MXPA99005156A - An oil composition of dihydropolyprenols - Google Patents

Abstract

The present invention provides an oil composition for parenteral administration comprising a dihydropolyprenol of formula (I) and a pharmaceutically acceptable oil, wherein n is an integer of 5 to 7.

Description

A COMPOSITION IN DIHYDROPOLIPREÑOL OIL FIELD OF THE INVENTION The present invention relates to a novel composition for parenteral application. More particularly, the present invention relates to an oil composition of dihydropolipreneols to improve the immune system of animals.

BACKGROUND OF THE INVENTION Dihydropolipreneols are a class of known polyprenols that have been found to improve non-specific host defenses against a variety of pathogenic microbes in roedorea, cows, calves or pigs and pigs. Due to their properties of improvement in host resistance, these compounds can be used as agents to treat or control infections in animals and humans. However, it becomes increasingly evident that drug development involves much more than simply finding the compound with maximum biological activity. Many additional aspects must be considered before an active compound can be a medicinal product. The points of great importance are the stability of the active agent, the absorption behavior of the site intended for administration, the physical state of the active agent and many other related considerations. Economic factors such as the cost of the drug by volume are considerations for those properties of the active agent itself. In recognition of these problems, the present invention provides an unexpected oil composition of dihydropoliprene, which is excellent from the pharmaceutical point of view and avoids all the problems mentioned in the above. This oil composition limits the components practically to the vehicle (i.e., to the oil) and to the dihydropolipreneols to be effective; therefore, it has the potential of a longer shelf life while there are very few components that interact with the dihydropoliprenoles in a harmful way. The oil composition also protects the dihydropoliprenoles from oxidation, a major form of degradation of the polyprenols, since the oxygen needs to diffuse through the vehicles in dihydropoliprene oil and more advantageously, some oils contain endogenous antioxidants . In addition, physical stability is not related to an oil composition since it is a single phase solution. On the other hand, other formulations such as, for example, the emulsions described in the related art, are biphasic and have the possibility of interacting with each other over time. The oil composition of the present invention is easy to administer since it can be more concentrated than the emulsion formulations, which results in a smaller volume than is injected into the animals. For example, the emulsion formulation is normally produced at 10 mg / mL while our oil-based formulation can be at least 150 mg / mL, with a reduction of about 15 times in volume. Also, this oil composition can be easily placed in a syringe because the viscosity is too low for it to flow through a syringe and needle typically used while for example, an implantable pill containing dihydropolyprenole could be more difficult to obtain. administer to animals. Finally, a simple method for making the dihydropolypureole oil compositions in a large scale production is available while more complicated and expensive methods often require other dosage forms.

