NZ220594A - Intraruminal delivery device comprising an active principle dispersed in a polymeric matrix - Google Patents
Intraruminal delivery device comprising an active principle dispersed in a polymeric matrixInfo
- Publication number
- NZ220594A NZ220594A NZ22059487A NZ22059487A NZ220594A NZ 220594 A NZ220594 A NZ 220594A NZ 22059487 A NZ22059487 A NZ 22059487A NZ 22059487 A NZ22059487 A NZ 22059487A NZ 220594 A NZ220594 A NZ 220594A
- Authority
- NZ
- New Zealand
- Prior art keywords
- active principle
- approximately
- duct
- release
- matrix
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0068—Rumen, e.g. rumen bolus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £20594
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Patents Form No. 5
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NEW ZEALAND
PATENTS ACT 1953
COMPLETE SPECIFICATION
IMPROVEMENT TO AN INTRARUMINAL DELIVERY DEVICE
c * ' ' ;Is-*?®
vJifcSflc-
X^We, A VIBRAC-S.A. of lere Avenue - 2065 M - L.I.D.,
06516 Carros Cedex, France, a joint stock company of France hereby declare the invention, for which %/we pray that a patent may be granted to we/us, and the method by which it is to be performed, to be particularly described in and by the following statement:
(followed by Page la)
220594
- la-
The invention relates to an intraruminal delivery device as disclosed in the British Patent Specification 21 55335 , i.e. a device enabling the release into a liquid medium, at a controlled speed, of one or more active principles formed by a solid macromolecular and thermoplastic matrix support of insoluble polymers or copolymers associated with adjuvants and additives enabling the progressive and programmed release of the active principle(s) contained therein, in which the initial concentration of the active principle(s), on the one hand, and the surface of the device through which diffusion takes place, on the other hand, are determined as a function of the desired duration of release and daily quantity to be released, the matrix support J-5 completely or almost completely enclosing one or more masses of dense materials which provide the assembly with a specific weight of more than 1.3 g/ml.
A device of this type may be used to diffuse drugs in humans or animals and, in the latter case, is administered orally to introduce it into the rumino-reticular sac of ruminants where it is retained for a long period of time.
Although such devices provide satisfactory results for the release of antiparasitic and/or anthelmintic substances, in particular in the case of bovine livestock, the fact that the diffusion of the active principle(s) takes place through the whole of the surface of the device may lead, firstly, to a release of the principle(s) which may not be uniform, whereas a device which can release the same daily dosage over a long period of time, at least three months, is what is actually needed in practice, and, secondly, to the fact that the release of active principled) may take the form of an asymptotic curve, as a function of time, 3^ which may be a drawback in the use of the devij
(followed by page 2)
220594
When theBe known devices are administered to young animals the various factors which control the release of the active principle(s) are calculated and combined so that the release of active principle(s) is compatible during the initial days of treatment with the weight of the animal being treated in accordance with the conventional rules of posology. Ifr however, the release of active principle(s) also increases as the animal grows and its weight increases, this increase is asymptotic, as mentioned above, because the elimination of the active principle(s) via the juices or fluids of the digestive tract takes place progressively from the exterior to the interior of the device, i.e., in the case of a body of general elongate shape, along progressively decreasing surfaces (and therefore also with decreasing quantities) whereas normal posology would require the quantities of substance(s) released to increase in a non-asymptotic manner as a function of the increasing weight of the animal being treated.
In addition, the manufacture of these known devices in accordance with the British Patent Specification 21 55335 may, in some cases, pose technical problems as regards the positioning of the mass(es) of dense material with respect to the remainder of the polymer 25 matrix.
It is for this reason that the Applicants, starting from the prior art set out above, have attempted to provide a device which satisfies practical requirements in an improved way with respect to known devices, in particular as regards the quantity of active principle(s) released over time, the uniformity of the dosages released daily and the progression over time of these dosages so as to achieve the optimum posology as far as possible, particularly in the case of growing animals .
2 205 94
An object of the invention is, in this respect, to provide a device of this type in which the daily release of active principle(s) evolves over time in linear steps, i.e. by providing a uniform daily quantity of 5 active principle(s) at the beginning of use and during an initial stage, and then, during a second stage, a further uniform daily quantity and, during a third stage, a new uniform daily quantity which is preferably, but not necessarily, different from the first and/or the 10 second, etc., so that the quantities released, which are suitably matched to the size and weight of the animals to which the devices are administered, enable the achievement of the best possible results.
