WO2001037811A1

WO2001037811A1 - Composition allowing predefined and controlled release of active ingredient, preparation thereof and use

Info

Publication number: WO2001037811A1
Application number: PCT/EP1999/008979
Authority: WO
Inventors: Sébastien HURON; Eric Lacoste
Original assignee: Akzo Nobel N.V.
Priority date: 1999-11-22
Filing date: 1999-11-22
Publication date: 2001-05-31
Also published as: AU1556000A

Abstract

A new composition is disclosed which is especially designed for combatting external and internal parasitoses. In one embodiment this composition contains, as an active ingredient, an endectocide, the form of a subcutaneous implant constituted by one or more pellets that release the active ingredient in a predetermined and controlled way. In specific embodiments the endectocide is an avermectin or a milbemicin, in particular ivermectin.

Description

COMPOSITION ALLOWING PREDEFINED AND CONTROLLED RELEASE OF ACTIVE INGREDIENT PREPARATION THEREOF AND USE

FIELD OF THE INVENTION

The present invention relates to a composition, preferably to a pharmaceutical composition containing an active ingredient, such as antiparasitics, which is capable to become administered to, preferably implanted subcutaneously into an organism, such as an animal, and to release said active ingredient in a predefined and controlled manner

DESCRIPTION OF THE PRIOR ART

Various ways of administration of acitve ingredients to an organism are knwon, e g via the oral route (per os) through tablets, capsules, liquids (suspensions or solutions), drops, syrup and slow release bolus Tor animals the administration of liquids, powder, paste, granules via the animal feed or drinking water is often used

The parenteral application [e g subcutaneous (s c ), intramuscular (I m ), intraperitoneal (I p ), intraveneous (I V )] can occur e g per injection, infusion or implantation

Another option is the local (topical) aphcation which can be made by using a spray, bath, dip ointment liquid suspension or solution, cream or pour-on

The treatment of various diseases requires the maintenance of a sufficient level of pharma- ceutically active ingredients in certain body fluids over a defined period One example is the control of infectious diseases with antibiotics that require a defined concentration of the antiinfective ingredient in the body fluids where the pathogen is located to kill the pathogens or control the bacteria replication Another example is the control of ^ parasites in and on the organism

On the other hand the pre-determination of an optimal and convenient treatment regime is considered as a further positive effect Especially in the prophylactic and therapeutic treatment of animals with pharmacologically active substances additional handling of animals that can it) lead to stress, body weight loss and labour effors for the farmers can be reduced

This effect can be reached through a composition allowing predefined and controlled release of an active ingredient Some of the known principle ways of adminstration are applicable for a controlled relase of an active ingredient to an organism 15

Examples are fomulations, known as „long acting injectable formulations", „slow release bolus" and also subcutaneous implants

But as of today there are only a few formulations available in the art which allow release of an 0 active ingredient in a predetermined and controlled manner to an organism Thus, there is a continued need for formulations allowing active ingredients to become administered to an organism, such as implanted subcutaneously and releasing said active ingredients in a predetermined and controlled manner, such as over a prolonged amount of time

5

Formulations that are administered as s c implants are known per se But as of today the known formulations are generally produced via extrusion of their components or via microencapsulation Both methods are costly and the production method can cause loss of activity in thermo-sensitive components or may contain residues of solvents used in the 0 production process The loss of activity in thermo-sensitve conponents does not allow the use of this method with thermolabile active ingredients The residues of solvents may lead to side- effects following the administration to the organism Thus there is a continued need for improved subcutaneous implant and an improved production method for such a formulation

Whereas the compositions of this invention can become administered to any kind of organism, such as humans and animals, preferably mammals, the invention will be described in more detail via the treatment of animals with pharmaceutically active substances, especially antiparasitics

One indication, which is economically important in agriculture, is the use of pre-defined and controlled release of pharmaceutically active ingredients in the control of parasites in livestock ruminants (e.g cattle, sheep and goat).