DESCRIPTION OF THE INFORMATION U.S. Patent 4,624,966 discloses ß r j-dihydropoliprenyl alcohol derivatives useful as a phylactic agent against infectious diseases of humans and animals and their methods of use. U.S. Patent 4,839,389 discloses polyprenyl alcohol containing injectable liquids comprising polyprenyl alcohols as essential ingredients. The United States Patent 5, 139,740 discloses a soft capsule composition containing a polyprenyl compound, a surfactant and / or an aliphatic acid. U.S. Patent 5,280,048 describes a method for using a polyprenyl compound against infections. Additional references of general interest include the following: H. Nagahata, GJ Kociba, H. Noda, M. Koiwa and M. Kimura, "Effects of Dihydroheptaprenol on the Neutrophil Function of Postpartum Dairy Co s", Veterinary Immunology and Immunopathology, 29, pp. 163-169 (1991). O. Yoneyama, S. Osa e, S. Ichijo, M. Kimura, S. Araki, M. Suzuki and E. Imamura, "Effects of Dihydroheptaprenol on Neutrophil Functions in Calves", British Veterinary Journal, 145, pp. 531-537 (1989). O. Yoneyama, S. Osame, M. Kimura, S. Araki and S. Ichijo, "Enhancement of Neutrophil Function by Dihydroheptaprenol in Adult Cows", Japan Journal of Veterinary Science, 51 (6), pp. 1283-1286 (1989). T. atari, R. Goitsuka, H. Koyama, T. Sako, T. Uchino, S. Araki, A. Hasega and S. otoyoshi, "Effect of Dihydroheptaprenol on Nitroblue Tetrazolium Reduction by Swine Alveolar Madrophages", Japan Journal of Veterinary Science, 51 (3), PP. 630-631 (1989). S. Araki, M. Suzuki, K. Ogura, M. Kimura, E. Imamura, C. Kuniyasu, K. Kagaya and Y. Fukazawa, "Enhancement of Phagocytosis and Bactericidal Activity of Neutrophils in Miniature Pigs by Dihydroheptaprenol, A Synthetic Polyprenol Derivative ", Microbiology, Immunol. , 33 (10), pp. 877-882 (1989). S. Araki, K. Kagaya, K. Kitoh, M. Kimura and Y. Fukazawa, "Enhancement of Resistance to Escherichia Coli Infection in Mice by Dihydroheptaprenol, to Synthetic Polyprenol Derivative", Infection and Immunity, 55 (9), pp. 2164, 2170 (1987). M. Kimura, S. Araki, t. Nakai and K. Kume, "Protective Effect of Dihydroheptaprenol in Combination with Vaccine to Experimental Actinobacillus Pleuropneumoniae Injection in Guinea Pigs and Pigs", Japan Journal of Veterinary Science, 55 (4), p. 627-630 (1993). E. J. Robb, D. D. Kratzer, C. H.-Ho, and K. J.

Give me, "Dose Characterization and Dosage Regime Evaluation of Dihydroheptaprenol in Induced Bovine Pneumonic Pasteurellosis," Journal of Animal Science, 71 (Suppl 1), p. 203 (1993).

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition comprising a dihydropoliprenol and a vehicle in oil that increases the innate resistance to infection and stimulates the immune system of animals and is biologically compatible with animals. A further object of the present invention is to provide an oil composition containing a high drug loading of a dihydropoliprenol such that a single volume can be used for convenient administration. Yet another object of the present invention is to provide an oil composition that possesses physical and chemical stability such that adequate shelf life is obtained when the composition is packaged in a container that is economical and the composition is ready for use. Another object of the present invention is to provide an oil composition having a low viscosity such that the composition can be easily introduced into a syringe. Still another object of the present invention is to provide an oil composition that can be manufactured with a simple method such that the final cost of the product is minimized. The objects of the present invention are met since the invention provides an oil composition for parenteral administration, which consists essentially of a dihydropoliprenol of the formula I and a pharmaceutically acceptable oil, wherein n is an integer from 5 to 7.

DETAILED DESCRIPTION OF THE INVENTION Surprisingly and unexpectedly, it has been found that the oil compositions of the present invention, which essentially do not contain water, improve the utilization of the dihydropolipreneols of the formula I. They provide drug release vehicles which are stable, easy to administer and less expensive to manufacture. Dihydropolipreneols with a class of known compounds. Their activities to improve the immune system of animals and the methods for preparing them are described in U.S. Patents 4,624,966; 4,839,389; 5,139,740; 5,280,048, which are incorporated herein by reference. The preferred dihydropoliprenol of the formula I for producing an oil composition of the present invention is dihydroheptaprenol, a compound of the formula I wherein n is 6.

