JPS62174030A - Composition and method for controlled local administration of biological drug - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION It is often necessary to apply biologically active agents, such as insecticides or fungicides, to the skin of animals. For example, farm animals (cows, horses, sheep, etc.) may require long-term protection from parasitic insects.

The problems that parasitic insects can pose to farm animals are most significant in the Southern Hemisphere, such as Africa and certain countries in South America. Aside from the risk of disease transmission by ticks, fleas, etc., these insects pose a substantial risk to the animal's health, often resulting in weight loss.

The magnitude of this problem can best be appreciated in beef cattle production areas, where the infestation of animal skin by parasitic insects is highest.

It is already known to treat animals with pyrethroid insecticides to eliminate this problem.

This is generally done by spraying or bathing the animal with an aqueous suspension of the active agent.

Although this method can be effective against insects, it nevertheless has certain drawbacks inherent in the mode of topical application. Skin sores often occur, causing discomfort to the animal, attracting flies, and even causing infection. Furthermore, this treatment is short-term (e.g., a week or less), meaning that animals must be frequently hunted and re-treated, making it a labor-intensive and expensive method. .

Therefore, pyrethroids and other bioactive agents can be released in a controlled manner over extended periods of time, minimizing injury from initial contact with high concentrations and significantly reducing the number of topical applications. However, it would be highly desirable to find a unique solution to the above problem.

As will be recognized, the number of application cycles is extremely important from an economic point of view.

The concept of controlled release toys for bioactive substances for localized application is not new.

For example, bandages, surgical flat foil supplies (dressin4),
Also known are methods for controlled release of drugs or pharmaceuticals from adhesive compositions applied to the skin. An example of this type of method is U.S. Pat. No. 3,577,516 (
Gould et al.); No. 3,579,628 (Gang et al.)
No. 3,734,097 (Zafaroni); and 4. ．．
310,509 (Bergland) specification,
Examples of patent claims include: The shortcomings of these products as applied to the treatment of livestock are easily recognized. These systems therefore do not provide any viable solution to the problem for which the present invention is primarily aimed.

U.S. Pat. No. 3,590,118 (Conraday et al.) discloses a persistent insect repellent solution that is applied as an ammoniated aqueous or organic solvent solution and forms a thin, water-insoluble film that gradually releases the insect repellent upon drying. Regarding. These solutions are water-insoluble, alkaline water-soluble compositions of insect repellents and certain thermoplastic resins.

Other systems for controlled release drugs use compositions that include polymers that swell in the presence of moisture (eg, moisture released from body tissues such as mucous membranes). For example, U.S. Pat. No. 4,292,299 (Suzuki et al.) discloses an adhesive layer consisting of a polymer that adheres to a wet mucosal surface and swells when heated; Sustained-release formulations that are administered by adhering to moist mucosal surfaces, consisting of non-adhesive, water-soluble or disintegrating layers, at least one of which contains a drug. It is shown. U.S. Patent No. 4,05
No. 9,686 (Tana Riki) relates to a formulation for oral administration that has excellent adhesion to local sites and consists of a pharmacologically active agent, a pharmaceutical carrier and sodium polyacrylate. The formulation adheres firmly to the local site and gradually dissolves over an extended period of time, releasing the drug which is absorbed through the oral mucosa. U.S. Patent No. 4,226,848
No. 4 and its divisional application No. 4. ．． No. 259,163 describes a preparation that adheres to the mucous membranes of the oral cavity and nasal cavity,
Certain water-swellable and mucoadhesive polymeric matrices are shown.

U.S. Patent No. 4,374,126 (Caldaret (+
o) K is a topical antiseptic that prevents infection of tissues in humans and other animals, and is resistant to physical removal but can be removed with soap and water. Those that are easily removed are taught. The composition contains one or more antimicrobial agents and an adhesive to enhance topical application. Evaporation of the carrier solvent results in an effective long-lasting topical film containing the antimicrobial agent.

U.S. Patent No. 4. ．． No. 409,206 (Stitesker) teaches a transdermal formulation consisting of a skin-friendly polyacrylate coating that swells in water and an amorphous active substance.

