AU608128B2 - Controlled release system for orally administered active substances - Google Patents

Description

APPLICATION ACCEPTED AND AMENDMENTS /7

ALLOWED

AUSTRALIA

Form PATE=S ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

60812 8 FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: 6 Complete Specification Lodged: Accepted: Lapsed: Published: Priority: 'Related Art: TO0 BE COMPLETED BY APPLICANT Name~ of Applicant: -Address of Applicant: -Actual Inventors: Address for Service: BOERRINGER INGELHEIM VETM 1 EDICA GMIBH of D-6507 Ingeiheim, am Rhein, Federal Germany Republic of OTTO KERN, GUENTHER ENTENMA.NN and HERERT STRICKER CALLINANS, Patent Attorneys, of 48-50 Bridge Road 1 Richm~ond 3121, Victoria, Australia.

Camplete Specification for the invention entitled: "CO)NTROLLED RELEASE SYSTEM FOR ORALLY ADMINISTERED ACTIVE SUBSTANCES" The following statement is a full description of this invention, including the best method of performing it known to us: 4i 24L53 863 -la- Controlled release system for orally administered active substances The invention relates to a controlled release system for orally administered active substances.

In animal husbandry, animals have to be given certain substances over a long period of time for particular purposes, which rules out regular daily) administration for reasons of practicability. Because of the way in which animals pasture animals) 0oo. feed or are fed, continuous administration by mixing o with a powdered feed) is often impossible.

°o°0 10 This latter method of administration is in any case 0ooo affected by inaccuracies of dosage, particularly 0 0 when whole groups of animals are being treated and 6 more particularly when only small and varying quantities of food are taken because of loss of appetite. Examples 15 of substances which might be administered for lengthy 0o p o0 00 periods for therapeutic or prophylactic purposes o op include, for example, anti-parasitics, anti-infective :"one* agents, and substances which regulate the metabolism 6 or promote weight gain. For the controlled administration of such substances over lengthy periods, various systems have been developed which increase the retention time of an active substance carrier in the single stomach or in one chamber of the several chambers of the stomach in ruminants.

Another possible method of increasing the retention time of an active substance system in one of the stomachs of ruminants (the second or first stomach) consists in constructing the system as a metal-containing bolus. A bolus of this kind consisting of a core and a shell is described, for example, in European patent application no. 0164241. The core consists PO-~ il cLII -2 of a bio-degradable polymer and one or more active substances. As the polymer matrix is degraded, the active substance is continuously released. The shell consists of a metal casing provided with openings.

The high density of the metal prevents the active substance from being transported further towards the intestine or from being carried back into the mouth, in the case of ruminants, whilst the openings allow the active substances released from the core 10 to pass into the stomach fluid. Numerous different ooe o..eo embodiments of the combination of metal and active 00 S°o000 substance carrier are known. These systems enable o0 0 a constant quantity of active substance to be released 0. in the first stomach of cattle over a fairly long 0 0 o 15 time which can be controlled by particular embodiments.

0 0 A disadvantage of all such systems is that the metal o 00o parts remain in the animals' stomachs. If such systems 00 00oo0 are used several times, substantial quantities of metal accumulate. In addition, a permanent magnet 20 is already introduced into the second stomach of pasture animals to protect them from any sharp iron objects swallowed accidentally. If the active substance 00 systems described above consist of magnetizable metal, these permanent magnets are blocked with the active substance systems and can no longer perform their protective function. If the metal parts of the active substance systems are made of non-magnetizable alloys, there is a risk of the release of toxic metal ions lead) or else the systems are made very expensive by the use of corrosion-resistant iron-free alloys.

There remains a need therefore for a system for controlledly releasing active substance which can be held in the stomach of an animal such as a ruminant, releases its active substances in controlled manner over a predetermined period, which does not remain in the stomach after the active i C C 3 substances have been released, and which is non-toxic.

We have now been able to devise a system which fulfils practically all of these requirements. In our proposal, the active substance releasing system comprises high- density particles which serve to make the system heavy and which are held together by a physiologically harmless excipient which decomposes over a predeterminable period of time and a portion containing the active substance (active substance deposit.) and optionally 10 one or more excipient parts.

tt te 0 The high-density part (hereinafter also referred 0o0°. to as the density-imparting part) ensures that the 0ooo active substance releasing system according to the 0o o° invention remains in the ruminant's stomach for a 4 15 predictable length of time.

According to one aspect, therefore the invention 0 0 oo provides a controlled release system for orally administered active substances comprising a component which contains active substance and a component containing a weighting 0 agent, in which the weighting agent is present in the form of small particles which are combined by 00° means of an excipient which will in use decompose into physiologically harmless constituents within a predetermined time.

According to a further aspect of the invention, we provide a process for the preparation of a controlled release system of the invention which comprises bringing into association an active substance, a weighting agent in the form of small particles, an excipient which binds these particles together and an active substance deposit.

