MXPA00005552A - Long acting injectable formulations containing hydrogenated castor oil - Google Patents

Abstract

This invention relates to novel, long-acting injectable formulations. These formulations comprise:(a) a therapeutic agent selected from the group consisting of, e.g., insecticides, acaricides, parasiticides, growth enhancers and oil-soluble NASIDS;(b) hydrogenated castor oil and (c) a hydrophobic carrier comprising:(i) triacetin, benzyl benzoate or ethyl oleate or a combination thereof;and (ii) acylated monoglycerides, propyl dicaprylates/dicaprates or caprylic/capric acid triglycerides or a combination thereof. Also provided herein is a method for the treatment or prevention of various disease states by the parental administration of the invention formulations.

Description

INJECTABLE FORMULATIONS OF PROLONGED ACTION CONTAINING HYDROGENATED RICINO OIL CROSS REFERENCE FOR RELATED REQUESTS Reference is made to the provisional application of E.U.A. with serial No. 60 / 067,374, issued December 3, 1997. Said application, as well as all documents cited therein and all documents cited in the documents cited therein, are hereby incorporated by reference.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the unexpectedly prolonged duration of activity that is observed when injectable formulations containing certain therapeutic agents are prepared using hydrogenated castor oil and a combination of hydrophobic or immiscible carriers in water. Thus, an objective of this invention is to provide such a prolonged therapeutic effect. A further objective is to describe the therapeutic agents that can be employed in the long-acting formulations. Still another objective is to provide additional components that can be used in the formulations. The additional objectives will become apparent after reading the following description.

BACKGROUND OF THE INVENTION The therapeutic agents that are used in the inventive formulations are known to the practitioner to which this invention pertains. The classes of therapeutic agents contemplated by the inventive formulations include insecticides, acaricides, parasiticides, growth promoters and non-steroidal oil-soluble anti-inflammatory drugs (NSA1DS). Specific classes of compounds found within such classes include, for example, avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridylmethyl derivatives, phenylpyrazoles and COX-2 inhibitors. The avermectin and milbemycin series of compounds are powerful anthelmintic and antiparasitic agents against a wide range of internal and external parasites. The compounds belonging to said series are natural products or semi-synthetic derivatives thereof. The structure of said two series of compounds is closely related and they share a 16-membered macrocyclic lactone ring complex, however, the milbemycins do not contain the disaccharide substituent at position 13 of the lactone ring. Natural product avermectins are described in the US patent. 4,310,519 to Albers-Schonberg, et al., And 22, 23-dihydroavermectin compounds are described in Chabala, et al., U.S. 4,199,569. For a general description of avermectins, which include a description of their uses in humans and animals, see "Ivermectin and Abamectin", W.C. Campbell, ed., Springer-Verlag, New York (1989). Milbemycins that occur naturally are described in Aoki et al., U.S. 3,950,360, as well as in the various references cited in "The Merck Index" 12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Semi-synthetic derivatives of such classes of compounds are well known in the art and are described, for example, in the US patent. 5,077,308, U.S. Patent. 4,859,657, patent of E.U.A. 4,963,582, US patent. 4,855,317, patent of E.U.A. 4,871, 719, patent of E.U.A. 4,874,749, patent of E.U.A. 4,427,663, patent of E.U.A. 4,310,519, patent of E.U.A. 4,199,569, patent of E.U.A. 5,055,596, patent of E.U.A. 4,973.71 1, patent of E.U.A. 4,978,677, and US patent. 4,920,148. European patent application 413,538 relates to an injectable formulation containing an avermectin and triacetin compound. European patent application 535,734 relates to an injectable formulation containing an avermectin compound and hydrogenated castor oil in a hydrophobic carrier such as triacetin. The formulations in both European patent applications provide efficacy against external and internal parasites in animals only for 42 days. None of these requests suggest or teach how to manipulate the composition of the formulation in order to achieve efficacy beyond 42 days.