Finally, U.S. Pat. No. 4,490,322 (issued to Zierenberg) describes a system for long-term transdermal administration of systemic drugs consisting of a homogeneous solution of the systemic drug and a specific lyophilized latex. Concerning preformed or packaged drug films.

Although the above cited references are not intended to be a complete or exhaustive survey of the relevant prior art, they nonetheless represent the state of the art known to the inventors regarding sustained administration of biologically active agents. It is considered to be illustrative and representative.

All of these prior art teachings address the problem addressed by the present invention: water-insoluble biologically active agents (particularly insecticides).
applied topically to cattle or other domestic animals to deliver an effective amount of the drug over an extended period of time, thereby reducing the number of applications required, and in which the initial topical formulation releases a concentration of the active ingredient that is injurious to skin contact. It does not represent or suggest a solution to the reduction of possible adverse effects (eg skin sores).

Prior art systems using bandages, tapes, films, etc. are clearly inadequate. Apparently these are not effective for topical application to the skin of animals to protect them from parasitic insects and the like.

Similarly, systems using water-soluble or water-swellable compositions are
Because the intended insecticides and other bioactive agents are insoluble, they have not been found to be useful.

The present invention provides a simple and highly effective solution to this problem.

According to the invention, the bioactive agent is characterized in that the polymer particles are capable of agglomeration and/or coalescence upon evaporation of the solvent and are swollen by skin oil. Compositions for topical application to animals are provided comprising an aqueous emulsion of a polymer having or encapsulating therein. As used herein and in the claims, the term "skin oil" refers to host-derived sebum (sebv, m) and/or skin lipid (sebv, m).
5kin 1ipids) 'f: Meaning.

To be effective for its intended purpose, the composition must physically interact with skin oils to the greatest extent possible on or near the animal's skin, rather than on the surface of the animal's fur, where the content of these skin oils is relatively low. The material must be applied in close proximity to the material and then aggregated or coalesced. Therefore, while the polymers and bioactive agents mentioned above are essential ingredients for topical applications in general, for effective applications such as in cattle, significant amounts must be present on the skin to aggregate or A means must also be included to allow the applied aqueous emulsion to rapidly penetrate the animal's living parts and reach the skin prior to coalescence. That is, to be effective, an applied solution must penetrate the skin closest to its surface.

It has been found to be an effective means to include substances that facilitate transport through the natural tissue to the skin by capillary action and then aggregate and/or coalesce there.

Materials useful for this purpose are anionic and nonionic surfactants, the latter being preferred.

As mentioned above, the present invention provides an essentially water-insoluble bioactive agent for use in animals, particularly farm animals and livestock, such as cattle, sheep, etc.
Novel compositions and methods for topical application to horses and the like. Since the need for this local application is particularly acute in the Southern Hemisphere, the invention is best understood and its significance best appreciated by reference thereto for purposes of illustration.

Beef cattle breeding and production is a very large industry in certain countries of the Southern Hemisphere, such as South Africa, as well as Argentina and other countries in South America. 1 in these countries
- Traditionally there are large populations of parasitic insects (e.g. mites) which pose real problems to livestock herds. Apart from the inherent risk of becoming a carrier of disease that can be spread in the herd, excessive penetration of the animal's skin over an extended period of time is likely to result in weight loss, which makes it difficult for animals to be used for slaughter. value decreases. Accordingly, it is common practice to hunt and gather animals frequently (eg, weekly) and to spray, dip, or douse the animals on their backs with solutions or aqueous suspensions of effective insecticides. many insecticides,
For example, the known pyrethroid insecticides are highly effective for this purpose.

However, this general mode of topical application is effective for a relatively short period of time (e.g., about a week or less) and therefore requires frequent and costly hunting and processing of animals.
and requires a time- and labor-intensive effort.

Furthermore, to ensure effective administration of the active agent, topical solutions or suspensions generally contain concentrations of pesticides or other active agents in excess of the required effective amount; Concentrations often cause skin irritation or sores, which can be uncomfortable, attract flies, and cause infections.

