HU182762B - Process for veterinary compositions containing pgf-2-alpha down - Google Patents

Abstract

The tablets of the present invention exhibit high storage stability at room temperature. They do not require refrigerated storage until they are used, their use is simple and requires no special medical intervention. -1-

Description

FIELD OF THE INVENTION This invention relates to a method for the preparation of a pharmaceutical composition containing * stabilized * PGF _{2x for} use in veterinary medicine.

It is known that in many veterinary practices it is necessary to open the uterus of the female mammal for diagnostic and therapeutic purposes. Examples of such interventions are the introduction of a catheter into the uterine cavity to remove unwanted uterine contents such as blood, pus, tissue debris, dead fetuses, etc., and the administration of drugs and pharmaceuticals that can be infused or inserted into the uterus, or superovated. . Even with difficult calving of primiparas, it may be necessary to open or loosen the rigid cervix or the uterus. In practice, both the inner * and outer uterus need to be opened and dilated * and the cervical mucus plug needs to dissolve.

It is also known that prostaglandins are used in the veterinary field for their luteolytic, ossatric synchronizing, and smooth muscle vasoconstrictor activity. Acad.Sci.Hung., 26, 455-463. / 1976 /; Hung.Vet.J., 33, 534-536, / 1978 / _7. To achieve the desired effect, the active compounds are administered to the animals in the form of injectables. However, this route of administration involves the administration of relatively large amounts of prostaglandin *, which contributes to the development of side effects. Because of the coexistence of major and side effects, such as smooth muscle cramps, injection formulations can only be used in a small number of cases.

Prostaglandins are known to be labile molecules that are easily converted to inactive products when exposed to the environment. A prostaglandin-containing pharmaceutical composition that is stable for six weeks is disclosed in U.S. Pat. U.S. Pat. Here, the active ingredient is PGE 0 and stabilization is achieved by the use of cyclodextrin, sodium chloride, succinic acid and polyvinylpyrrolidone in the composition, and the composition is prepared by lyophilization of the mixture. No. the fact that a medicinal product that lasts only six weeks is not commercially available and that it can only be used in the area of a clinic or hospital capable of producing the medicinal product requires further proof.

No. 78, 142517; According to Japanese Cocoa, stabilization of prostaglandins (PGE ₂ and PGF _{2 <} ) is accomplished by converting it into cellulose acetate Dele and then drying the mixture into nitrogen gas. Here the problem is * that the water-insoluble cellulose acetate carrier remains in the. after application of the formulation and the release of the active ingredient is highly dependent on the moisture of the application site.

No. 2840142; A disclosure document in the Federal Republic of Germany discloses the stabilization of prostacyclin, a very rapidly degradable acidic medium, by formation of a cyclodextrin inclusion complex.

Application problems have also occurred with the Intravaginal Foam Finished Conveyor. This is because the active ingredient is absorbed through the vaginal mucosa and at the same time contracts the smooth muscle of the vagina. In contrast, vaginal contraction causes the composition to be ejected from the vagina. Such formulations do not induce uterine dilatation.

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Based on the foregoing, it has been found that none of the prior art has been able to deliver a stable pharmaceutical formulation of prostaglandin as an active ingredient that is stable, easy and safe to use and manufacture.

It is an object of the present invention to provide pharmaceutical compositions which are free from the above-described disadvantages, which are stable and suitable for therapeutic use in the dilatation of the uterus in connection with livestock breeding and livestock breeding interventions which may require treatment of a large number of animals. .

Surprisingly, it has been found that all of these disadvantages do not occur, and that the opening of the uterus for 5 to 8 hours or, when used in the uterine cavity, the elimination of otherwise unaffected uterine inflammation can be achieved by using the composition of the present invention. These formulations contain from 3 to 30 mg of free or tracer PGF ₂ ~, 0-1 g of buffer, 0-1 g of non-ionic thickener, 0-1 g of emulsifier, 0-5 per unit dose. g aerosol propellant gas, 0-5 g chemotherapeutic agent and / or desire antibiotic 0-0.1 g carrier colloid, 0-0.3 g ethanol, 0-0.1 g lubricant, 0-0.5 g disintegrant, 0-0 g , 5 g of foam stabilize clay, 0-0.1 g of wetting agent, 0-1 g of solid organic acid, 0-0.1 g of sugar, 5 g of sodium bicarbonate and up to 15 g of water and up to 0.3 g contain ethanol with the understanding that their PGF _{2 <} free or in the cyclodextrin content should not exceed 25% by weight of the total weight of the preparation ·