Nodulisporic acid and its derivatives are a class of acaricidal, anti-site, insecticidal and anthelmintic agents known to a practitioner of the art. These compounds are used to treat or prevent infections in humans and animals. Such compounds are described, for example, in the patent of E.U.A. 5,399,582 and WO 96/29073. Additionally, the compounds can be administered in combination with other insecticides, parasiticides, and acaricides. Such combinations include anthelminthic agents, such as those described above including ivermectin, avermectin and emamectin, as well as other agents such as thiabendazole, febantel or morantel; phenylpyrazoles such as fipronil; and insect growth regulators such as lufenuron. Said combinations are also contemplated in the present invention. Generally, all classes of insecticides are provided in this invention. An example of these classes includes substituted pyridylmethyl derivatives such as midacloprid. Agents of said classes are described, for example, in the patent of E.U.A. 4,742,060, or EP 892,060. Within the level of the practitioner is to decide which individual compound can be used in the inventive flation to treat a particular infection of an insect. Phenylpyrazoles are another class of insecticides that possess excellent insecticidal activity against all insect pests including blood-sucking pests such as ticks, fleas, etc., and are parasites in animals. This class of agents kills insects by activating the invertebrate gamma-butyric acid receptor. Such agents are described, for example, in the patent of E.U.A. No. 5,567,429, patent of E.U.A. No. 5,122,530, and EP 295.1 17. Within the level of the practitioner is to decide which individual compounds can be used in the inventive flations. Insect growth regulators are another class of insecticides or acaricides, which are also provided for the inventive flations. The compounds belonging to this group are well known to the practitioner and represent a wide variety of different chemical classes. These compounds act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in the US patent. 3,748,356; patent of E.U.A. 3,818,047; patent of E.U.A. 4,225,598; patent of E.U.A. 4,798,837; and patent of E.U.A. 4,751, 225, as well as in EP 179,022 or R.U. 2,140,010. Again, within the level of the practitioner is to decide which individual compounds can be used in the inventive flation. Estrogens, progestins, and androgens refer to classes of chemical compounds that are also well known to a practitioner in this art. In fact, estrogens and progestins are among the most widely prescribed drugs and are used, for example, alone or in combination for contraception therapy or hne replacement in postmenopausal women. Estrogens and progestins occur naturally or are prepared synthetically. Said class of compounds also includes estrogen or progesterone receptor antagonists. Antiestrogens, such as tamoxifen and clomiphen, are used to treat breast cancer and infertility. Antiprogestives are used as contraceptives and drugs against cancer, as well as to induce labor or terminate a pregnancy. Androgens and antiandrogens structurally related to estrogens and progestins are also biosynthesized from cholesterol. These compounds are based on testosterone. Androgens are used for hypogonadism and promote muscle development. Antiandrogens are used, for example, in the control of hyperplasia and carcinoma of the prostate, acne, and baldness of human pattern, as well as in the inhibition of sexual behavior in men who are sex offenders. Estrogen, progestins and androgens are described, for example, in "Goodman &; Gilman's The Pharmacological Basis of Therapeutics ", 9th ed., J.G. Handman and L. Elimbird, eds., Chapters 57-60, Medicinal Chemistry", 2nd ed. W.O. Foye, ed., Cap. 21, pp. 495-559, Read & Febiger, Philadelphia (1981). Estrogens, progestins and androgens are also used in animal husbandry as growth promoters to feed animals. It is known in the art that the compounds of said classes act as growth promoting steroids of animals such as cattle, sheep, pigs, domestic poultry, rabbits, etc. Delivery systems for promoting the growth of animals are described, for example, in the patent of E.U.A.4,401, 507, patent of E.U.A. 5,288,469, US patent. 4,758,435, patent of E.U.A. 4,686,092, US patent. 5,072,716 and US patent. 5,419,910. NSAIDS are well known in the art. Classes of compounds belonging to this group include salicylic acid derivatives, para-aminophenol derivatives, indoleacetic acids and indenacetic acids, heteroaryl acetic acids, arylpropionic acids and anthranilic acids (fenamates), phenolic acids and alkanones. NSAIDS exert their activity through interference with prostaglandin biosynthesis through irreversible or reversible inhibition of cycloxygenase. Also included are COX-2 inhibitors that act by inhibiting the COX-2 receptor. The compounds of this group have analgesic, antipyretic, and non-steroidal anti-inflammatory properties. Compounds belonging to these classes are described in, for example, chapter 27 of Goodman and Gilman at pages 617 and 658 or in chapter 22 of Foye at pages 561 to 590 as well as in the patents of E.U.A. 3,896,145; patent of E.U.A. 3,337,570; patent of E.U.A. 3,904,682; patent of E.U.A. 4,009,197; patent of E.U.A. 4,223,299; and patent of E.U.A. 2,562,830, as well as the specific agents listed in The Merck Index. This invention contemplates those compounds that are soluble in oil. These and other embodiments are described or are obvious and are understood by the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a long-acting injectable formulation for use in human and veterinary medicine, depending on the specific therapeutic agent selected and the indication in which it is being treated. The inventive formulation comprises: (a) a therapeutic agent selected from the group consisting of, for example, insecticides, acaricides, parasiticides, growth promoters and oil soluble NSAIDS, (b) hydrogenated castor oil, and (c) a carrier hydrophobic comprising: (i) triacetin, benzyl benzoate, or ethyl oleate or a combination thereof. (ii) acylated monoglycerides, propyl dicaprylates / dicaprates and caprylic acid / capric triglycerides. Most preferred are long-acting injectable formulations wherein (a) a therapeutic agent selected from the group consisting of, for example, avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestin, androgens, phenylpyrazoles and COX- inhibitors. 2, (b) hydrogenated castor oil, and (c) a hydrophobic carrier comprising: (i) triacetin, benzyl benzoate or ethyl oleate or a combination thereof, (ii) acetylated monoglycerides, propyl dicaprylates / dicaprates. , or triglycerides of caprylic / capric acid or a combination thereof. The formulations of the present invention considerably prolong the duration of the activity. By the term "acyl" the applicants refer to an organic acid group in which OH of the carboxyl group is replaced by another substituent; that is, RCO, wherein R is, for example, a C1-C10 alkyl group or a carbocyclic aromatic or heteroaromatic group. Examples of such groups include acetyl, propionyl, butyryl, isobutyryl, and benzoyl. The term "prolonged duration of activity" refers to the activity of the therapeutic agent extending beyond the period normally achieved when the therapeutic agent is injected into a host using a conventional carrier of the prior art. Since conventional injectable formulations are well known in the art, one skilled in the art can easily understand the meaning of said term. Generally, depending on the host agent and the state of the disease, the activity can be prolonged for a period of up to 120 days up to 180 days. The preferable periods in which the duration of the agent is extended include from 14 days to 180 days, 30 days to 150 days, 42 days to 120 days and 60 days to 90 days. Although not intended to be limited by theory, it is believed that such an increase in activity is achieved because the inventive formulations significantly increase the plasma concentration in the tissue over a prolonged period of up to about 2 weeks to about 24 weeks, observing periods of up to around 6, 8, 10, 12, 16 and 20 weeks. With respect to the avermectins and milbemycins, it has been found that the present formulations have a considerably prolonged duration against internal and external parasites prior to the injectable formulation of avermectins or milbemycins. In addition, the present formulations for avermectin and milbemycin provide significantly higher plasma levels on day 42 than the previous long-acting formulations, thus producing efficacy for all relevant parasitic species. Preferred long-acting injectable formulations comprise: (a) from about 1.0 to about 10.0% w / v of a therapeutic agent, (b) from about 1 to about 3% w / v castor oil hydrogenated; and (c) a hydrophobic carrier comprising: (i) from about 30 to about 45% v / v triacetin; benzyl benzoate or ethyl oleate; and (ii) from about 55 to 70% v / v of acetylated monoglycerides, propyl dicaprylates / dicaprates, or caprylic / capric triglycerides.