It would therefore be highly desirable to devise a method for the topical administration of active agents, known per se, in such a manner that the treatment lasts for a long time and requires fewer treatments. It is highly preferred to control the rate of release of the active agent so that no excessive amount initially contacts the skin and the amount thus released remains effective over this long period of time.

That is, if the release rate is plotted on a graph with the measured time (days or weeks) on the horizontal or Y axis and the amount released on the vertical or Y axis, the curve will be a substantially horizontal straight line for a period of time and then gradually It is optimal for the concentration to decline and eventually reach a level below the effective concentration (I6), which indicates the effective treatment period. It cannot be applied to solve the problems of the present invention.

It is this problem that the present invention is primarily aimed at.According to the present invention, this problem is solved by the fact that the skin is swollen by the skin oil, and when it swells, it releases the active agent dispersed within the skin oil. An aqueous emulsion (preferably of low viscosity to facilitate topical application) of a pesticide or other active agent dispersed in a polymer is then prepared in which the agent is transported to the body surface by diffusion. This problem can be easily and effectively solved by providing the following. The polymer also aggregates on the surface of the skin, possibly forming a film, thus reducing the release rate for the drug it contains;
This is characterized by extending the shelf life of topical application.

As will be appreciated, the effect used here
The term iτe)' means the ability to give or achieve a desired effect. Therefore, the effective amount of
``effective amount'' means the amount necessary to obtain the desired result; ``effective amount''
tive cht, ration)” means the period during which this result is obtained.

Although skin oils do not seem to have a precise chemical definition or analysis, the art generally refers to sebum, a sebaceous gland secretion in the form of a thick, semi-liquid substance consisting of fat and epithelial debris from the Malpighian layer; It is understood that it consists of other host-derived lipids found on the skin. More simply, it can be described as an oily or fatty lubricant secreted by animals. However, it is not necessary to maintain a supply of these skin oils for laboratory experiments in determining polymers useful for practicing the present invention. It has been found that sesame oil serves as a model substance for this purpose. In general, it can therefore be said that polymers swellable in sesame oil are swellable in skin oils and therefore can be considered for use.

As mentioned above, in addition to being swollen by skin oils and releasing the active agent, the polymer particles must coalesce or aggregate when deposited on the skin. This is necessary because the rate of drug release from the polymer matrix depends on, among other factors, the size and geometry of the polymer particles. When the polymers tend to aggregate to form sufficiently large particles or films, the rate of release of the bioactive agent is so rapid that the challenge of continuing to release an effective amount over an extended period of time is not met.

Similarly, as previously mentioned, "film-forming" skin oil-swelling polymer particles containing a total dispersion of active agents adhere primarily to the skin surface at or near the neck due to its proximity to the skin oil source. The likelihood of penetrating animal hair is thus partly a function of particle size, with particles below 50 microns for optimal efficiency. Particles of the same size should be used.

The likelihood that polymer particles will penetrate the hair and reach the skin will depend in part on the likelihood that they will reach the skin before coalescing at the hair ends to form a film or aggregate. In other words, even if particles of 50 microns or less are used, if they trench or penetrate the skin fairly quickly before significant coalescence occurs, a large amount of them may become trapped in the hair follicles upon coalescence. It will be done. Otherwise, the liquid containing the dispersed drug will flow away from the animal's body. Therefore, in the case of animals whose body hair poses this particular problem (eg, cows), the aqueous emulsion should further contain substances that promote or assist the capillary flow of the polymer particles containing the dispersed active agent.

Materials useful for this purpose include anionic and nonionic surfactants, the latter being preferred.

However, it should be understood that there is not necessarily a need for surfactants in all animal topical treatments for which the present invention is intended. It will be appreciated that if it is recommended or necessary to use a surfactant, the amount used may vary for different animal treatments. In any event, the novel compositions of the present invention can be manufactured and sold initially without surfactants, in which case an appropriate amount of surfactant may be mixed in at some point prior to use. can do.