Parasites can be classified into Endoparasites and Ectoparasites Endoparasites, for example worms (nematodes), cestodes and trematodes are hosted inside (e g gastrointestinal tract, respiratory tract) the organism (human or animal). Ectoparasites, for example fleas, mites, ticks and lice are hosted on (on or in the skin) the organism (human or animal)

Active ingredients are known that control Endoparasites (Endoparasitics, e g Fenbendazol, Pyrantel, Praziquantel) or Ectoparasities (Ectoparasitics, e.g Deltamethrin, Fipronil, Lufenuron) and active ingredients that control both Endoparasites and Ectoparasites (Endectoparasitics, e.g Abamectin, Ivermectin, Milbemycin, Cydectin)

These active ingredients can be adminstered in various formulation, e g as powder, spray, pour-on, bath, dip, injection, tablets, bolus or suspension

For an effective control of the parasite in or on the animal the following facts are especially important, species and stage of the parasite as well as species, age, breed and sex, body weight and condition of the host animal Therefore it is for an effective control of parasites important to have a formulation available that allows an individual dosage of the active ingredient

On the other hand the administration of antiparasitics to animals, especially ruminante is a very labour intensive work and causes stress and loss of body weight of the animals It woud be therefore desirable to have a formulation available that allows pre-defined and controlled release of a prolonged time period

But as of today only a few formulations are available in the art that allow the pre-defined and controlled release of antiparasitics to animals that allow individual dosage and an be manufactured cost effectively

Consequently, there was a need for a formulation meeting these requirements, and the present inventor took on the task of creating and providing such a formulation

Another object of the present invention is an improved manufacturing process for such products minimizing or avoiding the risk of thermo-degradation of the components of such product and/or minimizing or avoiding the content of residual solvents from the manufacturing process in the product

Another object of the present invention is an easy to handle manufacturing process for such products using equipment that is common in the manufacturing of other parmaceutical formulations thus minimizing the cost of such manufacture

Still another object of the present invention is the provision of implants with dosages of active ingredients being individually adaptable to the needs of the specific prophylactic or therapeutic treatment Current products use a fixed dosage in the implants Individual dosages are especially desired for animal treatment with regard to different species, body weight, breed and age

BRIEF DESCRIPTION OF THE INVENTION

The present invention meets these requirements, by providing a composition, preferably a pharmaceutical composition for predefined and controlled release of an active ingredient The present invention relates to a composition allowing a predefined and controlled release of an active ingredient to an organism when administered to said organism, which composition comprises a combination A) of at least two components a) at least one active ingredient in dispersed solid form, b) at least one gelling agent, c) optionally at least one filler, and d) optionally at least one adjuvant which combination A) is in the form of discrete particles and is embedded into a matrix B) which is formed by a pore-forming agent and optionally at least one adjuvant.

The composition of this invention can be administered to an organism in various ways known to those skilled in the art. Preferred is the form of an implant, preferably a subcutaneous implant.

The composition of this invention preferably contains, as an active ingredient, an endectocide in the form of subcutaneous implants, constituted by one or more tablets that release the active ingredient in a predetermined and controlled manner during a period quite longer as known formulations allow, of up to about 1 year, preferably of about 4 months, thus reducing the labor costs, the movement of the animals, the losses of body weight and of production of milk due to such movements, besides protecting the animals and their hide against the attack of the parasites.

DETAILED DESCRIPTION OF THE INVENTION

The duration of the action of the composition of the invention can be easily controlled by manipulating the concentration of the active principle and of the excipients.

As an active ingredient a) in dispersed solid form any active substance can be used that is desired to become released when administered to an organism.

Active ingredients can be all types of biologically active substances, preferably pharmaceutically active substances. Examples of biologically active substances are antibiotics, antiparasitics, hormones, growth promotors. anti-cancer drugs, vitamines and vaccines.

More specific examples of pharmaceutically active substances are BST, trenbolone, zeranol, ivermectin, abamectin, doramectin, moxidectin, selamectin and other systemical compounds

More than one active ingredient can be used, for example a synergistic combination of two pharmaceutically active ingredients.

Thus, a composition according to the present invention can also additionally contain other biologically active agents used in human or veterinary medicine such as, for example, vaccines, antibiotics, growth promoters, agents that potentialize the antiparasite effect of the active ingredient or that improve or avoid its side effects

Preferably the active ingredient is an endectocide, especially preferred an avermectin or a milbemicin and most especially preferred ivermectin and abamectin.

