water-emulsifiable, possibly depending on the pH, and should preferably have a melting point below 100 0

C.

Preferred as binders are sugar alcohols (such as, for example, mannitol, xylitol and sorbitol) as well as their esters, acids encountered in foodstuffs (such as, for example, tartaric acid, citric acid, malic acid, lactide and lactic acid), fatty acids as well as their monoglycerides or diglycerides, L 4 sugar mixtures (such as, for example, monosaccharides or disaccharides or glucose syrup), monoglycerides or diglycerides and their derivatives, and mixtures of the said substances.

For excipients having high melting points, it is preferable to use eutectic mixtures having a melting point below 100°C.

One suitable binder for a fusible matrix is a mixture of sugar, lactose, sorbitol, starch syrup and water; this mixture is referred to as "Basic Mix" in the literature. "Basic Mix" is a glassy mass having a softening point of 55 to 90 0 C and a residual water content of about 0.5 to 2%.

Particularly preferred as hinders are polyethylene glycols, such as, for example, Polywax 1500, Polywax 6000 and Polywax 20,000, which have a solidification point of between 250 and 60 0

C.

Compositions according to the invention which readily disintegrate in an aqueous medium, releasing the pellets, are especially preferred since these may be broken down before administration to produce a suspension of the pellets which may be swallowed more comfortably than a tablet. Tn this regard, mouldings which contain polyethylene glycols as binders are preferred since the moulding rapidly disintegrates in an aqueous medium within a short time and the pellets can be swallowed comfortably as a kind of "aqueous suspension".

The invention thus also provides a pharmaceutical or veterinary form for pellets which form disintegrates in an aqueous medium within an acceptable period of time thereby releasing the pellets for easier ingestion.

K 5 Where the pellets are provided with a polymer shell to give delayed or controlled release of the active substance, the binder chosen should be one compatible with the polymer shell.

For use with certain active substances, the binder is preferably resistant to gastric juice.

According to another aspect of the present invention we provide a process for the preparation of a delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a porous matrix of a fusible, physiologically acceptable binder, comprising moulding or extruding a forming composition comprising said pellets and an at least partially fused physiologically acceptable binder, said binder being disintegrable in an aqueous medium.

In the case of extrusion the composition may be made by the extrusion of pellets in the binder, optionally with the extruded column being nipped at intervals to provide dividing lines defining individual tablets. The binder or mixture of binders should preferably have a broad softening point.

The mixing of the pellets with the binder and the o subsequent mechanical extrusion should not be so violent as to cause breaking up of the extrusion or rupture of the slow-release coating.

According to a further aspect of the present invention we provide a process for the preparation moulding containing pellets which comprise an active substance and which are held in a porous matrix of a fusible, physiologically acceptable binder, said binder being disintegrable in an aqueous solution said process comprising one of the following: introducing the pellets into moulds and subsequently 0' 6 filling said moulds by pourinq in a fused binder; coating the pellets with a binder, introducing the coated pellets into moulds and then heating briefly; mixing the pellets with a binder, introducing the mixture into moulds and then heating briefly; or introducing the pellets together with a binder and a blowing agent into moulds and heating briefly.

In process pellets which may, for example, have been manufactured by processes known from the literature and are provided with a slow-release coating are introduced into suitable moulds and an adequate amount of the molten binder is then poured into the mould. The amount of binder, which may contain qalenical additives, that is to be used is conveniently between 5 and 50% by weight, preferably 10 25% by weight, relative to the total weight of the pellets. When the material has cooled, the finished mouldings are taken from the mould and are packaged. Where appropriate, a release agent may be applied to the mould beforehand to permit easier release. Moulds which permit simple removal of the moulding when it has cooled are particularly suitable for use in this process.

In process the binder is applied as a coating, in a suitable thickness, to pellets which may conveniently already have been retarded, e.g. by the provision of a release delaying shell. Coating with the binder may be done, for example, by a dragee-coating process. The optimum thickness of the binder layer 7 is essentially dependent on the size of the pellet and can be determined by simple experiments. The amount of binder used is conveniently between and 50% by weight, preferably between 10 and by weight, based on the total weight of the pellets.

The pellets coated with the binder are introduced into moulds and are bonded together by brief heating, during which the binder briefly melts, at least at its surface. By brief heating it is meant that the heating should be sufficient for the binder on the surface of the coated pellets to melt sufficiently for adjacent pellets to be bound together on subsequent cooling. The heat required for melting the binder may, in the case of suitably designed moulds, be applied via the mould, which, where appropriate, may additionally be provided with cooling devices.

0 If it is not possible to apply heat via the mould, a the energy required for fusion may be applied from outside, for example by using microwave radiation or by using a heating device such as, for example, a simple oven. It is merely necessary to ensure that the retard layer of the pellets is not damaged by excessive heating.

In process the pellets, conveniently already in retard form, are mixed with the binder and the mixture is introduced into a mould. Further processing may be carried out as described for process (b) above.