The particles, preferably powdered particles, comprise high-density substances, hereinafter also referred l-F. I i,

'I

4 to as weighting agents. These substances must be chosen, in terms of their specific density, composition and quantity, so that the active substance releasing system remains in the stomach in spite of the natural regurgitation process. Depending on the size of the active substance releasing system and its surface area, the specific density may assume any desired value over 1 g cm 3 but a value above 2.3 g cm 3 is preferred. Since the density of the excipient is usually between 0.9 g cm 3 and-.3 g cm 3 the density of the weighting substance to be selected 0Bt' -3 is generally greater than 3.0 g cm preferably greater 0 -3 S°o, than 4.0 g cm depending on the composition of the density-imparting part.

o000 0 0 15 The density does not theoretically have an upper o limit though will of course be governed by the availability of materials that are suitable and economic.

0 0o The following is a list by way of example, without ooo restricting the invention, of weighting agents which a 20 have sufficiently high density for the production of a density-imparting component: o 0 -3 Silver 10.5 g cm 3 -3 Copper 8.9 g cm -3 Iron 7.8 g cm -3 Nickel 8.9 g cm -3 Lead 11.3 g cm -3 Antimony 6.7 g cm -3 Tin 7.3 g cm -3 Zinc 7.1 g cm -3 Hydroxylapatite 3.1-3.3 g cm Barium sulphate 4.5 g cm -3 Iron oxides 5.2-5.7 g cm -3 Barium titanate 6.1 g cm -3 Aluminium oxide 4.0 g cm i i lii il~"U~i- L I~

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5 Tin oxide Titanium dioxide (Rutile) 7.0 4.2 -3 g cm g cm-3 g cm Minerals such as Scheelite (Calcium tungstate) Ferberite (Iron tungstate) Fayalite (Iron silicate) Hercynite (Iron aluminium oxide) Powellite (Calcium molybdate) Calcium phosphates -3 6.1 g cm- 7.2 g cm-3 -3 4.4 g cm 4.3 g cm-3 4.3 g cm -3 4.3 g cm o o S00 001 0 o 0 0n 00 00 0 o 9 00 0 oo G S00 o o O 0 10 The densities given are intended only as a guide.

Non-toxic substances, such as barium sulphate or iron oxides, are preferably used.

In mineral substances, in particular, the levels may be either or lower, e.g. due to the presence of other substances. This list of substances is not restrictive. Numerous other substances from the groups of metals, metal oxides, salts and minerals have sufficiently high density and are suitable for use according to the invention, provided that they are not contra-indicated by toxicological considerations.

In one embodiment, powdered or granulated metals or metal compounds used as weighting agents are coated with a non-degradable polymer. An advantage of this embodiment is that it is also possible to use as weighting agents compounds which are not entirely without problems in terms of their physiological activities, since the coated particles no longer come into direct contact with digestive juices.

Suitable polymers for this purpose are already known, such as polyethylene. Suitable coatings may be produced for example by spraying the metal or compound with i- i 1- 6 a solution of the polymer.

The particle size of the substances which may be used to weigh down the system is not critical but should be selected so that after degradation of the binding excipient the particles can be transported onwards through the digestive system. This depends inter alia on the specific density of the particles.

The higher the specific density, the smaller the particles can and desirably should-be.

0.0. 10 Whereas for many substances substantially larger 0 °particles are acceptable, in the case of substances 0" 0 with a high specific density, particle sizes of less 0q00 than 1 mm, possibly less than 0.1 mm, are preferred.

o 0 o0 The shape and the surface appearance of the particles o0 15 are not critical. The particles may be spherical or rod-shaped or may be of any other desired form.

The surface may be smooth, rough or porous. In certain 00 0 0 oo cases it is convenient to improve the adhesion between the high-density particles and the excipient which 20 binds them by means of a particular shape a star shape) or a particular surface structure (e.g.

a porous structure).

o e The excipient which imparts cohesion to the high density particles comprises a substance which is decomposed after a certain time by the action of the gastric juices and as a result of this degradation brings about decomposition of the density-imparting component. Suitable substances for this purpose are any which are dissolved by gastric juices after a specific length of time. Preferred substances are bio-degradable polymers. Large numbers of these polymers are known e.g. polycyanacrylates, polymethacrylates, polyacrylates, polyorthoesters, polyglycols, polyphosphazenes, modified starch and cellulose and 7 o 0o o o 0 0 0 009 0 0 0 ao o 0 0 0 00 a S o00 00 0 0 00 0 0 0oo 0 0 o0 0 D natural polymers such as proteins (collagen, gelatine) starch and cellulose. Suitable polyesters and polylactones include, for example, polyglycolide, polylactides, polyhydroxybutyric acid, polycaprolactone, polydioxanone, polytrimethylenecarbonate, polymers obtained from variously substituted glycolides such as diethylglycolide, dipropylglycolide, and methyl ethyl glycolide, and statistical copolymers and block copolymers obtained from the monomers glycolide, lactide, dioxanone, trimethylenecarbonate, caprolactone and other monomers.

The preferred polymers are those whose decomposition is affected as little as possible by enzymes or by changes in the pH value. Polymers the decomposition of which is affected by the choice of specific molecular weights and/or comonomer compositions and whose decomposition products are non-toxic are also preferred.