When administering an endectocide to an animal, effective treatment and control of the different species of pulmonary and gastrointestinal round worms, ticks, myiases (known as "bicheiras"), larvae of Dermatobia hominis, lice, mites of mange and of the fly known as "mosca-dos-chifres" is possible

The active ingredient is solid and is applied in dispersed form, for example in the form of powder or preferred in the form of granules. Solid shall mean solid at 25°C

The gelling agent b) can be of any kind as long as this agent is physiologically acceptable and forms together a gel or a shapable mass with component a), with optional components c) and d) and with a liquid, for example water or body fluids

Examples of gelling agents are organic or inorganic gelling agents, such as modified cellulose, modified starch, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylates, polymethacrylates, or dispersed silica Preferred is modified cellulose, preferably alkylated cellulose, most preferred ethylcellulose

The filler c) can be of any kind as long as this is a pharmacologically inactive substance Examples of filler c) are carbohydrates and silica, preferably a disaccharide, and most preferred lactose

The matrix material B) embedding shaped particles from components a), b), optionally c) and optionally d) is a pore-forming agent This agent is soluble in body fluids and after being administered to the organism this agent dissolves thereby forming pores in the matrix Thus the body fluids become access to the combination A) comprising components a), b) and optionally c) and d) and the active ingredient is released in a predetermined and controlled manner Examples of pore-forming agents are polyalkylene ethers, polyvinyl alcohol, sugar and sugar alcohols Examples for sugars are lactose, glucose and preferred saccarose Examples for sugar alcohols are mannitol and sorbitol

Preferred as pore-forming agents are polyalkylene ethers or polyvinyl alcohol. Said polyalkylene ethers or polyvinylalcohols are available in different aggregate forms, depending on their molecular weight, as liquids or solids at 25°C. For use in the instant invention the polyalkylene ethers and the polyvinylalcohols should be matrix-forming and shapable via compression methods The molecular weight of the pore-forming agent should be selected adequately to allow pore-forming effects in contact with body fluids

Examples of polyalkylene ethers are polybutylene ethers, polypropylene ethers or especially polyethylene ethers Preferably a nonionic polymer of polyethylene oxide, a polyethylene glycol, a polyethyleneglycol alkyl ether or combinations thereof are used Said matrix material B) in addition can contain one or more adjuvants d)

Most preferred as a material forming matrix B) is a a nonionic polymer of polyethylene oxide possessing a molecular weight (weight average) between 3M and 10 M, whereby M stands for a million A very preferred matrix material B) for use in the instant invention is the excipient Polyox^ from Union Carbide Corporation, this being a nonionic polymer of polyethylene oxide with specifications of USP-NF 1990 In this respect reference is made to the leaflet of Union Carbide Corporation published in the USA in 1994 under the title "POLYOXYO

WATER-SOLUBLE RESINS FOR PHARMACEUTICALS", incorporated herein b\ reference The molecular weight of Polyox used in the implants of the present invention is of 4 M, 5 M and 7 M, where M stands for 1 million

In the compositions of the present invention one can use all the forms of Polyox mentioned in said leaflet as well as othei different forms of excipients that can be used for the same purpose as Polyox such as polyethylene glycol, polyethylene glycol alkyl ether, polyvinyl alcohol other derivatives of polyoxyethylene and other polymers usable for the same purpose

In a preferred form the composition of this invention is in the form of a tablet But other forms are also applicable for example rods, capsules, microparticles and granules

Besides components a), b) and optionally c) the compositions of the instant invention may contain additional adjuvants known in the art of formulations Examples of such adjuvants are carrier materials such as starch, starch derivatives, talc, steaπc acid or salts thereof, fats, waxes, natural or hardened oils, liquids, such as water, alcohols, e g ethanol, glycerin or polyols vegetable oils, polymers or copolymers, such as copolymers from glyco c acid and lactic acid, fillers, binders, lubricants, surfactants, stabilizers, emulsifiers, disperging agents thinners, thickening agents, solvents, preservation agents, buffer agents, salts, and antioxidants

Such adjuvants can be contained in the component A) and/or in the component B) of the composition of this invention

The amount of components a), b), c) and d) in composition A) can generally be varied in a broad range Typical amounts of component a) are 0.01 - 98 % by weight, preferred 20 - 95 % by weight and most preferred 35 - 85 % by weight.

Typical amounts of component b) are 0.01 - 20 % by weight, preferred 0. 1 - 10 % by weight and most preferred 0.5 - 5 % by weight.

Typical amounts of component c) are 0 - 60 % by weight and preferred 1 - 40 % by weight.

Typical amounts of component d) are 0 - 10 % by weight and preferred 0 - 5 % by weight. The indicated amounts for components a), b), c) and d) refer to the total of said components in a composition.

The weight proportion of combination A) and matrix material B) can also be varied in a broad range. Typical amounts of matrix material B) are 2 - 50 % by weight, preferably 5 - 40 % by weight, referred to the total composition of A) and B).