Inorganic or organic buffers may be used as buffering agents in the compositions of the present invention. Sodium acetate is highly preferred. Cetyl alcohol may be used as the nonionic thickening agent. Preferred emulsifiers are nonionic emulsifiers such as sorboxetane laurate. As the aerosol propellant, any propellant used in the preparation of pharmaceutical compositions, or a mixture of one or more such propellants and solvents, may be used. Preferred are various mixtures of halogenated hydrocarbons (freons), such as 4: 6 dichlorodifluoromethane / dichlorotrifluoroethane.

Any chemotherapeutic and / or antibiotic effective against Gram positive and / or Gram negative bacteria may be used in the preparation of the compositions of the present invention, such as primicin, sisomycin or doxycycline. Oxoacids - 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid - or 2-p-aminobenzenesulfonamido / -4-methyl-6 may be used as chemotherapeutic agents. - &quot; -nitro-2-fentylvinyl / pyrimidine, among others. Substances such as polyvinylpyrrolidone may be used as protective colloidal phenol. Glidants are materials used in tablet formulation to facilitate the rolling of the granules. Examples are stearin and alkaline earth metal stearates such as calcium and magnesium stearate. A preferred representative of these is polyvinylpolypyrrolidone. Foam stabilizers preserve the formed foam structure. Examples are cetyl stearyl alcohol and sodium isothionate coconut 2-tartaric acid ester. Sodium lauryl sulfate is preferably used as the wet wetting agent. Ceilard organic sa-31872762 and sodium bicarbonate are used in the preparation of effervescent tablets. The carbon dioxide gas produced during their reaction produces the foam. Preferably, medium strong solid organic acids are used which are sufficiently acidic to release carbon dioxide but do not cause etching in the vagina or uterus. The preferred representative of these is tartaric acid. THE . solid organic acid and sodium bicarbonate are suitably used in equivalent amounts. Preferably, the sugar is lactose.

The compositions of the present invention may be in the form of an emulsion, a spray or a solution or a tablet. '

The choice of formulation to be used for treatment will depend on the site of treatment and the purpose to be achieved. For example, adhesive, viscous emulsion or foam spray formulations are preferred for dilating the uterus. For such use, it is not necessary for the composition to contain an antibiotic or chemotherapeutic agent. These preparations adhere well to the uterus. Treatment of the uterine cavity requires that the composition uniformly covers the inner wall of the uterus. For this purpose, various foaming compositions are used. If a foaming tablet is selected, a small amount of water is added to form a foam and then delivered to the uterine cavity using a syringe. It may already be desirable to incorporate antibiotics and / or chemotherapeutic agents in these formulations to kill pathogens.

The emulsion formulations are conveniently formulated in doses necessary for a single treatment of an animal. They are conveniently packaged in plastic plastic containers which can also be used to apply the composition. The dispensing valve for the spray formulations should be configured to accommodate a plastic pipe attachment for delivering the formulation to the Draft.

During the treatment with the compositions of the present invention, it has been unexpectedly, and contrary to expectation, found to be useful in eliminating the cause of uterine inflammation that is beyond the control of other formulations, in repairing the inflamed uterine mucosa and in triggering an intermittent ovulation cycle.

These experiences are all the more surprising because, according to the literature, prostate-landins have an anti-inflammatory effect. The effect of several anti-inflammatory agents is based on their inhibition of prostaglandin synthesis in the body. Given these antecedents, it was not expected that PGP ₂ would be capable of controlling inflammation.

The reason for this unexpected phenomenon is probably that prostaglandin delivered to the uterus causes locally increased blood congestion, which increases the rate of removal of toxins accumulated in the inflamed area, and the increased oxygen and nutrient delivery to the inflamed area too. The facultative administered antibiotics and chemotherapeutics only supplement this anti-inflammatory effect.

The following experiments were conducted with the compositions of the invention.