These include, in particular, polymers and copolymers of L-lactide, D-lactide, D,L-lactide, meso-lactide, glycolide, dioxanone and trimethylenecarbonate according to the following structure: O CH 3 OO 0 0 0O L-lactide'"Glycolide Dioxanone Trimethylenecarbonate D-lactide D,L-lactide meso-lactide The following are particularly preferred: Poly(L-lactide), poly(D,L-lactide) or polyglycolide with molecular weights (determined by titration of terminal groups) of less than 10,000 for decomposition times of the density-imparting component within a

I_;

-8few weeks; Poly(L-lactide), poly(D,L-lactide) or polyglycolide with inherent viscosities of more than 0.1 dl/g (chloroform 0 preferably more than 0.3 dl/g (chloroform 25C) for decomposition times within a few months.

The polymers may be used in pure form as mixtures with one another or as mixtures with other degradable or non-degradable polymers. .t The preparation, purification and analytical character- 'o 10 ization of the polymers preferred according to the o 000 invention have been described in numerous patents and publications. By way of example, the following o: are mentioned: DE-OS 2700729, US 3912692 or DE-OS S2850824.

0e 15 The density-imparting component may be produced in 0 0 a manner known per se by hot compression, extrusion o s or injection moulding of mixtures of the weighting o: agent and a polymeric excipient. In another embodiment, the weighting agent is introduced into a hollow body consisting entirely or partly of degradable plastics.

a The proportion of weighting agent must be selected so that the density of the active substance releasing system as a whole is preferably greater than 2.3 -3 g cm-3. In the majority of systems, this is achieved if the density of the density-imparting component is greater than 3 g cm 3 A moulded body with this density may be obtained for example by hot compression of a mixture of one part by weight of poly(D,L-lactide) (density 1.2 g cm 3 and 4.5 parts by weight of barium sulphate (density 4.5 g cm-3). The moulding may be of any desired shape (spherical, cylindrical, disc-shaped, etc.), provided that it can be swallowed by the animal and can be introduced into the animal i ;i-i _i I; -9- 0090 o 0 0Q00 0 0 0 000 o0 0 0 0 0 00 0 0 00 0 00 0 0 0 6 o by suitable means. Means for administering a moulding of this kind are described in the prior art and require no further explanations.

In the accompanying drawings, Figs. 1 to 12, various forms in which embodiments of the invention may be realised are shown. In all these a cylindrical shape with rounded ends (bolus) as shown in and is preferred.

The size of the bolus is variable within wide limits, the upper limit being set by the method of administration 10 (through the oesophagus) and the lower limit being set by the fact that the bolus must not be eliminated intact. Boli are generally about 10 to 12 cm long and about 3 to 4 cm in diameter.

The part which releases the active substance (referred to as the active substance deposit) can be combined with the bolus in cavities in the active substancereleasing system as shown in Fig. 1 or Fig. 2, in the form of rings as shown in Fig. 3 or as a film wrapped around as shown in Fig. 4. In the embodiments 20 according to Figs. 2 and 3, the dosage of active substance can be influenced, in a technologically advantageous manner, by varying the number of parts which release the active substance whilst the densityimparting component has a unified construction (see Fig. 3b). In another embodiment, the density-imparting component consists of a container made of degradable polymer filled with high density particles. The container may be constructed as a "bottle/lid arrangement" as shown in Fig. 4, as an open bottle as shown in Fig. 6 or as a capsule in two halves as shown in Fig. 7. The active substance-releasing part is applied as shown in Figs. 5-7.

In a preferred embodiment the active substance-releasing system according to the invention consists of a sealable i I ;ii 1 i 10 I hollow body which simultaneously serves as the densityimparting component, and an associated separate active substance deposit. The hollow body has sufficient openings to allow the gastric juices to penetrate unimpeded to the active substance deposit enclosed therein, possibly in several parts, in order to dissolve the active substance out of the deposit. The active substance deposit is designed so that it can be introduced into the hollow body through a closeable opening and remains there until it has deg-raded after the predetermined time or the hollow body has fallen o apart. This embodiment has the advantage that only O a few different sizes of bolus are necessary (about two or three different sizes), which means that, depending on the particular needs, a suitable treatment can be put together by the veterinary surgeon in ip V accordance with the clinical picture and the quantity of drug required, depending on the size of the animal.

The range of variations of the system for releasing 0 9 20 active substance is obtained because a plurality 0 00 0 al of different active substance deposits (in terms 1000. of the drug and the quantity) are available, which can then be combined if desired in a hollow vessel.

"O Individual variants of this preferred embodiment are described hereinafter, without restricting the variety of possible configurations of the system according to the invention. Individual examples are illustrated in Figures 8 to 12 of the accompanying drawings. Here, the system consists of a cylindrical hollow vessel of degradable polymer provided with slots or holes, which has at least one rounded end (see Fig. 8a, 8b) and contains a mixture of a degradable polymer and high density particles (weighting agents) (see Fig. 9) or consists entirely of a degradable polymer containing a weighting agent (see Fig. The open end of the cylinder can be sealed by means -11of a closure, which optionally also contains windows or openings, and consists of one of the two materials mentioned hereinbefore (see Figs. 9 and The cavity of the bolus serves to receive the active substance deposit, which may take any of a variety of forms smooth, rolled or folded films, small sheets, small rods, balls, tablets, tubes, rings, etc of uniform or layered structure) (see Figs. 9 and 10). The dosage of active substance can be varied by means of the size and/or number of these bodies, depending on the different body weights of the animals o which are to be treated.

o q a In another variant, a half-capsule-shaped or cylindrical S° hollow vessel according to the invention provided with openings is sealed at one or both ends with a closure consisting of a mixture of degradable polymer 6and high density particles (see Figs. 11 and 12), S0o whilst the cavity contains the active substance-carrying 0 body, as described above.