The compositions of the instant invention can be prepared by mixing components a), b), optionally c) and optionally d) in a conventional mixing equipment. This can be performed in dry form or under addition of a liquid, preferably water. The mass thus formed should be shapable to form a plurality of small pieces, such as grains, of component A). The formation of such small pieces can be performed by conventional shaping means, for example by pressing the obtained mass through a mesh. The obtained small pieces are then combined with the matrix forming component or components. This can be performed in conventional mixing equipment. After the combination of components A) and B) is performed, this composition is given the final shape in a shaping equipment for said combination of components A) and B). Examples thereof are a pelletizer, an extruder or preferably a tablet press.

Thus the instant invention also relates to a process of manufacturing the above defined composition said process encompassing the measures: i) combining components a), b), optionally c) and optionally d) in a mixing equipment, ii) mixing said components together with a liquid to form a shapable mass A) iii) shaping said mass A) into a plurality of small pieces by applying a first shaping means to said mass A) and separating said mass A) into a plurality of small pieces, iv) combining said small pieces of mass A) with a pore-forming agent B) and optionally with at least one adjuvant d), v) mixing said combination of components A) and B) to form a shapable composition; and vi shaping said composition to a desired shape by means of a second shaping means

In a preferred process of this invention a tablet press is used as a shaping means In this process the application of heat and/or organic solvents can be avoided and easily available equipment can be used

The shaped composition, for example tablets, obtained according to this process can be combined to form an implant.

In a convenient form of presentation of the implants of the present invention, they are packed in plastic cartridges containing a plurality of implants, which are usable for treating of several animals

An implant is in general constituted by a certain number of tablets, for instance 5, 10, or 15 tablets These tablets are called "pellets".

A more specific formulation according to the present invention and containing the Endectoparasitics Ivermectin as an active ingredient typically contains approximately the following

active ingredient: 9 - 20 mg/pellet

Polyox ^• 10 - 30% (weight/weight) Lactose 20 - 50% (weight/weight)

- Talc 6 - 10% (weight/weight) Magnesium Stearate 1 % (weight/weight)

- Ethyl Cellulose N200 1 % (weight/weight)

resulting in a total weight of 30 mg/pellet

In veterinary applications the implant is preferably applied to the ear of the animal since this region has sufficient blood vessels, thus permitting a desired absorption of the active ingredient

As an example for the pharmacokinetics of an active ingredient from the compositions of this invention the specific product Ivermectin, after being absorbed, gets into the bloodstream deposits on the fat and is distributed by the secretions into the bloodstream, the digestive apparatus, respiratory apparatus, liver, and is eliminated by the feces and urine

The compositions of this invention can be applied to any orgamsm where predetermined and controlled release of an active ingredient is desired, especially where individual dosage is required Examples of organisms are vertebrates and non-vertebrates Preferred is the application to humans and animals

EXAMPLE OF MANUFACTURE OF THE PELLETS USABLE IN ACCORDANCE WITH THE PRESENT INVENTION

In order to prepare a batch of pellets, the following procedure was applied

1) On the day before a gel is prepared with ethylcellulose and alcohol in the following proportions

- ethyl alcohol 0 7 1

- ethylcellulose N200 0 045 kg Leave in a stirrer for 30 minutes until the lumps are eliminated Cover the excipient in order to avoid evaporation of alcohol and leave it standing overnight

2) In a GUEDU-type mixer, incorporate ivermectin and lactose

Cover and mix it for 5 minutes at maximum speed

Add the gel, under motion, during 1 30 minutes

Leave the mixer on for 1 minute more

3) Add absolute alcohol (0 05 1) previously passed in the container that contained the gel (washed from the container)

4) If necessary, complete with (absolute) ethyl alcohol (0 2 - 0 25 1)

Leave the GUEDU mixer in motion at top speed until a very fine granulate is obtained

5) Pass the granulate through 1 60mm mesh and put it on a stainless steel tray (5), forming a regular layer on each tray

6) Dry in a vacuum oven at room temperature for 2h30min

Pass the dried granulate through 3 trays of 1 6mm mesh and 2 trays of 1 0 mm mesh

Leave it dry in a vacuum oven at ambient temperature until the next day

7) Repeat the screening by passing it through 3 trays of 1 6 mm mesh and 2 trays of 1 0 mm mesh Put the material in a GUEDU mixer Add talc and Polyox, stir and add the magnesium stearate Perform the mixing action and transfer to obtained mixtures to a tablet press and produce tablets

Typical characteristics diameter - 3 mm shape - cylindrical approximate weight - 30 mg thickness - 3 3 - 3 7 mm

EXAMPLES OF THE FORMULATION OF PELLETS USABLE IN IMPLANTS ACCORDING TO THE PRESENT INVENTION

Following the procedure described in the preceding EXAMPLE OF MANUFACTURE and using the amounts of the various ingredients respectively indicated, pellets of the compositions given below in examples 1 - 16 were obtained, that were usable to release a sufficient level of ivermectin over a certain period.

