WO1995025546A1

WO1995025546A1 - Dispensing unit containing a particulate product for the administration of drugs or nutrient preparations to animals and process for the manufacture of the particulate product

Info

Publication number: WO1995025546A1
Application number: PCT/DK1995/000127
Authority: WO
Inventors: Jacques Treulle; Leif Højvang NIELSEN; Erik Jacobsen
Original assignee: Boehringer Ingelheim Agrovet A/S
Priority date: 1994-03-24
Filing date: 1995-03-23
Publication date: 1995-09-28
Also published as: EP0794795A1; JPH09510461A

Abstract

The invention relates to a dispensing unit for administration of drugs or nutrient preparations to animals consisting of a dispensing container containing a substantially water-free, particulate expanded product and adapted to allow said product to be dispensed in the form of a homogeneous paste after the addition of water.

Description

Dispensing unit containing a particulate product for the administration of drugs or nutrient preparations to animals and process for the manufacture of the particulate product

The present invention relates to a dispensing unit containing a particulate, expanded product for the administration of drugs or nutrient preparations to animals, a process for the manufacture of the product and use of the particulate product for producing the dispensing unit for use in the treatment of ailments and deficiency symptoms in animals.

In medical treatment of animals, including the prevention of diseases, it may be advantageous to administer a preparation, such as a drug, suspended in a relatively small amount of water in the form of a low-viscosity paste which is dispensed through a syringe directly into the throat of the animal, the swallowing reflex thus causing the animal to swallow the paste. Such pastes are known in the form of anthelmintics for horses, dogs and cats, which are available in a disposable plastic syringe for direct administration into the throat. The paste consists of an external liquid phase having a high viscosity and an internal phase containing the active agent.

However, the durability of water-containing, liquid prepara- tions may be relatively short as precipitation or fractiona- tion may take place and particularly in the case where the preparation contains substances which may interact in an aqueous environment. Examples thereof are Maillard reactions between amino acids and reducing sugars and browning as a result of the reaction between dextrose and amino acids/base. In both cases the undesired reactions are eliminated or reduced in a water-free environment or by reduction of the water activity. This restricts the use of paste as an admini¬ stration form.

Nutrient preparations and drugs for animals frequently contain powdered ingredients, such as starch, cellulose. silicates etc., which are wetted with difficulty and are subject to lumping.

However, it will often be possible to modify compositions consisting of powdered ingredients into larger solid par¬ ticles by pelletization or extrusion. The free surface area is hereby reduced and the tendency to form lumps during wetting is reduced. However, it has been found that added water in such complex particles is distributed unevenly, resulting in the formation of lumps which can hardly be pressed through relatively narrow openings, e.g. having a diameter of less than about 5-10 mm.

Thus, it is the object of the present invention to provide a dispensing unit for the administration of drugs or nutrient preparations to animals, comprising a substantially water- free product prepared from a mixture of powdered ingredients contained in the dispensing container, which after the addition of water is modified in situ to a concentrated, low- viscosity, homogeneous paste.

This object is obtained with the present invention which is characterized in that it relates to a dispensing unit consisting of a dispensing container containing a substanti- ally water-free, particulate, expanded product, said dis¬ pensing unit being adapted to allow the product to be dispensed in the form of a concentrated, low-viscosity homogeneous paste after the addition of water. The dispensing unit is particularly suitable for the administration of drugs or nutrient preparations to animals by direct dispension into the throat of the animal. A preferred dispensing container is a disposable plastics syringe or a tube or a bag, preferably of plastics, from which the paste formed can be dispensed by pressing it out through a nozzle or another outlet.

The particulate, expanded product is preferably made from a mixture consisting of at least one colloid selected among carbohydrates of plant or microbial origin as a sealing agent, an expansion agent selected among bicarbonate com¬ pounds, a wetting agent selected among phosphatides and polyalcohols, and optionally other ingredients, such as lubricating agents, pH adjusting agents, minerals, elec¬ trolytes, vitamins or drugs, which mixture has been subjected to a particle forming treatment by which the temperature is raised to between 50° and 120°C to release C0₂ from the expansion agent and by which the released C0₂ is entrapped in the colloid, the product being modified to said paste after the addition of from 50-200% by volume of water.