Even more preferred are the above formulations wherein from about 1.0 to about 5.0% w / v of a therapeutic agent is present. Especially preferred are the inventive formulations wherein from about 2.5 to about 5.0% w / v and a therapeutic agent is present. The especially preferred long-acting formulation of the present invention comprises: (a) an avermectin or milbemycin compound, (b) hydrogenated castor oil, and (c) triacetin and acetylated monoglycerides. In a particularly preferred embodiment, the long-acting formulation comprises: (a) from about 1.0 to about 5.0% w / v of an avermectin or milbemycin compound, (b) from about 0.5 to about 3.5% w / v of hydrogenated castor oil, and (c) from about 30 to about 45% v / v of triacetin and from about 55 to about 70% v / v of acetylated monoglycerides. In a more preferred embodiment, the long-acting formulation comprises: (a) 3.15% w / v ivermectin, (b) 1% w / v hydrogenated castor oil, and (c) 40% v / v triacetin and up to 60% v / v of acetylated monoglycerides. Another aspect of the invention is to provide a method for the prevention or treatment of infestations of parasites or insects in a host requiring it for a prolonged period by administering a single dose of a long-acting injectable formulation comprising the therapeutic agent. suitable. The duration is typically, for example, from about 1 month to about 6 months, depending on the agent, host and indication being treated. The extensions of the activity last from around 2 months to around 5 months and especially from 3 months to 4 months. Another aspect of this invention is to promote the growth of animals by administering a unique long-acting formulation according to the present invention, wherein the therapeutic agent is an estrogen, progestin or androgen. Another aspect of the present invention is a method for treating inflammation, pain or fever for a prolonged period in a host in need thereof by administering a single dose of a formulation according to the present invention, wherein the therapeutic agents are NSAIDS soluble in oil. An especially preferred aspect of the invention is to provide a method for the prevention or treatment of parasitic infestation in cattle for a minimum of 42 days comprising the administration to said cattle of a single dose of a long-acting injectable formulation according to the present invention. invention, wherein the therapeutic agent is avermectin or milbemycin. Therapeutic agents used in the formulations of the invention include avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestins, androgens, oil-soluble NSAIDS, phenylpyrazoles, substituted pyridylmethyl compounds, and agents that act as growth regulators of insects, which are compatible in the inventive formulations for their intended use. Also contemplated are the ester and amide derivatives of said compounds, where applicable, as well as their salt forms. The specific compounds belonging to said classes of therapeutic agents are well known to the practitioner of this technique. Similarly, the specific disease status as well as the particular dose are well known to the practitioner. The avermectins and milbemycins share the same common 16-membered macrocyclic lactone ring; however, milbemycins do not possess the disaccharide substituent at position 13 of the lactone ring. Although several avermectin compounds are known in the art, a structure representative of the class of compounds is as follows: wherein the interrupted line indicates a single or double link at positions 22, 23; Ri is hydrogen or hydroxy with the proviso that Ri is present only when the interrupted line indicates a single bond; R 2 is alkyl of 1 to 6 carbon atoms or alkenyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms; R3 is hydroxy, methoxy or = NOR5 wherein R5 is hydrogen or lower alkyl; and R4 is hydrogen, hydroxy or wherein Re is hydroxy, amino, mono- or di-alkylamino, lower alkanoylamino.