06 0 6o 0 In another embodiment, a core is formed from the density-imparting component, e.g. in the form of a" a sphere, which is then encased in the active substance deposit. In another embodiment, the active substancereleasing system consists of a homogeneous polymer or copolymer e.g. in the form of a solid ball or a solid cylinder in which both the weighting agent and also the active substance are embedded.

The active substance-releasing parts (active substance deposit) of the system are intended to release one or more active substances in controlled manner over a lengthy period of time. It is advantageous if the release of active substance is variable, so that the rate of release can be adapted both to the active

LLAIM

1. A controlled release system for orally administered active substances comprising a component which 4 /2 12 substance and also to the treatment. Depending on the objective and duration of the treatment, it may be desirable or necessary for the active substance to be released not only constantly but in some cases at a reduced or increased rate.

This invention also sets out to provide an active substance deposit which can be used orally in ruminants, with a controlled delayed release of active substance, which breaks up after all the active substance deposit is exhausted, into components which are eliminated C naturally. Although any active substance deposit COO is suitable if it releases the active substance over 0,44 4a lengthy period of time at a controlled rate of release and is then subsequently broken up into small components after the active substance has been released, it is preferable to have an active substance deposit in which the system consists of one or more active 0 substances and one or more polymers which are just 00 0 as degradable as the density-imparting components under the effect of gastric juices. The polymer (hereinafter also referred to as the carrier material) should therefore be selected for its degradability according to the same criteria as the density-imparting components of the system. However, since the release characteristics are of great importance in addition to the degradation time, it may be necessary to influence the release rate and/or the rate of degradation by means of additives. Thus, for example, in the treatment of acute diseases, the active substance has to be released within one to two weeks; for preventing infestation with worms, on the other hand, it is necessary for the active substance to be released over a period of several weeks. Active substance release systems with growth promoters may even be required to maintain their efficacy over some months.

of L-lactide, D-lactide, D,L-lactide, meso-lactide, dioxanone, glycolide, caprolactone or trimethylenecarbonate as the carrier material in the active substancereleasing part of the system.

Poly(D,L-lactide) is preferred, optionally containing defined amounts of additives.

Suitable additives include pharmaeelogically acceptable solvents and plasticizers, preferably an acetic acid ester, in an amount of up to 10%, and/or a biodegradable low molecular polymer, preferably polylactic acid, in an amount of up to 60%, and/or suspended watersoluble pore-forming agents such as lactose, in an amount of up to Poly(D,L-lactides) are known over a wide range of molecular weights. For the active substance-releasing part according to the invention it is particularly appropriate to use poly(D,L-lactide) types of moderate molecular weight having an inherent viscosity of SIn a preferred embodiment, the carrier material of the system according to the invention comprises poly(D,Llactide).

In another embodiment, the carrier material according to the invention comprises a copolymer of D,L-lactide and glycolide, but the proportion of glycolide in the polymer must not exceed 50% by weight.

Surprisingly, we have found that the rate of degradation of the active substance-releasing part can be controlled by means of a defined content of acetic acid ester or some other physiologically acceptable solvent

I

14 or a plasticizer or a mixture of solvents, which remains quantitatively in the polymer even after lengthy storage. This is of crucial importance since on the one hand the active substance-releasing part must be capable of being degraded fast enough, but on the other hand too fast a degradation of the component releasing the active substance would lead to uncontrolled release of the active substance. The content of acetic acid ester may be up to 10%, whilst an increasing amount of acetic acid ester accelerates the decomposition of the poly(D,L-lactide).

04 at 000 Surprisingly, we have also found that, in spite of influencing the rate of degradation of the part which o releases the active substance, the addition of acetic S° 15 acid ester has no appreciable effect on the release of the active substance.

.o Acetic acid esters used according to the invention 0° are the C 1

C

5 alkyl esters of acetic acid, such MO as methyl, ethyl, n-propyl, n-butyl, isobutyl, terto0%-o 20 butyl, n-pentyl, sec-pentyl, iso-pentyl and tert.pentyl esters. The use of ethyl acetate is particularly preferred.

0 o In another embodiment, the part which releases active substance according to the invention may also contain low molecular polymers such as poly(L-lactic acid), poly(D-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(L-lactic acid coglycolic acid), poly(Dlactic acid coglycolic acid) and poly(D,L-lactic acid coglycolic acid).

Poly(L-lactic acid) and poly(D,L-lactic acid) are preferred. The molecular weights (determined by titration of the of the terminal groups) are from 500 to 5000, preferably 1500 to 2500.

i: .L -I II il ii~l 15 These additives, either on their own or in conjunction with an acetic acid ester, will also make it possible to control the rate of degradation of the part which releases the active substance.