In summary, the polymer particles containing the bioactive agent in the aqueous emulsions of the present invention suitably have a diameter of 50 microns or less in order to penetrate the animal's capillaries and reach the skin. However, as will be appreciated by those skilled in the art, the rate of release of a bioactive agent entrained or dispersed therein is inversely proportional to the size of the polymer particles. Therefore, if the particles are simply present as individual deposits on the animal's skin,
As a result of swelling by skin oils, the bioactive agent would be released too quickly and the main objective of the invention would not be achieved. It is therefore necessary to agglomerate the particles on the surface of the skin and to prolong and thereby control the release over a long period of time (for example over a month).

The rate of release to be employed in the practice of this invention cannot be accurately measured quantitatively and will generally depend on the level desired to be maintained for the process, which level depends on the efficacy or effectiveness of the drug used for that purpose. It will be different each time.

For example, the bioactive agent may be a fungicide, fungicide, or insecticide. Different levels of doses or durations can be considered for each of these groups, and furthermore, the target concentrations within a particular class of drugs can vary widely depending on the particular drug chosen.

That is, some pyrethroid insecticides may require a certain level of dosage to be effective, while others may require higher or lower doses.

In any case, the selection of the desired emission level will be obvious to those skilled in the art. Once a target level has been identified for the particular drug to be used, the rate of release to achieve this level can be determined by determining the crosslink density within the polymer mixture, holding other factors constant. Generally, the release rate is inversely proportional to the degree of crosslinking, so the higher the crosslink density, the lower the release rate. It will be appreciated, however, that if the crosslink density is too high, diffusion within the polymeric barrier will become too slow to effectively release the contained drug.As will also be appreciated, The overall average release rate can be adjusted by mixing particles with different degrees of crosslinking and/or particles containing crosslinks with particles that are crosslinked to the same or different degrees.

In any case, the degree of crosslinking and/or the proportion of particles with different degrees of crosslinking that can be mixed cannot generally be transferred into precise mathematical terms, and in fact such attempts are inappropriate or even misguided. It will also be understood that this is possible. Values that are applicable to one system may be completely inappropriate for another system.

Their selection is made only by routine experimentation within the foresight of a skilled worker and can therefore be easily made by the exercise of inventiveness in view of the foregoing description and the examples below.

The selection of useful skin oil-swelling coalescent polymers will also be apparent to those skilled in the art. Of particular interest are copolymers of acrylic esters and acrylic acid, such as terpolymers of 2-ethylhexyl acrylate, ethyl acrylate, and acrylic acid.

The proportion of monomers can of course be varied within the range of the abovementioned parameters, ie sebum swelling and cohesiveness. For example, a terpolymer of the above three monomers in a weight ratio of 30:8:1 has been found to be particularly useful. Other monomers that may be used, the selection of which does not itself form part of the invention, will be apparent to those skilled in the art. To further illustrate, useful monomers of this type include vinylacetate, vinylopeacrylate, ethynopeacrylate, and methyl acrylate.

As mentioned earlier, the swelling properties and therefore the release rate can be controlled by careful crosslinking. Although it can generally be said that various crosslinking agents commonly known in the field of polymer chemistry can be used for this purpose, difunctional monomers added during the polymerization reaction (eg ethylene glycol dimethacrylate) are particularly effective.

Other useful crosslinking agents include butylene glycol dimethacrylate, bismethylene acrylamide, and the like. As mentioned above, the degree of crosslinking can vary quite widely depending on the components used and the release rate desired. However, for example, if the weight ratio of ethylene glycol dimethacrylate to the total monomer weight of the terpolymer is 1:90 to
A ratio of the order of 1:525 has been found useful. If it is determined that it is appropriate or desirable to do so, the polymer compositions used in the practice of this invention may have different degrees of crosslinking, in order to arrive at blends with particularly desirable release rates. It may also consist of a blend of polymer particles.

Apart from the particle sizes mentioned above, at least for certain animals, the polymer dispersion penetrates the fur and reaches the animal's skin before aggregation occurs at or near the skin to form agglomerates of the dispersion. It is necessary to contain all anionic or nonionic surfactants in order to obtain the desired results. However, it is not necessary that all the dispersion liquid penetrates the body hair. In fact, although no experiments have been conducted, it has been shown that some amount (e.g., less than 10%) may be present on the body hair, which may be released gradually over a period of time, or to extend the overall effectiveness of certain treatments. It would be advantageous. Preferably 25).