In process the pellets, conveniently already in retard form, are introduced, together with a binder, into a mould. Upon heating, the binder is uniformly distributed between the pellets by decomposition of the blowing agent, so that after cooling the desired moulding is obtained. Suitable -8as blowing agents are compounds which are pharmacologically safe and have a decomposition point in the range of the melting point of the hinder. Further, lowboiling solvents (such as, for example, hydrocarbons, halogenated hydrocarbons, perhalogenated hydrocarbons and alcohols) are suitable as blowing agents, provided they are compatible with the slow-release coatinq on the retarded pellets. If specially designed moulds are used, an inert gas, for example compressed air or nitrogen, may alternatively be used as the blowing agent.

On heating (sintering) the moulding, especially in the case of processes and as hereinbefore described, the softening of the loose mass of pellets causes a slight contraction in volume. To avoid crack formation and in order to achieve a uniform appearance it is advantageous to exert a slight pressure on the moulding while it is still warm, so as to assist the desired moulding action. However, it is, of course, obvious that the pressures exerted should be so slight that the pellets, and especially the slow-release coating of the pellets in retard form, are not damaged. Thus slight pressure is to be taken as meaning a pressure typically sufficient to 4 25 cause smoothing down, polishing or densification. In a suitable embodiment it may suffice to vibrate the mould briefly in order to achieve densification.

In a particularly preferred embodiment of the process, blister foils of thermally formed plastics film) with appropriate recesses for the mouldings (and, where appropriate, additional shapings to form division notches) are used.

The filling of these blister foils and the manufacture of the mouldings may be carried out in accordance with any one of processes to the recesses in the foil simultaneously serving as the moulds.

-9- When the mouldings have cooled, the blister foil is sealed with aluminium foil. When required for use, the mouldings are pressed out through the aluminium foil.

A moulding produced according to any one of processes or can, depending on the amount of binder used, have an uneven surface. However, this has no effect on the active substance release characteristics. If desired, an approximately uniform surface can be obtained on the moulding by a further application of binder or of a lacquer.

Mouldings produced by process have a porous inner structure. The bonding between the pellets occurs only at the points of contact of the binder coatings. Such mouldings therefore have particularly advantageous disintegration characteristics, since owater or the relevant digestive fluids can more rapidly penetrate and dissolve the binder.

To delay disinteqration of the mouldings, they may additionally be coated with a lacquer which is resistant to gastric juice or which has a retarding action. In this regard, it is also possible to manufacture the compositions of the invention using binders which are resistant to gastric juice, so that the pellet release only takes place on passage through the intestines.

The pharmaceutical composition is preferably divisible.

Such divisibility may be achieved, for example, by providing dividing notches by using moulds of appropriate shape, or subsequently by means of a heated tool, or by working the composition while it is still soft, i.e. not yet cooled, by means of a tool of appropriate design.

10 The present invention thus provides a pharmaceutical or veterinary form for pellets which can be subdivided one or more times and which permits such division with retention of the properties characteristic of the pellets, such as, for example, slow release.

An important advantage of the invention is that in the course of the manufacturing process according to the invention the pellets do not suffer any mechanical damage; accordingly, even after the composition has been subdivided, the pellets remain fully preserved. Indeed, mouldings may be produced according to the invention from pellets which are not provided with a slow-release or gastric juiceresistant coating.

The invention will now be illustrated by means of the following non-limiting Examples and with reference to the accompanying Drawings in which: Figure 1 shows moulded tablets prepared according to Example I; Figure 2 shows moulded tablets prepared according to Example 2; Figure 3 shows a capsule-shaped tablet provided with a dividing notch; jfFigure 4 shows moulded tablets prepared according to Example 4; Figure 5 shows moulded tablets prepared according to Example Figure 6 shows moulded tablets prepared according iir to Example 6; Figure 7 shows moulded strings of tablets; Figure 8 shows moulded strings of tablets provided with an additional outer coating of polyethylene glycol powder; Figure 9 shows moulded strings of tablets having undercuts, the right hand side showing spherical 11 mouldings, the left hand side showing divisible mouldings; and Figure 10 shows further possible shapes for the compositions of the invention.

It should be noted that the compositions shown in the Figures are shown on an enlarged scale.

All percentages and ratios referred to herein are by weight unless otherwise stated.

i 12- Example 1 Pellets, manufactured by a conventional process by introducing an active substance into so-called "starter pellets" (which may be purchased) comprising sugar and/or corn starch, are introduced into the capsule receiving wells of a blister foil and Polywax 6000 is poured in. A typical tablet with a volume of about 0.68ml preferably contains 450-600mg of pellets. The pellets are pharmaceutical pellets containing an active substance such as theophylline and have a size of 0.8-2mm. 100 such pellets weigh 140mg and 100 such pellets with a retard coat weiqh 160mg. Figure 1 shows the resultant tablets.

Example 2 Pellets from the same batch as for Example 1, mixed in the ratio of 1:1 with Polywax 6000 powder, are int.roduced into a capsule-like mould. The mould contents are fused at about 65°C and pressed together.