Example 1

Pellets containing 18 38 mg of ivermectin/pellet and 10% of Polyox 301

Ivermectin 136 0 g

Polyox 301 20.0 g

Lactose 42.0 g

Talc 8 0 g

Magnesium stearate 2 0 g

Ethylcellulose 2.0 g

To result in a total of 210 0 g

Example 2 Pellets containing 1428 mg of ivermectin/pellet and 10% of Polyox 301

Ivermectin 993 g

Polyox 301 190g

Lactose 638 g

Talc 119g

Magnesium stearate 19g

Ethylcellulose 200 146g

To result in a total of 1974 g

Example 3

Pellets containing 970 mg of ivermectin/pellet and 10% g of Polyox 301

Ivermectin 7248g

Polyox 301 202 g

Lactose 1006 g

Talc 157g

Magnesium stearate 20g

Ethylcellulose 200 106g

To result in a total of 212 lg

Example 4

Pellets containing 1930 mg of ivermectin/pellet and 10% of Polyox Coag

Ivermectin 13600 g

Polyox Coag 202 g

Lactose 32 Og

Talc 80g

Magnesium stearate 20g

Ethylcellulose 200 20g

To result in a total of 200 Og Example 5

Pellets containing 150 mg of ivermectinpellet and 10% of Polyox Coag

Ivermectin 12294 g

Polyox Coag 233 g

Lactose 7296g

Talc 93g

Magnesium stearate 23g

Ethylcellulose 200 18g

To result in a totall ooff 2326 g

Example 6

Pellets containing 1040 mg of ivermectinpellet and 10% of Polyox Coag

Ivermectin 9175g

Polyox Coag 25 Og

Lactose H97g

Talc lOOg

Magnesium stearate 25g

Ethylcellulose 200 13g

To result in a total of 2504 g

Example 7

Pellets containing 19,30 mg of ivermectin/pellet and 10%> of Polyox 303

Ivermectin 136 Og

Polyox 303 20 Og

Lactose 32 Og

Talc 80g

Magnesium stearate 20g

Ethylcellulose 200 20g

To result in a total of 200 Og Example 8

Pellets containing 15.00 mg of ivermectin/pellet and 10% of Polyox 303 :

Ivermectin: 147.5 g

Polyox 303 : 25.1 g

Lactose: 63. g

Talc: 10.0 g

Magnesium stearate: -5 g

Ethylcellulose 200: 2-5 g

To result in a tota ll ooff:: 250.6 g

Example 9

Pellets containing 10,40 mg of ivermectin/pellet and 10%> of Polyox 303 :

Ivermectin: 136.0 g

Polyox 303: 20.0 g

Lactose: 32.0 g

Talc: 8.0 g

Magnesium stearate: 2.0 g

Ethylcellulose 200: 2.0 g

To result in a total of: 200.0 g

Example 10

Pellets containing 18.60 mg of ivermectin/pellet and 30% of Polyox 301 :

Ivermectin: 130.5 g

Polyox 301 : 57.5 g

Lactose: 3.3 g

Talc: 4.0 g

Magnesium stearate: 1.9 g

Ethylcellulose 200: 1.9 g To result in a total of 1991 g

Example 11

Pellets containgmg 1484 mg of ivermectin/pellet and 30% of Polyox 301

Ivermectin 903 g

Polyox 301 519 g

Lactose 206 g

Talc 689g

Magnesium stearate 17g

Ethylcellulose 200 13g

To result in a total of 1726 g

Example 12

Pellets containing 1031 mg of ivermectin/pellet and 30% of Polyox 301

Ivermectin 5490g

Polyox 301 456 g

Lactose 432 g

Talc 52g

Magnesium stearate 15g

Ethylcellulose 200 08g

To result in a total of 1512g

Example 13

Pellets containing 18,60 mg of ivermectin/pellet and 30% of Polyox Coag Ivermectin 13046 o g Polyox Coag 575 g