The release of active substance may be influenced by various methods: a) By the addition of a pore-forming agent, such as lactose, etc. oA. b) By the state of the active substance (dissolved, *0 10 suspended, particle size).

1000 ao n 0 o c) By the form which the carrier takes (monolythic, 0o 0 °O polydispersed, laminar structure).

a o Thus, in addition to compounds which influence the rate of degradation of the carrier material, the 00 15 part which releases the active substance according 0" to the invention also contains substances in the 0ooa form of pore-forming agents which make it possible 0 0 to control the rate of release of the active substance.

Suitable pore-forming agents according to the invention gco 20 include, for example, water-soluble, pharmaceutically acceptable monosaccharides and disaccharides. Lactose is preferred, but it is also possible to use glucose, fructose, xylose, galactose, sucrose, maltose, saccharose and related compounds such as mannitol, xylitol and sorbitol. Other suitable excipients are salts such as lactates, glyconates or succinates of sodium, potassium or magnesium. A rapid release of the active substance right from the outset (once the drug has been administered) is achieved if the rate of dissolution of the pore-forming agent is very much higher than the rate of release of the active substance. This is the case, for example, when the pore-forming agent, which does not remain in the stomach after the active -16such as lactose, is highly soluble with a small particle size.

A delayed accelerated release of the active substance is obtained if the solubility of the pore-forming agent is very much lower than that of the active substance; e.g. when the pore-forming agent has poor solubility in water. The delayed accelerated release of the active substance is achieved by the fact that the linear release curve of the active substance is maintained even over long periods of administration.

o 0 Using the various parameters, it is possible to produce 0.4 active substance-releasing components which will have both an individually adjustable release rate and also an individually adjustable degradation rate.

According to the various embodiments of the densityimparting component as represented in Figs. 1-7, the following embodiments are preferred for the parts which release the active substance: 0 b A) Solid, porous or channelled rods for embodiments according to Fig. 1 or Figs. 8-12 B) Rolled rods (rolls of film) for embodiments according to Fig. 1, or Figs 8 to 12 C) Rings for embodiments according to Figs. 3 and 7a D) Spheres, hemispheres or plugs of other shapes for the embodiments shown in Fig. 5 or Fig. 6 E) Tubes for embodiments according to Fig. 4 or Fig. 7b.

i -rr r, ~L I~~ high-density substances, hereinafter also referred 17 F) Solid, porous or channelled spheres, hemispheres, discs, granules or other shaped particles for embodiments according to Figs. 8 to 12.

Solid rods of type A may be constructed in several layers and produced, for example, by the following method.

The active substance is suspended in the dissolved polymer, e.g. with ethyl acetate as- olvent, and the additives according to the invention are mixed therewith. If desired, other pharmaceutical excipients may be added to the dissolved polymer together with Sthe active substance and the additives. The suspension is then poured out onto a surface and dried to form a film. the drying conditions are such that the desired residual quantity of solvent remains in the polymer, generally an amount of between 1 and 7%.

The dried films are between 30 and 1000 mm thick, preferably about 100 ym thick. Equipment and processes a for producing such films are known to those skilled o a 20 in the art and require no further explanation. Naturally, the drying process must be carried out with a certain amount of care (slowly and with only slight variations of temperature, vacuum and humidity), to ensure that the films stay flat.

Multi-layered films can be obtained by fresh application of polymer solution (without or without active substance) After the film has dried, it is cut up into strips of the required length.

Rods of type B consist of one or more single- or multi-layered rolled polymer films.

The active substance-releasing part of type B according 18 to the invention is also produced from films containing active substance, the thickness of the films being substantially less, generally between 30 and 500 m, preferably 70 to 90 pm. After drying, the films are cut and rolled up into rods of the required diameter, up to about 3 mm, which are then cut to the required length. The rods may be rolled up so that the core contains a cavity. In the laminate of type B, a plurality of films may be poured one above the other or preferably poured one above the-other and then rolled up to form a rod. By combining a plurality ,a Pof layers of film it is possible to combine active i substances quite simply and produce layers having different concentrations of active substance. The CO o individual layers may have different rates of release.

6 o In addition to an alternating layer sequence it is also possible first of all to form a rolled up core poop and then apply additional layers of film around the GO outside.

By the use of layers of film having different release o characteristics, different active substances can be released in a predetermined time sequence. It ,o0 is not absolutely necessary for all the film layers Cda to contain active substances.

When producing the active substance-releasing part of type B according to the invention, the films should have a relatively high content of residual solvent (about 10%) when they are rolled up. This prevents the films from becoming brittle. The finished, rolled-up rod is then subjected to another drying process in order to achieve the desired residual solvent content.