Preferred compounds are avermectin Bla / Blb (abamectin), 22, 23-dihydro avermectin Bla / Blb (ivermectin) and 4"-acetylamino-5-ketoximino, avermectin derivative Bla / BIb. Abamectin and ivermectin are approved as broad spectrum antiparasitic agents The structures of abamectin and ivermectin are the following: wherein for the abamectin the interrupted line represents a double bond and Ri is not present and for ivermectin the double bond represents a single bond and Ri is hydrogen; and R2 is isopropyl or sec-butyl. The 4"-acetylamino-5-ketoximino derived from avermectin Bla / Blb has the following structural formula: wherein R2 is isopropyl or sec-butyl. The avermectin products are generally prepared as a mixture of at least 80% of the compound wherein R2 is sec-butyl and not more than 20% of the compound wherein R2 is isopropyl. Other preferred avermectins include ememectin, epinomectin and doramectin. Doramectin is described in the patent of E.U.A.5, 089,490 and EP 214738. Said compound has the following structure: In the present formulations, the invermectin is especially preferred. A representative structure for a milbemycin is that for milbemycin ai: An especially preferred milbemycin is moxidectin, whose structure is as follows: The compound is described in the patent of E.U.A. No. 5,089,490. The insecticides contemplated by this invention are also well known in the art and such compounds include substituted pyridylmethyl derivatives and phenylpyrazoles. A substituted pyridylmethyl derivative which is especially preferred is imidacloprid. A particularly preferred phenylpyrazole is fipronil, whose chemical name is 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-pyrazole. Fipronil is well known in the art as a flea and tick agent. Additional insecticides included by the invention include insect growth regulators. Especially preferred insect growth regulators include diflubenzuron, lufenuron, methoprene, phenoxycarb, pyriproxyfen, and cyromazine. The specific estrogen, progestin and androgen compounds are well known to the practitioner. Especially preferred compounds belonging to this class include progesterone, estradiol benzoate and trenbolone acetate. Oil soluble NSAIDS are also well known to the practitioner. The NSAIDS classes that are preferred are indoleacetic and indecenacetic acids and acetic heteroaryl acids. Especially preferred compounds include indomethacin, ketorolac, caprofen, flunixin, ketoprofen, meloxicama, naproxen and phenylbutazone. Hydrogenated castor oil is refined, hydrogenated and deodorized castor oil, mainly containing the triglyceride of hydroxystearic acid. Hydrogenated castor oil is readily prepared using standard techniques known to those skilled in the art of preparing hydrogenated castor oil and a suitable form of hydrogenated castor oil is commercially available under the tradename "Thixcin R" from NL Industries. Although not intended to be limited by theory, it appears that hydrogenated castor oil, being a waxy hydrophobic solid, is left in the injection site containing the therapeutic agent after the hydrophobic carrier has diffused from the injection site; said hydrophobic hydrogenated castor oil / therapeutic agent matrix is that which forms a "deposit" of the active material that diffuses slowly from the injection site over a prolonged period. The hydrogenated castor oil constitutes approximately 1% w / v of the present formulation. The hydrophobic carrier of the present formulation comprises a mixture of (i) triacetin, benzyl benzoate, ethyl oleate or a combination thereof; and (ii) acylated monoglycerides, propyl dicaprylates / dicaprates, or caprylic / capric triglycerides or a combination thereof. Said compounds, as well as their sources, are well known in the art. For example, triacetin (glyceryl triacetate or glycerol triacetate) and acetylated monoglycerides (available under the tradename "Myvacet 9-45" from Quest International) The ratio of component (i) to component (ii) used in the present formulation it is generally from 45:55 to 30:70; preferably the ratio is approximately 40:60. In addition to hydrogenated castor oil, the therapeutic agent and the hydrophobic carrier, the formulation may contain other inert ingredients such as antioxidants or preservatives. The antioxidant such as a propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene) monothioglycerol and the like can be added to the present formulation. Antioxidants are generally added to the formulation in amounts of about 0.01 to about 2.0% (w / v). Preservatives such as parabens (methylparaben and / or propylparaben) are suitably used in the formulation in amounts ranging from about 0.01 to about 2.0% w / v. The long-acting injectable formulation of the present invention can be prepared by the addition of a dispersion of hydrogenated castor oil in acetylated monoglycerides, propyl dicaprylates / dicaprates or caprylic / capric triglycerides to a solution comprising the therapeutic agent, and any other inert ingredient, benzyl benzoate of triacetin or ethyl oleate, and the mixture of liquids until uniform. Since the long-acting formulation is intended for injection, it is necessary that it be sterilized. Heat sterilization should generally be avoided in the situation where the avermectin or milbemycin compounds are used since such compounds are unstable at autoclave temperatures. On the contrary, membrane sterilization is preferred in situations with dissolved solids and gamma sterilization for hydrogenated castor oil. The sterile hydrogenated castor oil is then dispersed in the product aseptically and packaged aseptically.