The Applicants have now discovered, in a surprising 15 manner, that it was possible to obtain this result from a device of the type set out above, by providing a through duct in the solid matrix support, through which duct the active principle(s) is(are) diffused, diffusion being prevented, in contrast to the devices of the prior 20 art, on the outer surface of the matrix support which is covered, for this purpose, with a film which cannot be permeated by the active principle(s).
In a device of the invention, the density, which is preferably kept fairly high, is obtained by distributing 25 a material of high density throughout the whole of the support, for example metal powder, filings or grit,
which provides the assembly of the device with the desired density.
In an advantageous embodiment, the device is oblong 30 in shape and somewhat ogival with a rounded end with a longitudinal axis along which the through duct is disposed, this duct having-a cross-section which is constant or which increases slightly from one end of the device to the other.
Given that the whole of the outer surface of the
2205
4 -
device is covered by a polymerisable impermeable film, for example of a material such as a cross-linkable silicone elastomer, an epoxy resin, a polyurethane varnish and/or an acrylic varnish or a like material, 5 the progressive release of the active principle(s) takes place through the wall of the cavity bounded by the duct with the result that the active principle(s) is(are) released in constant daily dosage steps.
By incorporating a high density product in the 10 solid thermoplastic and macromolecular matrix of insoluble polymers or copolymers in order to achieve the desired final density, a very homogeneous product is simultaneously obtained which therefore has no damaging side effects on the animal to which it is administered. 15 By means of an appropriate selection of the concentration of the active principle(s) in the polymer matrix, the shape and dimensions of the through duct and the addition, if necessary, of adjuvants or additives to the polymers or copolymers of the matrix as a function 20 of the nature of these polymers or copolymers, the duration of the diffusion stages and the daily dosages of active principle(s) released by the device within, for example, an animal organism, may be regulated.
The active principle(s) may be selected for their 25 prophylactic or therapeutic effects from amongst antiparasitics, antibiotics, antibacterial agents, antifungals, vitamins or nutritional preparations.
In the case of substances with anthelmintic properties, the active principles are advantageously 30 selected from the group including levamisole,
tetramisole, morantel, pyrantel, or their soluble salts, nitroxynil, albendazole, oxibendazole, oxfendazole, mebendazole and ivermectin.
A particularly advantageous embodiment involves the 35 use of levamisole hydrochloride as the active principle.
2 2Gd
Mineral chemical substances may also be selected to provide micronutrient supplements.
The concentration of the active principle in the polymer matrix may vary from 1 to 60% by weight of the matrix portion, as a function of the desired steps and daily dosages to be released.
The specific weight of the device is determined by the quantity of metal introduced in the form of powder, filings or grit, the amount of this product being between 10 and 75% of the matrix portion.
Among the insoluble polymer or copolymer-based macromolecular thermoplastic materials, a preferred embodiment of the invention uses a copolymer of ethylene and vinyl acetate (EVA).
To produce a device of the invention, the polymer(s) or copolymer(s), the active principle(s) and the powder of dense material are mixed homogeneously and the mixture obtained is hot-moulded to obtain a product which contains the desired through duct directly on demoulding or, as a variant, to obtain an intermediate component which is then shaped, for example by machining, to form the desired through duct.
In both cases, the outer surface of the device is then covered under cold conditions by an impermeable film, for example a cross-linkable silicone elastomer, an epoxy resin, a polyurethane varnish or an acrylic varnish.
This production technique, which is much simpler than that of known devices, enables a substantial reduction of the production cost of such devices, in particular for their use in veterinary medicine.
The invention is illustrated in the following description, given by way of example, with reference to the attached drawings, in which:
Fig. 1 is a diagrammatic perspective view of a
2205
device of the invention;
Fig. 2 is a view in longitudinal section.