Rings of type C may be obtained by stamping out W--i~l--iL i~i~i 19 from single- or multi-layered films such as those obtained in the production of active substancereleasing parts of type A or B. Like the active substance-releasing parts of type A, D, E or F, they may also advantageously be produced by extrusion of granulates obtained from active substance and polymer or copolymer, optionally with additives such as polylactic acid or a pore-forming agent such as lactose. Mouldings of type A, C, D, E and F may also be produced by compressing a mixture of active substance and polymer or copolymer optionally with additives, whilst the pressure, temperature O. and compressing time should be adjusted so as to achieve the desired mechanical strength. Findings 0, o 15 have hitherto shown that components which release active substance produced by the "solvent method" °show different degradation characteristics from Io extruded materials, i.e. the extruded materials are degraded more slowly, despite having the same 20 polymer composition (cf. Fig. The difference A is based on the fact that, because of the relatively Soo. high temperatures prevailing during extrusion, a defined higher content of residual solvent cannot S° be achieved.

In another embodiment, the active substance is formed from small, separate particles which contain active substance and which also bring about delayed release of the active substance but are not degraded after the active substance has been released.

(Delayed release may be achieved, for example, by means of suitable coatings or carrier materials consisting of emulsion-polymerised polyacrylates (Eudragit)). This presupposes that the particles which contain the active substance are so small that they can be expelled without difficulty after the bolus has been broken down. In this embodiment, i .i .L i _I: 20 the bolus has to be constructed so that the gastric juices can reach the particles, but the openings provided in the bolus are dimensioned so that the particles remain in the bolus until it is broken down.

Suitable active substances are those which are present in the polymer in suspended form. Particularly suitable substances include, for example, the watersoluble salt forms of bases, such-as hydrochlorides or hydrobromides. Clenbuterol hydrochloride is particularly suitable.

o v 0 *9 0.00 0o° In addition, in the field of application of veterinary 0 000 medicine, the following groups of substances and on A 0 compounds may be used in the release systems according 15 to the invention.

On .0 00 0 o Glucocorticoids for inducing labour, e.g.

dexamethasone, betamethasone, flumethasone 0oo. and the esters and derivatives thereof, D 0o 0 0 gestagens for synchronising heat, and for D 0 0 0" 20 suppressing heat and rut, o00 B2-adrenergics for the treatment and prevention 0 0 of respiratory diseases, for preventing abortion and labour, for promoting growth and influencing Oo the metabolism, such as clenbuterol, ethyl 0 4-(2-tert.butylamino-l-hydroxyethyl)-2-cyano- 6-fluoro-phenylcarbaminate hydrochloride, a-[[[3-(l-benzimidazolyl)-l,1-dimethylpropyl]amino]-methyl]-2-fluoro-4-hydroxy-benzyl alcohol methanesulphanate monohydrate (cimaterol), 1-(4-amino-3-cyanophenyl)-2-isopropylaminoethanol, -blockers for reducing travel stress, a 2 adrenergics to counteract enteritic diseases and for treating hypoglycaemic conditions and for sedation clonidine, 2-[2-bromo- 6-fluorophenylimino]-imidazolidine), -21benzodiazepines and derivatives such as brotizolam for sedative purposes, antiphlogistics for anti-inflammatory treatment, e.g. meloxicam endorphins for stimulating the motility of the rumen, steroid hormones (natural and synthetic) for promoting growth, e.g. oestradiol, progesterone and the esters and synthetic derivatives thereof such as trenbolone, antiparasitics for combating endo- and entoparasites, such as levamisol, avermectin, O o* benzimidazoles, pyrantel, morantel, febantel, o substances affecting the heart and circulation, e.g. etilefrin or pimobendan.

0 Various active substance-release systems according to the invention and comprising density-imparting components and active substance-releasing components 0. are illustrated in Figs. 1 to 12: 0 20 In the examples shown in Figs. 1 and 2, rods of type A or B are inserted in bores in the 0 density-imparting component.

In the examples according to Figs. 3A, 3B and 7A rings of type C are pulled over mouldings provided with suitable notches.

In the examples shown in Figs. 4 and 7 the density-imparting component is inserted in a tube of type E.

Active substance-releasing systems according to Fig. 4 may also be produced by coextrusion.

When producing active substance releasing ~L U i 22 systems according to Figs. 5 to 7B, first of all the containers are produced by injection moulding, then filled with high density particles and finally sealed as shown in Fig. 5 or 6.

The embodiments according to the invention as illustrated in Figures 8 to 12 may be produced by known methods of producing cylindrical shapes of this kind. After the finished shapes have been filled with-the active substance deposit, they are sealed with a lid.

Although the active substance-release system according to the invention is preferably for use in ruminants, oO in particular cases it may also be advantageous to use it in other types of animal.

0 0 Aspects and considerations to be taken into account in the invention are hereinafter further illustrated by means of some Examples which may be related to the graphs.

a o 0 a 0 I 0 0 a a o o 0 040 i i) -L ILr 23 Example 1 (Relates to factors of polymer degradation: method of processing, tacticity, molecular mass) g of D,L-polylactide are dissolved in 75 g of ethyl acetate and spread out on a flat surface with a doctor blade to form a film. After drying for at least 24 hours this process is repeated twice or three times until a multi-layer film 250 microns thick is produced. The film is then dried first at 23°C, then at 400C in vacuo until a predetermined residual solvent content is obtained. The film g is then cut into pieces measuring 3 x 2.5 cm and shaped into rolls (3 cm long, 2.8 mm in diameter).