Potatoes may contain known nonionic surfactants, such as monoglycerides of higher fatty acids, octoxynol, etc.
trademark of Haas Corporation). Generally, a proportion of surfactant on the order of about 3 volumes of the emulsion is preferred.

Bioactive agents that can be used in the practice of this invention generally consist of known topical agents. However, as mentioned above, the present invention is particularly directed to the treatment of cattle and other livestock to prevent them from the harmful effects of mites and other blood-sucking parasitic insects.

It has been recognized that pyrethroid insecticides are particularly useful insecticides for this purpose. The most common pyrethroid insecticide is Cypermethrin (commercially available from FMC).
cybermethrin).

The bioactive agent can be dispersed or contained within the polymeric component in a variety of ways. For example, it may be encapsulated within a polymeric skin or wall. A particularly convenient method is to disperse the drug in one of the liquid monomers, then load the remaining monomers and polymerize in known manner.

The following examples present useful compositions that are illustrative of the invention, by way of illustration and not limitation.

Example 1 Three separate solutions were all prepared. (1) Monomer premix solution; (2) reduced cancer fluid; and (3) reaction solution. The monomer premix solution contains the ectoparasitic insecticide Cypermethrin 29.811-acrylic acid, 2-ethylhexyl 426.0'j (71.2 pph), ethyl acrylate 1 ], 3.69 (19.0 pph), acrylic acid 14.2g (2,37pph), surfactant Alipal EP-110 (Alipal EP-110) 47
．． 3zo(2,3spph), 1-functional t-butyl hydroperoxide (initiator) aqueous solution 255.69. and deionized water 3
It was prepared by dissolving in a solution of 55 zo. The reduced cancer solution consisted of a 170.4-p aqueous solution of sodium formaldehyde sulfoxylate. The reaction solution was deionized water 1562. , Oj;' consisted of 14 drops of ferric ammonium monopolysulfate. Dissolved oxygen was purged from all three solutions by bubbling the solutions with nitrogen for at least 30 minutes. Approximately 10% of the monomer premix and reduced cancer fluid were added to the reaction solution under a nitrogen atmosphere.

The remaining 90% monomer premix and reduced cancer fluid were added to the reaction mixture over a period of 2 hours under a nitrogen atmosphere. The temperature was controlled throughout the reaction by circulating thermostatically regulated water in a jacket surrounding the reaction vessel.
Maintained at 8-42°C.

4 while stirring the solution after addition of the monomer premix.
It was kept at 0°C for 1 hour. As a result, 2-ethylhexyl acrylate (63.5 moles) and ethyl acrylate (311 moles) containing the ectoparasiticide Zypermethrin were found.
An aqueous emulsion of a terpolymer of acrylic acid (5,4 molar) and acrylic acid (5,4 molar) was obtained.

Analysis: Theoretical solids content, 22.52%; Measured solids content, 22.
5%; one part of the polymer solidified; conversion rate (based on residual monomer) 99. s6 staff.

Example 2 Example 1 was repeated except that the quinomer premix consisted of: Cypermethrin 29.96
g (4,99'pph), 2-ethylhexyl acrylate 426.0 g (71,0 pph), ethyl acrylate 113.69 (18,9 pph), acrylic acid 14.2 g (2,37 pph) , ethylene glycol dimethacrylate 1.065 p (0,18 pph
), Alipal EP-110: 49.7g<2.49
pph), 1% aqueous t-butyl hydroperoxide solution 255.
6p, and 35.59° deionized water.The total batch was 2-ethylhexyl acrylate (63.4 mol%), 2-ethylhexyl acrylate (63.4 mol%), ethylene glycol dimethacrylate (02 mol%) containing cypermethrin, ethyl acrylate (31 mol%), and 35.59° deionized water.
, 1 molar) and acrylic acid (5,4 molar).

Analysis: Theoretical solids content, 22.56%; Measured solids content, 22.
3%; 1% of polymer coagulated: conversion (based on residual monomer) 99.86.