The instant formulation is equally applicable to other compounds used for injection as long as said compounds are soluble in the mixture of the hydrogenated castor oil and the hydrophobic carrier. The additional compounds that can be used in this formulation are other antiparasitic and antibiotic agents, therapeutic vitamin and mineral supplements, and other agents that are assisted in their therapeutic effect by having their effects extended over a prolonged period. Again, said compounds are well known to the practitioner. The instant long-acting formulations are administered to warm-blooded animals such as humans, cattle, sheep, pigs, cats, dogs, horses and the like by intramuscular or subcutaneous injection. The amount of therapeutic agent depends on the individual therapeutic agent, the animal being treated, the disease state, and the severity of the disease state. The determination of these factors is within the level of the practitioner. Generally, said preparation normally contains from about 0.0005 to about 50% w / v of therapeutic agent. Preferred formulations are those containing from about 0.01 to 10% w / v of therapeutic agent and the especially preferred formulations are those containing from about 2.5 to about 5% w / v of therapeutic agent. For avermectins and milbemycins, the formulations will generally be prepared to administer from about 0.1 to about 2 mg / kg, preferably from about 0.4 to about 0.85 mg / kg and more preferably from about 0.6 to about 0.7 mg / kg of active ingredient. In a preferred dose volume of about 1 ml to treat 50 kg of body weight of the animal, the formulation contains from about 5 to about 50 mg of the active agent per ml of solution or about 0.5 to about 10 p / v. , preferably from about 2.5 to about 5% w / v. However, depending on the activity of the compound and the animal being treated, doses of about 0.3 w / v of the active ingredient can be used. For nodulisporic acid and its derivatives, a formulation containing from about 0.0005 to about 5% w / v active compound is preferred. The present formulation is provided for a prolonged period of treatment. For avermectins and milbemycins a minimum of 42 days of activity against endo- and ectoparasites is obtained without causing tissue irritation. The prolonged period for the other therapeutic agents is readily determined by one skilled in the art and is determined by such factors as the therapeutic agent, disease status, host and severity of the infection. Although the previously reported avermectin formulation containing hydrogenated castor oil in triacetin produced a prolonged plasma level compared to a formulation without hydrogenated castor oil, it did not reach an effective plasma level against all relevant parasitic species in the 42 day target . In contrast, the present formulation using avermectins or milbemycins surprisingly provides a significantly higher plasma on day 42 and other days. The present formulation is also effective against ticks and Dermatobia hominis up to 75 and 140 days respectively. The following example is provided so that the invention can be more fully understood. Said example should not be given as a limitation of the invention.