The related animals are cattle, poultry and pets. However, the invention can also be practiced with other vertebrates and with lower species that comprise invertebrates. The oil compositions of the present invention can be prepared by combining a dihydropoliprenol of the formula I with a pharmaceutically acceptable oil. The methods for making such compositions are conventional techniques and are well known to those skilled in the art. For example, the required weight or volume of oil is placed in a glass or stainless steel container. The oil can be filtered through a sterilizer filter (0.22 micron filter) inside the container. The weight or volume of a dihydropoliprenol for an established concentration is calculated and emptied into a vessel containing the oil. The two solutions are then stirred until a homogeneous mixture is obtained. The stirring time depends on the size of the container and the type of mixing equipment used. In general, for a batch size of 100 mL it takes approximately 5 minutes to obtain a homogeneous solution and for a batch size of 1000 L it may take approximately 30 minutes. Once the homogeneous solution is made, it can be filtered through a sterilization filter (0.22 micron filter) and filled in ampoules. The term "pharmaceutically acceptable" refers to those properties that are biologically compatible with the treated subjects from a pharmacological / toxicological point of view and for the chemical pharmaceutical manufacturer from a physical / chemical point of view with respect to stability, solubility and bioavailability . The pharmaceutically acceptable oil is coconut oil. The terms "Miglyol 810", "Miglyol 812" and "Miglyol 829" refers to different grades of fractionated and purified coconut oil consisting mainly of medium chain triglycerides sold under the tradename Miglyol by Huís, Inc. The oil compositions of the present invention are provided in a form intended to be administered parenterally. The preferred route of administration in cattle is subcutaneous to minimize damage to edible tissue. However, routes of intramuscular or other parenteral administration can be used. The amount of dihydropoliprenol of formula I that can be used and the concentration of an oil composition of the present invention can be varied or adjusted widely depending on the potency of the compound used in particular, the dose required, the desired concentration and / or the particular animal that will be treated. In general, the amount of the active component will vary between 0.1 and 1000 mg / kg, and the concentration will vary between 1 mg / mL and 500 mg / mL. The upper concentration limit is reached when the oil composition becomes very viscous to be introduced into the syringe. For example, when dihydroheptaprenol is used to prevent bovine respiratory disease (BRD) in calves, in feeding portions, the dose may be between 1 and 10 mg / kg. Another example, when treating calves in feeding portions at a dose of 2 mg / kg of dihydroheptaprenol to avoid BRD, a solution at a concentration of 150 mg / mL is preferred. Therefore, an injection of 1.3 mL will provide the dihydropoliprenol required for the average of treated animals.

The oil compositions of the present invention will be better understood together with the following examples, which are intended to be illustrative and not limiting of the scope of the invention. Without further elaboration, it is believed that one skilled in the art can, by using the foregoing description and the information provided in the following example, practice the present invention to its fullest extent.

EXAMPLE 1 0.341 g of dihydroheptaprenol are placed in a glass beaker containing 10,997 g of Miglyol 812. A magnetic stirring rod is added and the solution is stirred for 30 minutes. The solution is then placed in 5 mL glass ampoules, closed, coated and labeled. The concentration of dihydroheptaprenol is 30.1 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 28.2 LD50.

EXAMPLE 2 They place 0. 339 g of dihydroheptaprene I in a glass beaker containing 10 996 g of Miglyol 812. A magnetic stirring rod is added and the solution is stirred for 30 minutes. The solution is then placed in 5 mL glass ampoules, closed, coated and labeled. The concentration of dihydroheptaprenol is 26.5 mg / mL of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 12 LD50.

EXAMPLE 3 1,886 g of the product of EXAMPLE 2 are diluted with 26,467 of Miglyol 810, stirring the two liquids in a beaker for 10 minutes. The concentration of dihydroheptaprenol is 9.8 mg / mL. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 10 LD50.

EXAMPLE 4 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of Miglyol 810. The vial is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled.

The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 22 LD50.

EXAMPLE 5 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of Miglyol 812. The vial is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 22 LD5Q.

EXAMPLE 6 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of Miglyol 829. The vial is vortexed for 1 minute using a Yamato whirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 22 LD50.

EXAMPLE 7 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of safflower oil. The ampoule is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 22 LD50.

EXAMPLE 8 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of sesame oil. The ampoule is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 25 LD50- EXAMPLE 9 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of soybean oil. The ampoule is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 6 LD50.

EXAMPLE 10 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of cottonseed oil. The ampoule is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 9 LD50.

EXAMPLE 11 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g of peanut oil. The ampoule is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 25 LD50.