Example 3 Repeat Example 2, but instead of the amounts shown in Example 2 Cypermethrin 29.899 (4,97 pph)
, ethylene glycol dimethacrylate 3.00 p
(0,50 pph), and Alipal EP-110:
47.36 g (2.36 ppA) was used. The total batch is about 2658g ethylene glycol dimethacrylate (0
, 2-ethylhexyl acrylate (62,2 molar), ethyl acrylate (30,4 molar), and acrylic acid (7,1 molar) containing the above-mentioned ectoparasiticides. It was an aqueous emulsion of a terpolymer with a molar ratio.

Analysis: Theoretical solids content 22.61%: Measured solids content, 20.4
H; Part 1 of the polymer solidified; Conversion rate (based on residual monomer) 99.77 part.

Example 4 Example 1 was repeated using the following components for three solutions.

Cypermethrin 2.00. 2.42
Ethyl acrylate 16.00 19.30 Acrylic acid 2,00 2.42 Ethylene glycol 0.80 0.97 Alipal dimethacrylate EP-1106,672,42 Deionized water
500 Reductant 1% Sodium Formaldehyde 24.1 Sulfoxylate aqueous solution Reactant Deionized water 22.0 Zo monovalent ammonium ferric sulfate aqueous solution 2 drops A total batch of about 3729 was crosslinked with dimethacrylate (0.5 mol%); It was an aqueous emulsion of a terpolymer of 2-ethylhexyl acrylate (63,2 moles), ethyl acrylate (310 moles), and acrylic acid (53 moles) containing the ectoparasitic insecticide Cypermethrin. .

Analysis: Theoretical solids content, 22.20%; Measured solids content, 208
Part: 66 part of the polymer solidifies.

In the above examples, the anionic surfactant Alipal E
It will be appreciated that P-110 was used in the preparation of emulsions, for example in the polymerization step to prepare the emulsions. In the context of the present invention, the resulting emulsion does not necessarily contain surfactants to enable the polymer dispersion to penetrate the hair and reach the skin before agglomeration occurs as described above.

In animal treatments that require a surfactant for this purpose, the surfactant can be added to the emulsion at any time prior to use.

To illustrate, each of the emulsions prepared in Examples 1-4 was treated with 3 volumes of the nonionic surfactant Triton X-100.
i was added to prepare an ectoparasitic insecticide suitable for treating cattle.

On each side, the bioactive agent was dispersed in one of the liquid monomers prior to polymerization.

In the examples below, this was contained within particles of prefabricated polymer.

Example 5 41 of Elvax-250 (trademark of EI du Pont de Nemois for ethylene-vinyl acetate copolymer, believed to contain 20% by weight of vinyl acetate) was added to 30 (It/!) 258i mixed (ortho-, meta-1 and para-)xylene 6
Dissolved at 0°C. The solution was cooled to 23°C and then Cypermethrin 4. Then, a 5-weight aqueous solution of Alipal EP-110 surfactant was added dropwise to the xylene solution obtained above under high-speed stirring using a Gifford-Wood homogenizer to obtain a so-called oil-in-water emulsion. A phase inversion occurred upon addition of approximately 36 volumes of the aqueous solution to the xylene, which caused the polymer (ethylene-vinyl acetate) particles to swell with the xylene and disperse in the water with the cypermethrin incorporated therein.

Three volumes of Triton X-100 were then added to allow the polymer particles to quickly penetrate the animal's body parts and reach the skin as described above.

Upon penetration, the particles aggregated near the skin to form large film-like particles.

The effectiveness of the present invention in providing controlled release of effective amounts of water-insoluble bioactive agents over extended periods of time was first confirmed by in vitro testing.

On each side below, a piece of hide containing natural hair (approximately 8 x l
OCfrL) was used. A portion of this skin was shaved to facilitate collection and measurement of released drug. As an alternative to the skin oils that would normally be present in live bulls,
Cover the skin with a thin layer of sesame oil.