The invention further relates to a process for the manufac¬ ture of the particulate product for use in the dispensing unit according to the invention, which process is charac¬ terized in that a substantially water-free mixture consisting of at least one colloid selected among carbohydrates of plant or microbial origin as a sealing agent, an expansion agent selected among bicarbonate compounds, a wetting agent selected among phosphatides and polyalcohols, and optionally other ingredients, such as lubricating agents, pH adjusting agents, minerals, electrolytes, vitamins or drugs, is subjected to a particle forming treatment, such as extrusion, roll pressing, mould pressing or pelletization at a tempera- ture of from 50°-120°C, as a result of which C0₂ is released from the expansion agent and entrapped in the colloid.

Said mixture preferably contains from 20-70% by weight of dextrose, preferably from 30-40% by weight of dextrose; from 5-30% by weight of pregelatinized starch, preferably from 15- 25% by weight of pregelatinized starch; from 5-30% by weight of pectin, preferably from 10-20% by weight of pectin; a bicarbonate compound in the form of sodium, potassium or ammonium bicarbonate in an amount of more than about 0.25% by weight and up to 10.0% by weight, preferably from 0.5-2.0% by weight; from 2.5-12.5% by weight of phosphatide, preferably lecithin; from 2.5-10.0% by weight of polyalcohol, preferably propylene glycol; and furthermore from 2-20% by weight of silicates, preferably kaolin and/or sepiolite; from 1.5-13% by weight of electrolytes, preferably sodium and/or potassium chloride; from 1-7% salts of organic acids/amino acids, preferably sodium citrate and/or sodium glutamate, the water content of said mixture being 5% by weight or less. This product composition is particularly suitable for the treat¬ ment of diarrhoea in animals.

The particulate, expanded product is preferably prepared by extrusion with e.g. an extruder of the brand W&PC37-Werner/ Pfleider, Type Continua 37-belt cooler/belt dryer Lytzen, and consists of cylindrical pellets having a maximum diameter of up to 10-15 mm, preferably of up to about 3 mm and preferably with an expansion percentage (expanded volume.unexpanded volume) of more than about 103-105%, more preferably of more than 110%. During the extrusion process no water or steam is added.

The dispensing unit according to the invention presents the following advantages:

It allows dry technology to be applied in the filling process, which, as opposed to wet technology used in the con- ventional filling of paste, i.a. facilitates filling and dosing in the dispensing container. The hygiene requirements are less stringent as no conditions for microbial growth are created in the particulate product. The durability is consi¬ derably extended as chemical interactions in the product can be kept at a minimum due to the low water activity. As the particulate product consists of sealed particles no demixing of the individial ingredients will take place.

Furthermore, the product is stable within a wider temperature range than a corresponding water-containing paste. As sealing agent in the process for preparing the particulate product colloids are preferred in the form of low and high molecular carbohydrates, such a polysaccharides and oligosac- charides of plant or microbial origin, including

starch or derivatives thereof, such as pregelatinized starch, dextrins and maltσdextrins, pectin or pectinaceous products/by-products, thickening agents, such as cellulose derivatives, alginates and caraganans,

- other polysaccharides characterized by their relatively high content of cellulose, hemicellulose or lignocellu- lose.

In addition thereto sugars, such as glucose, fructose, maltose, sucrose and lactose.

The expansion agent is preferably a coated or uncoated bicarbonate compound which is decomposed when heated to over about 50°C, thereby releasing C0₂. Optionally, the particula¬ te, expanded product can be expanded by means of steam or preferably by incorporated inactive gases, such as C0₂ or N₂.

The wetting agent used in the process according to the invention preferably consists of a combination of lecithin and a polyalcohol, such as propylene glycol, and preferably in the ratio of 1:0.5-1:3, most preferably about 1:1.

The lubricating agents are preferably selected among the group of silicates, i.a. kaolin and sepiolite, which in addition have a certain sealing effect and, besides, an absorbing effect in the treatment of diarrhoea.

Electrolytes, such as sodium and potassium chloride, typical- ly form part of antidiarrhoeic agents. Salts of organic acids/amino acids are e.g. sodium citrate which is a pH adjusting agent, or sodium glutamate, a taste improving agent.