The mould is removed after coolina, releasing tablets as shown in Finure 2.

Example 3 A dividing notch or notehes may he introduced, producing tablets as shown in Figure 3.

0 jxample 4 S 20" ot ol 1 00 and a small amount of ammonium bicarbonate are introduced into the ower part of a two-part mould, and pellets, produced by a conventional process, are then introduced into the lower part of the mould. The quantity of ammonium bicarbonate used in strongly dependent A' n on the viscosity of particular binder used. The L---i-cl-rrll~-aa~l*n~~ ";UI-I~-"I.IYa -~llllll~-ly-.ll 13 quantity required can be determined by simple experiments.

In this particular case about 5mg of ammcnion bicarbonate per moulding is used. The upper part of the mould, which is provided with a plurality of aperatures, is then pushed on to the lower part and sintering is carried out at about 65°C. The excess gas and Polywax is able to escape. Figure 5 shows Examples of tablets produced by this process.

Example In addition to the Examples described above, rod shaped mouldings have been produced in order to emphasise the broad range of overall shapes possible for divisible compositions according to the invention.

Placebo pellets, having a weight of 25mg per 100 pellets, corresponding to a sieve fraction of 0.6 0.71 mm are provided, in a dragee-making kettle, with a coating of 20% by weight of polyethylene glycol o 20 1500. These pellets have no active substance.

o 0 Moulds are produced by casting from silicone rubber, 0 0 0 with the aid of precision-engineered rod patterns 0 made from aluminium.

o a On directly sintering the above pellets in a microwave oven and lightly pressing the mould in by hand, the rods shown in Figure 7 are produced.

o a 0000 S 0 030 0 0 oo In order to seal the interstices between the pellets, the compositions of the invention may also be produced :0 35 which consist of pellets provided with an additional "outer phase" or coating of polyethylene glycol .0P%,M j powder. Such compositions are illustrated in Figure 8.

14 The use of plastically resilient moulds as described above also permits the manufacture of mouldings having under-cuts such as are shown in Figure 9.

The term "under-cut" refers to the situation when the mould opening is smaller than the greatest width of the moulding. Thus in order to remove the moulding the mould must either be broken or it must be elastic made of silicone rubber).

o 0 00 0 0 O 00 000 0 0 o 00 0000 o0000 S a0 0 0 000 0 c 0 0 8

Claims (11)

1. A delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a fusible porous matrix comprising a physiologically acceptable binder, said binder being disintegrable in an aqueous medium.

2. A composition as claimed in claim 1 being in the form of a mouldinq.

3. A composition as claimed in either one of claims 1 and 2 being in the form of a tablet.

4. A composition as claimed in any one of claims 1 to 3 comprising means for subdivision. A composition as claimed in any one of claims 1 to 4 capable of readily disintegrating in an o0 aqueous medium whereby to release said pellets. o °o 20 6. A composition as claimed in any one of claims 1 to 5 wherein said binder is water-soluble or water-emulsifiable.

7. A composition as claimed in any one of claims 1 to 6 wherein said binder is a polyethylene glycol. 1 I, 8. A composition as claimed in any one of claims 1. to 4 wherein said binder is resistant to gastric juice.

9. A composition as claimed in any one of claims 0 a 1 to 4 further provided with a gastric juice resistant lacquer coating. /<cj cL. -6^ 16 A composition as claimed in any one of claims 1 to 9 wherein said pellets are in retard form.

11. A pellet-containing pharmaceutical or veterinary composition substantially as herein disclosed with reference to any of the Examples and the accompanying drawings.

12. A process for the preparation of a composition as claimed in claim 1 comprising moulding or extruding a forming composition comprising said pellets and an at least partially fused physiologically acceptable binder.

13. A process for the preparation of a delayed release or retard form of a moulding containing pellets which comprise an active substance and which are held in a porous matrix of a fusible, physiologically acceptable binder, said binder being disintegrable in an aqueous medium, said process comprising one of the following: o 3 0 introducing the pellets into moulds and subsequently filling said moulds by pouring in a fused 005 binder; oao coating the pellets with a binder, introducing Sthe coated pellets into moulds and then heating briefly; 030 0 Cc) mixing the pellets with a binder, introducinq the mixture into moulds and then heating briefly; or introducing the pellets together with a binder 4 and a blowing agent into moulds and heating briefly. 17

14. A process as claimed in claim 13 further comprising exerting a slight pressure on said moulding while it is still warm, whereby to assist the moulding action, to avoid cracks and to achieve a substantially uniform appearance. A process as claimed in either one of claims 13 and 14 wherein the walls of a blister foil are used as said moulds.

16. A process as claimed in claim 13 substantially as herein described and with reference to any of the Examples and the accompanying drawings. DATED this 4th Day of May, 1990 BOEHRINGER INGELHEIM INTERNATIONAL GMBH o 0 By their Patent Attorneys CALLINAN LAWRIE 0 0 o e 0 0 f l\