Example 6 The test formulation of Example 1 was applied to hairy areas in an amount such that 1457±01 kg of Cypermethrin was applied. After 24 hours, an amount of sesame oil from the shaved area was extracted to determine the amount of cypermethrin present due to lateral diffusion from the formulated hairy area. 0 by analysis
7±0.5■ was measured (45±2.9 of the amount applied)
%).

Example 7 The above process was repeated using instead the formulation of Example 2, with a dose of 15.87±0.07 rrL1- of drug administered. Actual value 20450.05771. F(2,8±
Section 0.3).

Example 8 The above process was repeated substituting the formulation of Example 3 with a dose of 1226±0.5 ffl, P of drug administered. Actual value: 0.26 0.20 my (2.3 ± 16 divisions) drug.

The above in vitro tests confirmed that an effective amount of the drug (cypermethrin in this case) was present in the cells after 24 hours. Furthermore, the amount measured is not an excess, indicating that there is an unreleased amount in the applied hair area.

The following examples illustrate other forms of in vitro testing that can be employed in determining the effectiveness of the present invention.

Example 9 Polymer particles were dispersed in sesame oil under mild agitation at a maximum weight ratio of 1-5 to sesame oil. Samples of the dispersion were taken periodically, centrifuged, and the concentration of cypermethrin in sesame oil was determined. Cypermethrin concentration is determined by adding sesame oil containing a certain amount of dissolved cypermethrin to 1 part of hexane.
It was determined by dissolving (depending on the absorbance) of the solution at a concentration of about 25-100 fflP in 0-2 Fl/ and then measuring the absorbance of the solution at 278 mμ. [This assumes that the absorbance of sesame oil can be ignored under these conditions.] At this wavelength, the extinction coefficients of each compound, cypermethrin and sesame oil components, differ by a factor of 1000. ] Alternatively, the absorbance at two wavelengths (278 and 258 mμ) was measured, thereby taking into account the absorbance of sesame oil. Since the measurements were carried out in the range of absorbance in which Beer's law holds at the two chosen wavelengths, the contribution of sesame oil to the total absorbance at each wavelength is at the same time 2 with respect to the concentration of ectoparasiticide and sesame oil. This could be determined by solving the linear equation for the species.

In Examples 6-9 reference was made to in vitro experiments.

The effects of the present invention were further confirmed by in vivo tests. A composition prepared according to Example 3 containing three volumes (of emulsion) of the surfactant Triton X-100i was applied to a number of cattle in South Africa by showering. This ectoparasitic insecticide treatment was found to be effective in protecting animals for one month.

From the foregoing description and examples, it will be appreciated that the present invention provides an excellent and highly effective means for the topical application of bioactive agents to the skin of animals that must remain effective over long periods of time. Dew.

A specific example is Cypermethrin (cyclopropanecarboxylic acid, 3-(2,2-dichloroethynyl)-2,2-dimethyl-cyano(3-
Although topical administration of methylesterenope C. No patentable novelty is foreseen in the selection of any particular bioactive agent herein; substantially water-insoluble bioactive agents known per se;
For example, insecticides (generally used to include pyrethroids, ectoparasitic insecticides, etc.), fungicides,
Fungicides, insect repellents, drugs, and other chemicals conventionally applied to animal skin for known purposes are also contemplated by the present invention. The agent selected must be non-reactive in the preparation of the emulsions for the purpose of this invention, i.e. it must be able to react with the monomers and other materials used in the preparation of these compositions and act accordingly. It is of course an essential condition for the implementation of the invention that the performance should not be adversely affected.

Examples of other bioactive agents of this type include fenvalerate, flumethrin, permethrin, tecamethrin, cyhalothrin, fluparinate, amitratu, and the like.

It is to be understood that the above description is illustrative and not restrictive, as certain changes may be made in the compositions and methods cited above without departing from the scope of the invention.