EXAMPLE 1 Material% Quantity Ivermectin 3.15% w / w 17.6 gm n-propyl gallate 0.02% w / w 0.10 gm Thixcin R 1.0% w / w 5.0 gm triacetin 40.0% w / w 200.0 gm Myvacet 9-45 cbp 100% w / w cbp 500.0 gm Triacetin was added to the n-propyl gallate and ivermectin in an Erlenmyer flask and mixed until all the n-propyl gallate dissolved. Myvacet 9-45 was placed in beaker without glass in a water bath at 50 ° C, was mixed at a low speed with a disperser mixer until the temperature of the content reached 50 ° C. Then Thixcin R was slowly added to the swirl of the Myvacet 9-45 mixture. When all the Thixcin R was added, the speed of the mixer was slowly increased to 60 rpm and the mixing was continued for 20 minutes. The beaker was removed from the water bath and allowed to cool to 30 ° C, although mixing continued at about 25 rpm. The triacetin solution was added to the Thixcin R / Myvacet 9-45 mixture and the liquids were mixed until they were uniform.

EXAMPLE 2 Material% Amount / 2000 L Ivermectin 3.15 p / p 63.0 kg triacetin 40.0 v / v 800.0 L castor oil 1.0 p / v 20.0 kg hydrogenated BHT 0.02 p / v 0.4 kg methylparaben 0.18 p / v 3.6 kg propylparaben 0.02% p / v 0.4 kg Myvacet 9-45 cbp 100% v / v cbp 1200.0 L Ivermectin, BHT, methylparaben and propylparaben were dissolved in 800 L of triacetin, and the solution was sterile filtered in a 200 L tank equipped with an agitator. Myvacet 9-45 was sterile filtered in a 150 L tank capable of maintaining a batch temperature at 60 ° C and equipped with an agitator and with an aseptic addition of sterile powder capacity. The sterilized hydrogenated castor oil range was dispersed in Myvacet 9-45, and the dispersion was heated to 50 ° C, then transferred to the triacetin solution through a microfluidizer. The liquids were mixed until uniform and then packed aseptically in low density polyethylene containers.

EXAMPLE 3 Vermectin plasma levels administered once subcutaneously at a dose of 630 mcg / kg body weight were determined in cattle for two formulations: formulation I contains 3.15% ivermectin, 0.02% n-propyl gallate, 1.5 % of Thixcin R and triacetin cbp 100%, formulation II has the composition given in example 2. 10 animals were used for formulation I and 6 were used for formulation II. The average plasma levels (ng / ml) are shown in the following table: Days after the dose Formulation 3 14 21 28 35 42 80 18 10 6 4 2 II 21 25 22 16 13 9 The average plasma level for formulation II was greater than 3 ng / ml on day 70. The plasma level on day 42 of formulation I (2 ng / ml) is not sufficient to produce efficacy against Cooperativa oncophora and Nematodirus that requires an ivermectin plasma level of 3 to 4 ng / ml.