C-C0 SActive substance-releasing components produced C 15 by the solvent method exhibit different characteristics than, for example, extruded components in terms of the reduction in molecular mass in a buffer o solution, i.e. they are advantageously degraded °O more quickly (Fig. The tacticity of the polymer plays a more important part in the speed of degradation than the molar mass or limiting viscosity (Fig. 2).

On the other hand, the pH of the solution plays o* no part, see for example Makino et al., J. Microencapsul.

3, 203-212 (1986).

A significant reduction in mass occurs after about days, i.e. after the limiting viscosity has fallen to a value of 0.3 (100 ml/g).

Example 2 (Relates to factors of polymer degradation: residual ethyl acetate content, addition of polylactic acid) Multi-layer rolls of film are produced as described -I :IC r. II~ 24 in Example 1 but in the case of batch I 50% of the D,L-polylactide are replaced by D,L-polylactic acid (molecular mass 2000).

Fig. 3 shows that the reduction in molecular mass in an aqueous medium is accelerated by a residual ethyl acetate content of 4 or 7% but not by a content of The addition of 50% D,L-polylactic acid has a very marked effect in this respect.

The reduction in mass is correlated with the reduction in molecular mass as described in Example 1 (Fig. 4).

o o Example 3 o 0 o (Relates to factor of release of substance: addition S° of lactose) 00 4 o 0 8.8 g of D,L-polylactide II 2.2 (100 ml/g)) are dissolved in 45 g of ethyl acetate and 2.7 g of clenbuterol.HCl 2 0m x 53 pm) are suspended 0 therein and a three-layer film is produced in accordance with Example 1. In the case of batch L, an additional 25% by weight of lactose (1 5 mm) are suspended in the polymer solution for the middle layer.

e* Fig. 5 shows that the addition of lactose makes it possible to accelerate the release of clenbuterol in an aqueous medium and thereby control it.

Example 4 (Relates to factor of release of substance: addition of polylactic acid) The three-layered roll of film L from Example 4 is compared with a preparation produced analogously in which 25% of the D,L-polylactide II are replaced I-

I

by D,L-polylactic acid (molecular mass 2000).

Whilst the release of clenbuterole in an aqueous medium is greatly accelerated by the addition of polylactic acid, the residual ethyl acetate content in the region of 1 4% still had no effect on the release characteristics.

Polylactic acid can therefore be used like lactose as an additive which will control-release (Fig. 6).

In the Examples the following polymers are used: 10 Poly-D,L-lactide I 1.0 (100 ml/g) MW* 123,000 o 9o I o0**9 Poly-D,L-lactide II 2.2 (100 ml/g) MW 300,000 0 Poly-D,L-lactide III MW 11,500 0 Poly-D,L-lactic acid (MW 2000) a 0 intrinsic viscosity 0 04 0 15 MW molecular weight Determined by gas phase chromatography (standard: polystyrene) The Examples refer to intrinsic viscosity which is determined from the inherent viscosity when test concentration C tends to zero; in practical terms under the experimental test conditions, the intrinsic and the inherent viscosities are the same.

Unless otherwise stated, all percentages used herein are by weight and all molecular weights are number average molecular weights.

-26- 100i f~Ogill)

A

0'1 00 0 0 50 1;Dy Fig 0:Rdcini oeua aso oyatd ~~00B Fig x1: ruedcin ine moeua mass of polylactide A0 Rolled od of DL-Ipowdatier slvn 27 RI loogMi) ,p 0.31 .3 .3 0.30.3 .3 .3 0 000 .3.3.30 .3 .3 .3.3.3.3 0 0e#.3~ .3 .3 .3.3 .3.3 .3 .3 0 .3 .30*0 .3 .3 .3 .3.3 0 .3 .3.3 .3.3 .3 .3 0.3 0* 00 0 .3 0 0,10 0,01 0 50 100 Days .3.3 .3.3 Fig. 2: Reduction in molecular mass of polylactide mould ings Test conditions: isotonic phosphate buffer pH 7.4; Preparation: rolled rods of polylactide (solvent method) A: D,L-polylactide 1; 7% ethyl acetate, Tg =26 D: D,L-polylactide 11; 7% ethyl acetate, Tg 3 E: L-polylactide, 7% ethyl acetate, m.p. 1720 37 0

C

0oC

C

(comparison Example) -28- 2 a h.44 00 0 a a a a 0 0 50 100 Days Fig. 3 Reduction in molecular mass of polylactide mould ings Test conditions in vitro: isotonic phosphate buffer; pH 7.4; 37 0

C

Preparation: film rolls (solvent method) A: D,L-polylactide 1; 7% ethyl acetate; Tg 26*C F: D,L-polylactide 1; 1% ethyl acetate; Tg =48*C G: D,L-polylactide 1; 4% ethyl acetate; Tg H: D,L-polylactide 11; 1% ethyl acetate; Tg 520C I: D,L-polylactide II polylactic acid 1% ethyl acetate; Tg 30 0

C

-29 Polymer mass()