Lactose 33 g

Talc 40 g Magnesium stearate 19 g

Ethylcellulose 200 19 g

To result in a total of 1991 g

Example 14

Pellets containing 1480 mg of ivermectin/pellet and 30% of Polyox Coag

Ivermectin 9103 g

Polyox Coag 52 Og

Lactose 243 g

Talc 43g

Magnesium stearate 17g

Ethylcellulose 200 13g

To result in a total of 1745 g

Example 15

Pellets containing 10,31 mg of ivermectin/pellet and 30% of Polyox Coag

Ivermectin 6162 g

Polyox Coag 508 g

Lactose 498 g

Talc 49g

Magnesium stearate 17g

Ethylcellulose 200 09g

To result in a total of 1696 g

Example 16

Pellets containing 18,60 mg of ivermectin/pellet and 30% of Polyox 303 Ivermectin 13046 g Polyox 303 575 g

Lactose 33g

Talc 40g

Magnesium stearate 19g

Ethylcellulose 200 19g

To result in a total of 1991 g

Example 17

Pellets containing 1464 mg of ivermectin/pellet and 30% of Polyox 303

Ivermectin 8317 g

Polyox 303 473 g

Lactose 22 lg

Talc 62g

Magnesium stearate 16g

Ethylcellulose 200 l-2g

To result in a total of 1613 g

Example 18

Pellets containing 10,40 mg of ivermectin/pellet and 30%) of Polyox 303

Ivermectin 5746g

Polyox 303 475 g

Lactose 469 g

Talc 62g

Magnesium stearate 16g

Ethylcellulose 2000,8 g

To result in a total of 1605 g

Claims

1 A composition allowing a predefined and controlled release of an active ingredient to an organism when administered to said organism, which composition comprises a combination A) of at least two components a) at least one active ingredient in dispersed solid form, b) at least one gelling agent, c) optionally at least one filler, and d) optionally at least one adjuvant which combination A) is in the form of discrete particles and is embedded into a matrix B) which is formed by a pore-forming agent and optionally at least one adjuvant

2 A composition according to claim 1 wherein the active ingredient is a pharmaceutically active substance

3 A composition according to claim 1 wherein the active ingredient is selected from the group consisting of antibiotics, antiparasitics, hormons, growth promoters, anti-cancer drugs, vitamines and vaccines.

A composition according to claim 2 wherein the pharmaceutically active substance is an antiparasitics, preferably an endectocide, and most preferably an avermectin or a milbemicin

A composition according to claim 3 or 4 wherein the avermectin is ivermectin and/or abamectin

A composition for combatting external and internal parasitoses according to claim 1 , which contains an endectocide as an active ingredient and which is in the form of a subcutaneous implant constituted by one or more pellets that release the active ingredient in a controlled and prolonged way. A composition according to claim 1 wherein the gelling agent is selcted from the group consisting of modified cellulose, modified starch, pectin, polyvinyl alcohol, polyvinyl pyrrolidone and dispersed silica or combinations thereof

A composition according to claim 7 wherein the modified cellulose is an alkylated cellulose, preferably ethylcellulose

A composition according to claim 1 wherein the filler is selected from the group consisting of carbohydrates and silica or combinations thereof

A composition according to claim 9 wherein the carbohydrate is a disaccharide, preferably lactose

A composition according to claim 1 wherein the pore-forming agent forming matrix B) is selected from the group consisting of polyethylene ether, polyvinyl alcohol, sugar, sugar alcohol or combinations thereof

A composition according to claim 1 wherein the polyethylene ether is a nonionic polymer of polyethylene oxide, a polyethylene glycol or a polyethyleneglycol alkyl ether

A composition according to claim 1 wherein the composition is in the form of a pellet

A composition according to claim 13 wherein an implant is constituted by a plurality of such pellets

A composition according to claim 14 wherein said implants are packed in plastic cartridges

A process of manufacturing the composition of claim 1 said process encompassing the measures i) combining components a), b), optionally c) and optionally d) according to claim

1 in a mixing equipment, ii) mixing said components together with a liquid to form a shapable mass A) iii) shaping said mass A) into a plurality of small pieces by applying a first shaping means to said mass A) and separating said mass A) into a plurality of small pieces; iv) combining said small pieces of mass A) with pore-forming agent B) and optionally with at least one adjuvant d); v) mixing said combination of components A) and B) to form a shapable composition; and vi) shaping said composition to a desired shape by means of a second shaping means.

17. A process according to claim 16 wherein said second shaping means is a tablet press.

18. A method of treating an organism with an active ingredient in a predetermined and controlled manner said method comprises administering to said organism a composition according to claim 1.