EXAMPLE 12 0.1 g of dihydroheptaprenol is placed in a 20 mL glass vial followed by the addition of 9.9 g 1! of mineral oil. The ampoule is vortexed for 1 minute using a Yamato swirl agitator placed at its maximum speed. After allowing to stand for 1 hour, the ampoule is vortexed again for 15 seconds. The vial is closed, covered and labeled. The concentration of dihydroheptaprenol is 10 mg / g of formulation. The formulation is tested in the Systemic Protection Test for Mouse with a challenge dose of Pasteurella haemolytica at 9 LD50.

EXAMPLE 13 The preparation of the formulation is conducted in a laminar flow hood using good aseptic techniques. 9.02 g of dihydroheptaprenol and 47.73 g of Miglyol 810 are added and filtered through a 0.22 micron filter in a 100 mL sterile glass beaker. A magnetic stirring rod is added and the solution is stirred for 10 minutes. The solution is. place it in a 50 mL sterile glass vial, close it, cover it and label it. The tested concentration is 142.2 mg / mL. The placebo is prepared by filtering, through a 0.22 micron filter, approximately 50 ml of Miglyol 810 in a 50 mL sterile glass ampule. The vial is closed, covered and labeled. The formulation is tested in a bovine challenge test with Pasteurella haemolytica.

EXAMPLE 14 The preparation of the formulation is conducted in a laminar flow hood using good aseptic techniques. 21.43 g of dihydroheptaprenol and 110.94 g of Miglyol 810 are added and filtered through a 0.22 micron filter in a sterile 200 ml glass beaker. A magnetic stirring rod is added and the solution is stirred for 10 minutes. The solution is then placed in 50 mL sterile glass ampoules, closed, coated and labeled. The tested concentration is 149.8 mg / mL. The placebo is prepared by filtering, through a 0.22 micron filter, approximately 50 ml of Miglyol 810 in a sterile glass ampoule of 50 L. The ampoule is closed, covered and labeled. The formulation is tested in a bovine challenge test with Pasteurella haemolytica.

EXAMPLE 15. SYSTEMIC PROTECTION PROOF FOR MOUSE The compositions of EXAMPLES 1-12 are evaluated in a systemic protection test for mouse with Pasteurella haemolytica. In this test, each mouse is administered subcutaneously one dose of a composition, then with a challenge dose with P. h emolyt i ca 24 hours later. The challenge dose of EXAMPLE 1 is 28.2 times with respect to the dose required to kill 50% of the mice (LD50 = 28.2). The challenge doses of the other examples are listed in Table 1. The dose varies from 25 to 400 mg / kg. The compositions are diluted with the oil to be tested before dosing in such a way that the injectable volume for a mouse is available. The group receiving 0 mg / kg is injected with Miglyol 812 as control. The strain of P. has been used is UC6531 and is originally isolated from a case of bovine respiratory disease. The test strain is kept in 3 mm glass beads immersed in trypticase soy broth (Becton-Dickinson Microbiology Systems) with 10% glycerol and kept at -70 ° C until it is revived. The number of mice that survive after seven days is recorded. From the number of survivors, an ED50 is calculated. TABLE 1 summarizes the results of the test.