EXAMPLE 4 To facilitate large-scale batch manufacturing, the following procedure was developed that results in a product that meets the same release specifications as the product manufactured in Example 2. The formula is also the same as that used in Example 2. Vermectin, BHT, methylparaben and propylparaben are dissolved in a mixture of triacetin and Myvacet 9-45. The sterile filtering solution. The range of sterilized hydrogenated castor oil is aseptically dispersed in a sterile solution using an eductor / homogenizer system. Said online system can be an instantaneous mixing system. The product is heated and recirculated in the system until the temperature of the product is 42 to 50 ° C. Then the product is packaged aseptically. Having thus described in detail the preferred embodiments of the present invention, it should be understood that the invention defined by the appended claims is not limited by particular details set forth in the foregoing description since many apparent variations thereof are possible without departing from the scope of the invention. spirit and scope of the invention.

Claims (37)

NOVELTY OF THE INVENTION CLAIMS

1. - A long-acting injectable formulation comprising: (a) a therapeutic agent selected from the group consisting of insecticides, acaricides, parasiticides, growth promoters and oil-soluble NASIDS, (b) hydrogenated castor oil, and (c) a hydrophobic carrier comprising: (i) triacetin, benzyl benzoate or ethyl oleate or a combination thereof; and (ii) acylated monoglycerides, propyl dicaprylates / dicaprylates, caprylic / capric triglycerides, or a combination thereof.

2. A long-acting injectable formulation comprising: (a) a therapeutic agent selected from the group consisting of avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyrimidylmethyl derivatives, phenylpyrazoles, and inhibitors of COX-2, (b) hydrogenated castor oil, and (c) a hydrophobic carrier comprising: (i) triacetin, benzyl benzoate or ethyl oleate or a combination thereof; and (ii) acetylated monoglycerides, propyl dicaprylates / dicaprates, caprylic / capric triglycerides, or a combination thereof.

3. The long-acting injectable formulation according to claim 1 comprising: (a) from about 1.0 to about 10.0 p / v of a therapeutic agent; (b) from about 0.3 to about 5% w / v of hydrogenated castor oil; (c) a hydrophobic carrier comprising: (i) from about 30 to about 45% v / v of triacetin; benzyl benzoate or ethyl oleate; and (ii) from about 55 to 70% v / v of acetylated monoglycerides, propyl dicaprylates / dicaprates, or caprylic / capric triglycerides.

4. The long-acting injectable formulation according to claim 2, further characterized in that it comprises: (a) from about 1.0 to about 10.0 p / v of a therapeutic agent; (b) from about 0.3 to about 5% w / v of hydrogenated castor oil; (c) a hydrophobic carrier comprising: (i) from about 30 to about 45% v / v of triacetin; benzyl benzoate or ethyl oleate; and (ii) from about 55 to 70% v / v of acetylated monoglycerides, propyl dicaprylates / dicaprates, or caprylic / capric triglycerides.

5. The long-acting injectable formulation according to claim 2, further characterized in that about 5.0% w / v of a therapeutic agent is present of about 2.5.

6. The long-acting injectable formulation according to claim 2, further characterized in that the therapeutic agent is an avermectin or a milbemycin.

7. The long-acting injectable formulation according to claim 6, further characterized in that avermectin is vermectin, abamectin, ememectin, eprinomectin or doramectin and milbemycin is moxidectin.

8. The injectable long-acting formulation according to claim 2, further characterized in that the therapeutic agent is an estrogen, progestin or androgen.

9. The long-acting injectable formulation according to claim 8, further characterized in that the estrogen, progestin or androgen is estradiol benzoate, progesterone or trenbolone acetate.

10. The long-acting injectable formulation according to claim 2, further characterized in that the therapeutic agent is nodulisporic acid or its derivatives. 1.

The long-acting injectable formulation according to claim 2, further characterized in that the therapeutic agent is a substituted pyridylmethyl derivative or a phenylpyrazole.

12. The long-acting injectable formulation according to claim 1, further characterized in that the therapeutic agent is midachloropid or fipronil.