Claims (27)

[Claims] (1) An emulsion comprising a polymer containing a substantially water-insoluble bioactive agent, the polymer comprising particles capable of agglomerating or coalescing upon evaporation of the emulsion solvent, and the polymer particles coming into contact with animal skin oils. a substantially water-insoluble bioactive agent that is swellable when exposed to the skin of the animal, thereby making the composition suitable for controlled release of an effective amount of the bioactive agent over an extended period of time. Novel composition for application. (2) The composition of claim 1, wherein the bioactive agent is selected from the group consisting of insecticides, fungicides, and fungicides. 3. The composition of claim 1, wherein the polymer particles have a diameter of about 50 microns or less prior to application. (4) The composition of claim 1, wherein the polymer particles are suitable for agglomeration upon evaporation of the solvent to form particles that retard the rapid release of the contained bioactive agent. thing. (5) The composition according to claim 1, wherein the polymer is crosslinked. (6) the crosslink density of the crosslinked polymer is sufficient to provide a predetermined and targeted release rate for the contained bioactive agent, thereby allowing for the application of an effective amount of the agent over an extended period of time; A composition according to claim 5. (7) The composition according to claim 6, wherein the crosslinked polymer consists of a mixture of polymer particles having different crosslink densities. 8. The composition of claim 1, further comprising a substance that facilitates rapid transport of the bioactive agent through the animal's hair and into the animal's skin by capillary action. (9) A composition according to claim 8, wherein the substance promoting rapid transport consists of an anionic or nonionic surfactant. (10) The composition according to claim 9, wherein the bioactive agent is an insecticide. (11) The composition according to claim 10, wherein the insecticide is an insecticide for ectoparasites. (12) The composition according to claim 1, which forms a film or an aggregate on the skin of an animal upon application of the polymer. (13) The composition of claim 1, wherein the bioactive agent is dispersed or encapsulated in the polymer. (14) A novel composition for topically applying a substantially water-insoluble biologically active agent to the skin of an animal to provide a controlled release of an effective amount of the agent over a period of time, the composition comprising: consisting of an aqueous emulsion of a polymer containing particles of a diameter small enough to penetrate the animal's fur toward the skin, the polymer particles being capable of flocculating or coalescing upon evaporation of the emulsion solvent; and is swellable on contact with animal skin oils. (15) the polymer is crosslinked and the crosslink density is sufficient to reduce the release rate of the bioactive agent but insufficient to prevent effective release and subsequent diffusion of the effective amount of the drug; A composition according to claim 14. 16. The composition of claim 15, further comprising a substance that facilitates rapid transport of the bioactive agent through the animal's hair and into the skin. (17) The composition according to claim 16, wherein the substance that supports rapid transport is a nonionic surfactant. (18) The composition according to claim 17, wherein the bioactive agent is an insecticide. (19) The polymer is acrylic acid/2-ethylhexyl,
19. The composition of claim 18, comprising a terpolymer of ethyl acrylate and acrylic acid. (20) The composition according to claim 19, wherein the terpolymer is crosslinked with a difunctional monomeric crosslinking agent. (21) The composition according to claim 20, wherein the crosslinking agent is ethylene glycol dimethacrylate. (22) A method for providing an effective amount of a substantially water-insoluble biologically active agent on or near the skin of a haired animal for an extended period of time from a single application of the agent, the method comprising: (A) (B) passing at least a substantial portion of the applied agent through the fur of the animal; (C) diffusing a first portion of said amount of drug through skin oils produced by the animal, thereby providing an effective amount of drug at the beginning of said period, while delivering said amount of drug to the skin of the animal; a barrier is provided to the diffusion of said second part into the skin oil; (D) said second part is then gradually transported through said barrier and brought into contact with the skin oil, thereby diffusing the effective amount throughout the remainder of said time period; (23) The method of claim 22, wherein the bioactive agent is selected from the group consisting of insecticides, fungicides, and fungicides. (24) The method according to claim 22, wherein the drug is an insecticide for ectoparasites. (25) The barrier consists of aggregated polymer particles applied to or near the animal's skin at the same time as the drug, and the polymer particles are swellable by skin oils, thereby allowing the second
23. A method as claimed in claim 22, through which the parts can be gradually transported into contact with skin oils. (26) The method according to claim 24, wherein the drug is initially encapsulated in a polymer. (27) A method of treating with an effective amount of a substantially water-insoluble bioactive agent for an extended period of time after a single topical application of the agent, comprising the step of topically applying the composition of claim 1.