EXAMPLE 16 PROOF OF SAFETY FOR BOVINE WITH PASTEURELLA HAEMOLYTICA The composition of EXAMPLE 13 is evaluated in a challenge test for bovine with Pa s t e urel l a ha em olyt i ca. In this test the male calves Holstein from 35 to 50 days of age are randomized by weight for the treatment groups. Fifteen animals are assigned to a placebo group that receives only the Miglyol 810 vehicle or a group that receives 4 mg / kg as the oil formulation. The dose of 4 mg / kg is administered subcutaneously to each animal followed by a challenge dose 24 hours later. The challenge dose consists of intratracheal inoculation of 6 x 106 colony forming units (CFU) per calf of P. has virulent emulsion (Al) in 10 mL of infusion broth from Central Brain Region (BHL) acid (pH 4.5) followed, 4 hours later, for a challenge dose of 4 * 108 CFU per calf of P. has emolyti ca in 10 mL of BHl broth without acidification. The calves were observed for 10 days, they were weighed, they were killed without pain and they were necropsied. The decision criteria are mortality, the number of calves that gain 2.27 kg during the study and the calculated lung consolidation result. The study was designed to have an 80% detection power of 21-23% of differences in mortality and growth with alpha = 0.2. None of the calves died in the group that received 4 mg / kg, while a significant difference of 2 of the 15 calves in the placebo group died (P = 0.04, single part). Significantly, more calves (P = 0.006, single part) gain 2.27 kg in the 4 mg / kg group (14 of 15) compared to the negative control (7 of 15). There is no significant difference in the results of lung injury. The composition of EXAMPLE 14 is evaluated in the same bovine challenge test with Pa ste urel has emolyt i ca used for EXAMPLE 13. Fifteen animals are assigned to a placebo group that receives only the Miglyol 810 vehicle, a group which receives 0.5 mg / kg, 1 mg / kg, 2 mg / kg or 4 mg / kg as the formulation in oil. The dose of dihydroheptaprenol is administered subcutaneously to each animal followed by a challenge dose 24 hours later. The calves were observed for 10 days, they were weighed, they were killed without pain and they were necropsied. The decision criteria are mortality, the number of calves that gain 2.27 kg during the study and the calculated lung consolidation result. The study was designed to have an 80% power of detection of differences. Mortality is 4 out of 15 (placebo), 2 out of 15 (0.5 and 1 mg / kg), 0 out of 15 (2 mg / kg) and 1/15 (4 mg / kg), with the only animal dying of twisting of intestines and is not related to the challenge dose). The statistically lower deaths (P = O.ll, single part) are present with those groups that receive 0.5 mg / kg or more of dihydroheptaprenol. The number of calves that gain more than 2.27 kg is 3 of 15 (placebo), 5 of 15 (0.5 mg / kg), 9 of 15 (1 mg / kg), 12 of 15 (2 mg / kg) and 13 of 15 (4 mg / kg). Those treatment groups receiving 1 mg / g or more of dihydroheptaprenol are statistically different (P <0.03, single part) from the placebo group. The results of the lung injury are 18.9 + 8.4% (placebo), 22.7 ± 16.8% (0.5 mg / kg), 15.6 ± 14.1% (1 mg / kg), 17.8 + 19.9% (2 mg / kg) and 9.3 ± 10.2% (4 mg / kg). The results of the lesion of the calves' lung which were administered 4 mg / kg are significantly lower (P = 0.03, single part) than those of the calves of the placebo group.

TABLE 1. PROOF OF SYSTEMIC PROTECTION FOR MOUSE

Claims (10)

1. CLAIMS 1. An oil composition for parenteral administration, consisting essentially of dihydropoliprenol of the formula I and a pharmaceutically acceptable oil characterized because n is an integer from 5 to 7.
2. 2. A dihydropoliprenol of the formula I, according to claim 1, characterized in that n is 6.
3. 3. A dihydropoliprenol of the formula I, according to claim 1, characterized in that it is dihydroheptaprenol.
4. 4. An oil composition, according to claim 1, characterized in that the oil is coconut oil, safflower oil, sesame oil, soybean oil, cottonseed oil, peanut oil or mineral oil.
5. 5. An oil according to claim 1, characterized in that it is coconut oil.
6. 6. An oil according to claim 1, characterized in that it is Miglyol.
7. 7. An oil according to claim 1, characterized in that it is peanut oil.
8. 8. An oil according to claim 1, characterized in that it is oil of garlic.
9. 9. An oil according to claim 1, characterized in that it is safflower oil.
10. 10. An oil composition according to claim 1, characterized in that a dihydropoliprenol of the formula I is present at a concentration of about 1 mg / mL to about 500 mg / mL.