13. The long-acting injectable formulation according to claim 2, further characterized in that the therapeutic agent is a COX-2 inhibitor.

14. - The long-acting injectable formulation according to claim 1, further characterized in that the therapeutic agent is an oil-soluble, non-steroidal anti-inflammatory drug.

15. The long-acting injectable formulation according to claim 14, further characterized in that the therapeutic agent is caprofen, flunixin, ketoprofen, meloxicama, naproxen or phenylbutazone.

16. The long-acting injectable formulation according to claim 1, further characterized in that the therapeutic agent is an insect growth regulator.

17. The long-acting injectable formulation according to claim 16, further characterized in that the therapeutic agent is diflubenzuron, lufenuron, methoprene, phenoxycarb, pyriproxyfen, and cyromazine.

18. The long-acting injectable formulation according to claim 1, further characterized in that it comprises an antioxidant or a preservative.

19. The long-acting injectable formulation according to claim 2, further characterized in that it is present from about 1 to about 3.0% w / v of hydrogenated castor oil and the hydrophobic carrier comprises about 40% v / v of triacetin, benzyl benzoate or ethyl oleate and about 60% v / v of acetylated monoglycerides, propyl dicaprylates / dicaprates, or caprylic / capric triglycerides.

20. The long-acting injectable formulation according to claim 2, further characterized in that it comprises: (a) from about 1.0 to about 5.0% w / v of an avermectin compound, (b) from about 1 to about 3% w / v of hydrogenated castor oil, and (c) from about 30 to about 45% v / v of triacetin and 55 to 70% v / v of acetylated monoglycerides.

21. The long-acting injectable formulation according to claim 2, further characterized in that it comprises: (a) about 3.15% w / v of ivermectin, (b) about 1% w / v of hydrogenated castor oil, and (c) about 40% triacetin and about 60% v / v acetylated monoglycerides.

22. The long-acting injectable formulation according to claim 2, further characterized in that it comprises an antioxidant.

23. The long-acting injectable formulation according to claim 2, further characterized in that it comprises a preservative.

24. The long-acting injectable formulation according to claim 22, further characterized in that said antioxidant is selected from n-propyl gallate, BHA, BHT and monothiolglycerol.

25. - The long-acting injectable formulation according to claim 23, further characterized in that said preservative is selected from parabens.

26. The long-acting injectable formulation according to claim 21, further characterized in that it comprises an antioxidant selected from n-propyl gallate, BHA, BHT and monothiolglycerol.

27. The long-acting injectable formulation according to claim 26, further characterized in that it comprises preservatives selected from parabens.

28. The long-acting injectable formulation according to claim 21, further characterized in that it comprises BHT and one or more preservatives of the parabens.

29. The use of a long-acting injectable formulation as claimed in claim 6 for the manufacture of a parenteral drug for the prevention or treatment of parasitic infestation in a host.

30. The use of a long-acting injectable formulation as claimed in claim 1 for the manufacture of a parenteral medicament for the prevention or treatment of parasitic infestation in a host, wherein said medicament is administered for a minimum of 42 days

31. The use of a long-acting injectable formulation as claimed in claim 2 for the manufacture of a parenteral drug for the prevention or treatment of parasitic infestation in cattle for a minimum of 42 days.

32. The use of a long-acting injectable formulation as claimed in claim 21 for the manufacture of a parenteral drug for the prevention or treatment of parasitic infestation in cattle, wherein said medicament is administered for a minimum of 42 days.

33. The use of a long-acting injectable formulation as claimed in claim 10 for the manufacture of a parenteral drug for the treatment or prevention of insect infestation for a prolonged period in a host.

34.- The use as claimed in claim 33, where the insects are fleas.

35.- The use of a long-acting injectable formulation as claimed in claim 1 for the manufacture of a parenteral drug for the treatment or prevention of insect infestation for a prolonged period in a host.

36. The use as claimed in claim 35, wherein the injectable formulation as the therapeutic agent is imidacloprid or fipronil and the insects are fleas.

37. - The use of a long-acting injectable formulation such as that. it is claimed in claim 8 for the manufacture of a parenteral medicament for the promotion of growth in animals. 38.- The use of a long-acting injectable formulation as claimed in claim 14 for the manufacture of a parenteral drug for the treatment of inflammation, pain or fever for a prolonged period in a host.