Drugs for incorporation into the particulate product are e.g. anthelmintics, antibiotics, such as ampicillin, enzymes, vitamins, probiotics, such as lactic acid producing bacteria, and macro- and microminerals, such as Ca, Fe, Zn, I.

The invention furthermore relates to a process for the manufacture of a ready-made dispensing unit for the admini¬ stration of drugs or nutrient preparations to animals, containing a concentrated, low-viscosity, homogenous paste, characterized in that 50-200% of water based on the volume of the particulate composition is added to the dispensing container filled with a particulate, expanded product prepared according to the invention.

In a preferred embodiment 1/4 to 1/2 of the volume of a plastic syringe is filled with the particulate, expanded product. The syringe is placed with its tip/outlet in water, and by pulling back the plunger the syringe is filled with from 50-200% of water which is sucked in and distributed uniformly in the particles. After a short period of resting, i.e. for about 1 to about 5 minutes depending on the particle volume charged, the particles are completely suspended in the water, and a concentrated, 200 g/1 - 600 g/1, homogeneous, low-viscosity paste can be dispensed e.g. directly into the throat of the animal by means of the plunger.

The invention will now be explained in further detail by way of the following examples:

Example 1

Preparation of a dispensing unit containing a particulate product for antiinfectious purposes. A mixture consisting of:

Ampicillin, water-free 27 . . 5% Dextrose, water-free 30 . . 0% Pregelatinized starch (low water content) 22 . . 5% Lecithin 7. . 5% Propylene glycol 5 . . 0% Disodium citrate 2 . . 0%

Sodium bicarbonate (coated 70% or uncoated) 0. . 5% Kaolin 5 . . 0%

100 . . 0%

is extruded at a temperature of about 70^βC for forming pellets having an expansion percentage of about 110 and a density of about 0.60 kg/1. 20 ml plastic syringes are filled with 5 g of the pellets. After sucking in 5 ml of water, a ready-made unit dosage of 1.375 g of ampicillin in the form of a paste can be administered to an animal either internally through the throat or externally as an ointment.

Example 2

Preparation of an agent against diarrhoea.

The following mixture of ingredients was extruded:

Basic composition

Dextrose 35% Pregelatinized starch 20%

Pectinaceous substances (citrus pulp) 13.5%

Sodium chloride 3.5%

Potassium chloride 1.2%

Kaolin 5.0% Sepiolite 5.0%

Sodium glutamate 1.0%

Sodium citrate 2.0% Phosphatides (lecithin) 5.0%

Polyol (propylene glycol) 5.0%

as well as taste adjusters and bicarbonate in varying amounts according to the following schedule:

Test run No.

23 Sodium bicarbonate 0.5% 24 Sodium bicarbonate 0.25%

25 Sodium bicarbonate 0.50% via an 85% coated product

26 Sodium bicarbonate 0.50% via a 70% coated product

27 Ammonium bicarbonate 0.50%

25-1 Sodium bicarbonate 2% via an 85% coated product 23-4 Sodium bicarbonate 2%

29 Sodium bicarbonate 0.5% with addition of amino acid

30 Sodium bicarbonate 0.5% without addition of amino acid

32 Identical with 29 without sodium bicarbonate

33 Identical with 30 without sodium bicarbonate

The various test preparations are prepared in a double screw extruder having a nozzle plate with a bore diameter of 12 x 1.5 mm. The process is carried out without addition of water/steam at a temperature of 85-100°C with a basic mixture containing 2.5% intrinsic water. The water content in the final product is approx. 2.5% or below.

In the schedule below data are given which illustrate bicarbonate form and addition percentage.

pellet colour after cooling to room temperature pellet colour after dissolution (EBC method) reactivity between dextrose and amino acid as compared to a powdered product (TNBS method) - pellet density compared to unexpanded pellets, thus in¬ dicating the "expansion percentage" pellet diameter in mm wetting tests carried out with 25 g of the test preparation to which 30 ml of tap water is added at 40^βC - the wetting result is evaluated after 4 minutes.

Under the given conditions where the different test products are extruded without addition of water or steam, the follo¬ wing observations are made:

- Lecithin alone (5.0/7.5%) acts as a suitable surfactant.

Lecithin (5) in combination with 2.5/5.0% pro¬ pylene glycol exhibits satisfactory lubricating properties. - The addition of bicarbonate has a positive effect resulting in varying expansion at an addition level from approx. 0.5%.