H

1 00 500 000 0 9 0 5010 Dy *%co Fi.4 euto0i aso lplyat olig 59 Invtots9odtos iooi hsht ufr 0H 7.%03 Fig 4:Rduto i as fd-polylactide 11mouldinaeat;gs vitro test cdtions: +50 isooicct pohacufer F: ,L-ollacideI; 1% ethyl acetate; Tg 0 0C Clenbuterol content W% co* 09 ago# 0 40 Oq 90 9 0 04 0 99 0 9 0 9 9 0.0 ~40 60 Days Fig. 5: Release of clenbuterol from D,L-polylactide mould ig 5 Test conditions: isotonic phosphate buffer; pH 7.4; 37*C Preparation: 3-layer rolls of film (100 ml/g)) containing 23.5% by weight of clenbuterol.HCl and 4% ethyl acetate Lactose by weight) 2nd layer 3rd layer 1st layer 0 1, I 31 Clenbuterol content 100 o #~a t 0O I~ 00 0t *0 r *000 0 0000 0 0 O*9g 0 0 01 0'0 00 0 0 0 0 00 00 0 00 00 0 o Qi 00 00 00 0 0 0 00 00 0 00.

0 20 ~40 60 Days Fig. 6 Release of clenbuterol from D,L-polylactide mouldings In vitro test conditions isotonic phosphate buffer pH 7.4; 370C.

Preparation: 3-layer rolls of film containing by weight of lactose and 23.5% by weight of clenbuterol HCl di-polylactide II 2.2 (100 ml/g)) L: 4% ethyl acetate M: 1% ethyl acetate N: 1% ethyl acetate 25% di-polylactic acid Additives:

Claims (15)

1. A controlled release system for orally administered active substances comprising a component which contains active substance and a component containing a weighting agent, in which the weighting agent is present in the form of small particles which are combined by means of an excipient which in use decomposes into physiologically harmless constituents within a predetermined time.

2. A system as claimed in claim 1 in which the 10 excipient which decomposes within a predetermined fa length of time is a polymer which is degradable "oo under physiological conditions. 0 000444

3. A system as claimed in claim 1 or claim 2 S" O in which the weighting agent is a powdered metal or metal compound with a density of more than 3.0 g cm-3 00 4. A system as claimed claim 3 in which the 0 metal or metal compound has a density of more than -3 o. 4.0 g cm 0 o A system as claimed in any of claims 1 to so 20 4 in which the polymer with which the particles of the weighting agent are combined is a polymer or copolymer based on glycolide, lactide, dioxanone and/or trimethylene carbonate.

6. A system as claimed in any of claims 1 to 5 in which the component containing the active substance releases the active substance in delayed manner.

7. A system as claimed in claim 6 in which the active substance is enclosed in a polymer which is degradable under physiological conditions. 33

8. A system as claimed in claim 7 in which the polymer is a polymer or copolymer based on glycolide, L-lactide, D-lactide, D,L-lactide, meso-lactide, dioxanone and/or trimethylene carbonate.

9. A system as claimed in claim 6 in which the component which contains active substance deposit comprises a non-degradable carrier material which is present in the form of small, precipitatable particles. A system as claimed in any of claims 6 to o1oor 9 in which the component containing the active 6 substance comprises a carrier material based on oc a oot o. 45 poly-D,L-lactide in admixture with an active substance, the carrier material containing also defined amounts of additives in the form of pore-forming agents, and up to about 10% by weight of a physiologically harmless solvent or plasticiser and/or below molecular .c 50 polylactic acid. a

11. A system as claimed in claim 10 in which 0 the carrier material comprises a copolymer of D,L- lactide and glycolide, the proportion of glycolide not exceeding 50% by weight. 55 12. A system as claimed in claim 10 or claim 11 in which the carrier material contains up to by weight of an acetic acid ester.

13. A system as claimed in one of claims 6, 7, 11 or 12 in which the carrier material contains low molecular mass polylactic acid and/or lactose.

14. A system as claimed in any one of the preceding claims which comprises a hollow body containing the weighting agent and provided with small openings 34 and a single- or multi-part active substance deposit enclosed. A system as claimed in any of the preceding claims in which the active substance comprises a combination of several drugs.

16. A system as claimed in claim 1 substantially as hereinbefore described and with reference to Figs. 1 to 12 of the accompanying-drawings.

17. A system as claimed in claim 1 substantially r 10 as hereinbefore described and with reference to the Examples and accompanying Figures.

18. A process for the production of an active j *substance-releasing system as claimed in any one of claims 1 to 17 which comprises bringing into association an active substance, a weighting agent 6o<> in the form of small particles, an excipient which I binds these particles together and an active substance deposit.

19. A process as claimed in claim 18 substantially as hereinbefore described. The use of an active substance-releasing system as claimed in one of claims 1 to 17 for the prevention and/or treatment of diseases in ruminants.

21. The use of an active substance-releasing system as claimed in one of claims 1 to 17 for influencing growth, metabolism, body weight, tissue composition and/or feed utilisation in ruminants. C" 35 D AT ED -Chis 7th day of March, 1989. BOEHRINGER INGELHEIM VETMEDICA GMBH By its Patent Attorneys: CALLINANS o'tf et tf o ~ir o Wi t 01 o 00 on I O 0O 00 0 4 80 0 I 0# 0* 04 8 4 4 0# sq 0 ,oE