The device 10 shown in Figs. 1 and 2, which is described here by way of non-limiting example, has a 5 general oblong shape, substantially of revolution about an axis 11, with one rounded end or apex 12 and another, distal, end 13 which is planar and substantially perpendicular to the axis 11. The body 14 of the device is formed by the solid macromolecular matrix support of 10 insoluble polymers or copolymers, one or more active principles and one or more materials of high density, for example powdered metal filings or grit shown here by reference numeral 15 for the purposes of illustration, whereas the assembly is in fact completely homogeneous. 15 According to the invention, the device 10 has a through duct 16 passing through it along its axis 11, which duct may have a constant circular cross-section, i.e. may form a cylindrical surface 17 with an axis 11 or, as an alternative and as shown in the drawings, may 20 form a duct with a circular cross-section which increases progressively from the base 13 to the apex 12, i.e. a slightly frustoconical surface 17 which opens out at the face 13 through an aperture 18 and at the apex 12 through an aperture 19. When the device is positioned, 25 for example in the rumino-reticular sac of an animal, its inner surface 17 is in contact with the ruminal fluid which passes through the device via the apertures 18 and 19.
In accordance with the invention, the outer surface 30 of the device 10 is covered by a film 20 of impermeable, polymerisable material, such as a cross-linkable silicone elastomer, an epoxy resin, a polyurethane varnish or an acrylic varnish, this film extending over the whole of the outer surface of the device, i.e. 35 between the periphery of the aperture 18 and the
jL dL
periphery of the aperture 19 with the exception of the inner surface or wall 17 of the through duct 16.
As a result of this, at the beginning of use, the solvation fluid, such as bovine ruminal fluid or any 5 other like fluid, comes into contact with the wall 17 ariH~the~^^trive~principle is released through this wall. Over time the solvation fluid progresses from the wall 17 in the direction of the outer surface of the body 14 and, bearing in mind the geometry of the device, the 10 solvent contacts and dissolves increasing quantities of active principle(s); the speed of penetration of the solvent into the matrix simultaneously decreases,
bearing in mind the increase in the distance to be travelled by the solvation fluid to reach the active 15 principle, while the elimination of the substance (which is a function of the quantity conveyed across the regions of the matrix which have already been dissolved) is regulated by the matrix which acts to some extent as an intermediate membrane.
This behaviour of the device is particularly advantageous when a drug is to be released in young, growing animals.
When appropriate parameters, such as the volume and the shape of the through duct, the concentration of 25 active principle(s), the nature of the matrix and that of the material incorporated to achieve an appropriate density, are selected for the device, this behaviour also makes it possible to define time stages or steps during each of which a constant daily dosage is released 30 by the device.
If a daily dosage which is greater than that selected at the beginning of use is selected at the end of the life of the device, the dosage of active principle(s) is increased in correlation with the 35 increase in the weight and size of the animal being
z 2 03
treated in accordance with the conventional rules of posology.
Examples
Example 1
The following composition, in parts by weight, was initially prepared:
Levamisole hydrochloride 15
Powdered iron 66
Ethylene/vinyl acetate copolymer with 10 28% vinyl acetate (EVATANE 28-05
produced by the company ATOCHEM) 19
The three constituents were mixed homogeneously and the mixture obtained was injected, at a temperature of 105°C, into a mould with a core which thus provided, 15 after demoulding, a device as shown in Figs. 1 and 2.
This device, which was approximately 105 mm long with a greater diameter at the apex of its front,
rounded end 12 of approximately 30 mm and a plane circular base with an external diameter of approximately 20 27 mm, weighed approximately 150 g and had a density of approximately 2.6 g/ml. The through duct 16 had a circular cross-section of approximately 8 mm at the base 13 and a diameter of approximately 10 mm at the front, rounded portion 12.
After the device had been cooled, its entire outer surface was covered with a thin film of polyurethane varnish to a thickness of 1/10 mm, which therefore covered the whole of the surface of the device with the exception of the wall 17 of the through duct 16. 30 The device was then subjected to in vivo and in vitro release tests.
In vitro release tests
The test device was immersed in a litre of drinking water adjusted to a pH of 7 and kept at 37°C by a thermostat. 35 The container was fitted with a mechanical plunger
&~S«
w-
agitation system (of the anchor or propeller type) which was rotated slowly (approximately 100 rpm) ensuring that the solution was homogeneous.
The entire assembly was placed in darkness and 5 daily samples of 1 ml of solution were taken, the fluid volume being topped up with drinking water.
The active principle concentration, released daily, was calculated by the high performance liquid chromatography technique and the release kinetics are shown in Table 1 below which shows the amounts of levamisole hydrochloride released, expressed as cumulative percentages of the initial dosage.