- The various additions mentioned above result in pellets having a suitable appearance, a thermal resistance ranging from fair to satisfactory and wetting properties which are suitable for in situ preparation of homogeneous pastes in plastic syringes.

Claims

C l a i m s

1. A dispensing unit for the administration of drugs and/ or nutrient preparations to animals, c h a r a c t e r i ¬ z e d in that the unit consists of a dispensing container containing a substantially water-free, particulate expanded product, said dispensing unit being adapted to allow the product to be dispensed in the form of a concentrated, low- viscosity, homogeneous paste after the addition of water.

2. A dispensing unit according to claim 1, c h a r a c ¬ t e r i z e d in that after the addition of water the particulate product contained can be dispensed directly into the throat of the animal.

3. A dispensing unit according to claim 1 or claim 2, c h a r a c t e r i z e d in that the dispensing container is a plastics syringe.

4. A dispensing unit according to claims 1, 2 or 3, c h a r a c t e r i z e d in that the particulate, expanded product is prepared from a mixture consisting of at least one colloid selected among carbohydrates of plant or microbial origin as a sealing agent, an expansion agent selected among bicarbonate compounds and/or inactive gases, a wetting agent selected among phosphatides and polyalcohols, and optionally other ingredients, such as lubricating agents, pH adjusting agents, minerals, electrolytes, vitamins or drugs, which mixture has been subjected to a particle forming treatment by which the temperature is raised to between 50° and 120°C to release C0₂ from the expansion agent and by which the released C0₂ is entrapped in the colloid, which product is modified to said paste after the addition of from 50-200% by volume of water.

5. A dispensing unit according to claim 1, 2, 3 or 4, c h a r a c t e r i z e d in that the particulate product has a maximum diameter of up to 10-15 mm, preferably up to 3 mm.

6. A process for the manufacture of a particulate, expanded product for the administration to animals, c h a ¬ r a c t e r i z e d in that a substantially water-free mixture consisting of at least one colloid selected among carbohydrates of plant or microbial origin as a sealing agent, an expansion agent selected among bicarbonate com- pounds and/or inactive gases, a wetting agent selected among phosphatides and polyalcohols, and optionally other ingre¬ dients, such as lubricating agents, pH adjusting agents, mi¬ nerals, electrolytes, vitamins or drugs, is subjected to a particle forming treatment, such as extrusion, roller pressing, mould pressing or pelletization at a temperature of from 50-120°C, as a result of which C0₂ is released from the expansion agent and entrapped in the colloid.

7. The use of the particulate product prepared according to claim 6 for the manufacture of a dispensing unit for the administration of drugs or nutrient preparations to animals.

8. A process according to claim 6, c h a r a c t e r i ¬ z e d in that the mixture contains from 20-70% by weight of dextrose, preferably from 30-40% by weight of dextrose; from 5-30% by weight of pregelatinized starch, preferably from 15- 25% by weight of pregelatinized starch; from 5-30% by weight of pectin, preferably from 10-20% by weight of pectin; a bicarbonate compound in the form of sodium, potassium or ammonium bicarbonate in an amount of more than about 0.25% by weight and up to 10.0% by weight, preferably from 0.5-2.0% by weight; from 2.5-12.5% by weight of phosphatides, preferably lecithin; from 2.5-10.0% by weight of polyalcohol, preferably propylene glycol; and furthermore from 2-20% by weight of silicates, preferably kaolin and/or sepiolite; from 1.5-13% by weight of electrolytes, preferably sodium and/or potassium chloride; from 1-7% by weight of salts of organic acids/amino acids, preferably sodium citrate and/or sodium glutamate, the water content of said mixture being no more than 5% by weight.

9. The use of the particulate product prepared according to claim 8 for the manufacture of a dispensing unit for use in the treatment of diarrhoea in animals.

10. A process for the manufacture of a ready-made dis- pensing unit containing a concentrated, low-viscosity, homogeneous paste for the administration of drugs or nutrient preparations to animals, c h a r a c t e r i z e d in that 50-200% by volume of water of the particulate composition is added to a dispensing container filled with the particulate, expanded product prepared according to claim 6 or 8.