Table 1
Days in vitro % levamisole hydrochloride released
1 2.9
2 3.2 4 4.6 7 6.5
14 10.1
21 12.9
28 15
16.9
42 18.5
49 19.4
56 20.1
63 22.05
70 27.2
84 35.1
105 49
126 58.7
147 72.4
168 82.8
After 169 days, the device was removed from the
& - \
; 10 5 9 4
container and the residual quantity of levamisole hydrochloride in the matrix was calculated by analysis.
This showed a residual quantity of approximately 16% which confirmed the cumulative values eliminated. 5 it would seem from the above Table that the elimination of the active principle in vitro corresponds in effect to three successive stages with different kinetics.
In the first stage, or kinetic stage 1, lasting 21 10 days, the daily amount released was substantially
152 mg. In a second stage, or kinetic stage II, between day 21 and day 73, the daily amount released was approximately 54 mg per day, while during the third stage, or kinetic stage III, i.e. from day 73 to day 15 168, the daily amount released was substantially 143 mg.
It can therefore be seen that after a first stage of constant daily release, the release decreased and then increased again in contrast to known devices in which release is asymptotic, i.e. decreases towards the 20 end of the service life of the device.
The above tests were supplemented by in vivo tests conducted as follows.
In vivo tests '
The speed of release of the active principle (mg 25 per day) was calculated using devices as described above administered to 12 young cattle with a ruminal fistula.
The devices were removed after 5, 21, 42, 70, 98 and 126 days to evaluate the residual quantity of active principle.
The quantities of levamisole hydrochloride released were expressed as percentages of the initial dose, and are shown in Table II below as a mean for two animals per test.
\
Table II
Days
Animals
% levamisole hydrochloride released
21 42 70 98 126
A and B C and D E and F G and H I and J K and L
7.1
19.8 33.5 55
75.2
94.9
The amount released per day was approximately 186 mg for the entire duration of the tests, with kinetics which differed somewhat from those of the in vitro tests.
it can be seen that the speed of release is greater than that of the in vitro tests and also that it is not possible to discern steps of the type discussed above. Despite the difference in behaviour, due, undoubtedly, to the nature of the solvent liquid and to complex 20 factors predominating in the animals' rumens, the non-asymptotic release of the active principle provided major advantages with respect to known devices.
Similar results were obtained using a device with a matrix formed by an ethylene/vinyl acetate copolymer of 25 the type sold under the trademark ESCORENE ULTRA by the company ESSO CHIMIE.
Example II
The following composition, in parts by weight, was initially prepared:
Copper carbonate Cobalt carbonate Sodium selenite Powdered iron ..
19.30 0.73 0.47 59.50 20.00
EVATANE 28-05
The constituents were mixed homogeneously and the
Claims (13)
1. A device enabling the release into a liquid medium, at a controlled speed, of one or more active principles formed by a macroraolecular and thermoplastic solid matrix support formed by insoluble polymers or copolymers associated with adjuvants and additives enabling the progressive and programmed release of the active principle(s) incorporated therein, in which the initial concentration of the active principle(s), on the one hand, and the surface of the device through which diffusion takes place, on the other hand, are determined as a function of the desired duration of release and daily quantity to be released, this matrix support completely or almost completely enclosing one or more masses of dense material which provide the assembly with a specific weight of more than 1.3 g/ml, characterised in that the surface of the device through which diffusion takes place is solely that of a through duct the outer surface of the matrix support being covered with a film which cannot be permeated by the active principle(s).
2. A device as claimed in claim 1, characterised in that the device is provided with a specific weight of more than 1.3 g/ml by the incorporation in the matrix of metal powder, filings or grit distributed homogeneously throughout the matrix support.
3. A device as claimed in claims 1 or 2, characterised in that it has an oblong shape with a longitudinal axis along which the through duct is provided, this duct having a cross-section which is constant or which increases slightly from one end of the device to the other.
4. A device as claimed in any one of claims 1 to 3, characterised in that the impermeable film is a material of the type of cross-linkable silicone - 14 - 2l0S°t^ elastomers, epoxy resins, polyurethane varnishes and/or acrylic varnishes.
5. A device as claimed in any one of claims 1 to 4, characterised in that it is produced by moulding a homogenous mixture comprising: polymers or copolymers, approximately, 1 to 60%, in parts by weight of the solid matrix support, and of one or more active principles / 10 to 75%, in parts by weight, of metal powder, fillings or grit.
6. A device as claimed in claim 5, characterised in that the matrix has an ethylene/vinyl acetate * copolymer base.
7. A device as claimed in claim 5, characterised in that the metal powder is powdered iron.
8. A device as claimed in any one of the preceding claims, characterised in that the active principle(s) has(have) prophylactic or therapeutic effects and are selected from antiparasitics, antibiotics, antibacterial agents, antifungals, vitamins and nutritional preparations.
9. A device as claimed in claim 8, characterised in that the active principle(s) has(have) anthelmintic activity and are selected from the group including levamisole, tetramisole, morantel, pyrantel, or their soluble salts, nitroxynil, albendazole, oxibendazole, oxfendazole, mebendazole and ivermectin.
10. A device as claimed in claim 8, characterised in that the active principle(s) coraprise(s) nutritional supplements such as micronutrients.
11. A device as claimed in any one of the preceding claims, characterised in that it releases the active principled) which it contains in substantially constant daily dosages over a period of time of more than three months .
12. A device as claimed in claim 11, characterized in that the active principle(s) is(are) released, in three successive stages with different kinetics, in substantially constant daily dosages, for each stage. 220594 - 15 -
13. A device as claimed in claim one arranged, constructed and adapted to operate substantially as hereinbefore described with reference to the accompanying drawing. VIRBAC S.A. y thWir) attorneys ALDWQIM.SON & CAREY
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8608268A FR2599624B2 (en) | 1986-06-09 | 1986-06-09 | PROGRAMMED RELEASE DEVICE |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ220594A true NZ220594A (en) | 1990-04-26 |
Family
ID=9336128
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ22059487A NZ220594A (en) | 1986-06-09 | 1987-06-08 | Intraruminal delivery device comprising an active principle dispersed in a polymeric matrix |
Country Status (6)
Country | Link |
---|---|
DE (1) | DE3719185A1 (en) |
FR (1) | FR2599624B2 (en) |
GB (1) | GB2191400B (en) |
IE (1) | IE61860B1 (en) |
NL (1) | NL192818C (en) |
NZ (1) | NZ220594A (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8820353D0 (en) * | 1988-08-26 | 1988-09-28 | Staniforth J N | Controlled release tablet |
GB9009331D0 (en) * | 1990-04-26 | 1990-06-20 | Polysystems Limited | Sustained release |
ES2077243T3 (en) * | 1990-10-01 | 1995-11-16 | Upjohn Co | PHARMACEUTICAL COMPOSITIONS WITH CONTROLLED RELEASE AND COATED SIDE CONTOUR. |
GB2306325B (en) * | 1994-11-25 | 1997-09-10 | William Leslie Porter | Bolus for supplying biologically beneficial substances to ruminant animals |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3851648A (en) * | 1973-10-11 | 1974-12-03 | Mead Johnson & Co | Zero-order release device |
IE54171B1 (en) * | 1982-06-22 | 1989-07-05 | Univ Glasgow | Device for introducing nutrients and/or therapeutic materials into ruminant animals |
FR2560768A1 (en) * | 1984-03-07 | 1985-09-13 | Crb Virbac Sa | PROGRAMMED RELEASE DEVICE |
US4649042A (en) * | 1984-05-31 | 1987-03-10 | Eli Lilly And Company | Rumen delivery device |
-
1986
- 1986-06-09 FR FR8608268A patent/FR2599624B2/en not_active Expired - Lifetime
-
1987
- 1987-06-03 IE IE145887A patent/IE61860B1/en not_active IP Right Cessation
- 1987-06-04 GB GB8713086A patent/GB2191400B/en not_active Expired - Lifetime
- 1987-06-05 NL NL8701317A patent/NL192818C/en not_active IP Right Cessation
- 1987-06-08 NZ NZ22059487A patent/NZ220594A/en unknown
- 1987-06-09 DE DE19873719185 patent/DE3719185A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
FR2599624A2 (en) | 1987-12-11 |
IE871458L (en) | 1987-12-09 |
FR2599624B2 (en) | 1990-06-29 |
GB2191400B (en) | 1990-04-18 |
NL8701317A (en) | 1988-01-04 |
DE3719185A1 (en) | 1987-12-10 |
GB8713086D0 (en) | 1987-07-08 |
GB2191400A (en) | 1987-12-16 |
NL192818B (en) | 1997-11-03 |
IE61860B1 (en) | 1994-11-30 |
NL192818C (en) | 1998-03-04 |
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