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Examination of uterine dilator effect:

From the foam spray formulation of Example 2, foams of 5 ~ θ g were applied to 87 cows' bees (equivalent to 4.1-6.6 mg PGF _2X ). Examination of the animals showed that in 93% of the animals the uterus completely opened within 30-60 minutes after treatment and that the mucus plug which closed its a uterus was continuously dissolved. The opening of the cervix was incomplete in 7% of the animals, but again, it was sufficient to perform the intervention in the uterine cavity.

At 5-θ after treatment, the uterus of the animals closed spontaneously. Irreversible lesions were not detected in any of the cases.

Influencing Subclinical Uterus:

irregular cows with subclinical uterine catarrh at mid / late end of the sexual cycle, the result was the same / treated with a spray formulation into the uterine cervical duct. Symptoms completely disappear in 11 cases / within 5 days of ovulation /. In 5 cases the effect was not clear, in 9 cases it was not evident.

Influencing difficult calving;

a pregnant cow treated with a heavy calf was expected. The treatment consisted of administering to the uterus a quantity of spray formulation corresponding to 10 mg of PGF _2z active ingredient. In 22 cases, the use of the agent facilitated the delivery. The involution occurred relatively quickly, around day 20, the oestrus occurred regularly, and the conception results were above the average for the cow. In 7 cases the above treatment was ineffective / or not sufficiently effective.

Treatment of Pyometra:

animal was treated with 2x10 mg of PGF _{2 x} spray formulation into the uterine canal. / The second treatment took place 6-8 hours after the first. / In 9 cases, we observed a remarkably fast recovery and within 25 days of conception. In 6 cases the uterine emptying was smooth but the conception only occurred after 50 days. In 5 cases, no positive effects were observed.

Treatment of subinvolutionary disorders, metritis, uterine catarrh: · Cows were treated so that 20 of them were treated again after 12 hours. The treatment consisted of administering to the uterus of animals an amount of spray formulation corresponding to 10 mg of PGF- _{x by} catheter.

In 13 of the twice treated patients, the involution was completed quickly, the catarrhal process was abolished, the oestrus occurred within 25 days and the conception was within 50 days.

Of the 30 animals treated once, 14 had the above beneficial effect, and 16 had no or insufficient effect.

Honeybee involution in pig sows:

Studies were performed on 12,000 animals. We divided them into three groups of 40 individuals. The first group received treatment 12 hours after parturition, the second only if it was

-5182,762 had fever within 3 days, received one or two treatments (the last one needed 20 cases). Δ The third group received standard antibiotic bee treatment at the farm. The treatment was the delivery of the preparation to the uterus using a Melrose catheter.

Results:

Experiment Group 1 Doing Fertilization - Pregnancy Mean Forced

First group Second group Third group 75% 9.15 77.5% 9.00 67.5% 9.00

Further details of the invention are illustrated in the experimental examples without limiting the invention.

Example 1

Emulsion Preparation / for cervix /

Crystalline sodium acetate (260 g) was dissolved in water (5590 mL) and the resulting solution was filtered through a sintered glass filter.

In one third of the solution, 5 6 of the active ingredient PGF8 are dissolved (1 solution). 150 g of cetyl alcohol and 200 g of azorboxetane laurate are homogenized by heating in a water bath, the filtrate is filtered if necessary, and 2/3 of the previously prepared sodium acetate solution is heated to 5 ° C and stirred with the cetyl alcohol melt. mixed. The resulting mixture was stirred until cooled (solution II). The resulting solutions I and II are then mixed. The resulting emulsion formulation is filled into plastic plastic ampoules. Preferably, it is dispensed into 12 g single dose ampoules. Such an ampoule of 12 g contains 10 mg of PGF ₂ .

Example 2

Foam Spray Preparation / For Cervix /

120 g of the emulsion composition of Example 1 and 36 g of a 4: 6 dichlorodifluoromethane / dichlorotetrafluprethane mixture are filled into an aerosol can. An exemplary dose of the resulting hah spray formulation is sufficient to treat 10 animals. For better applicability, a plastic tube extension may be fitted to the valve of the bottle to facilitate the transfer of the foam to the uterus.

3 · Example

Combination tablets / for uterine cavity /

100 kg of oxolinic acid / 5 ~ ethyl ~ 5,8-dihydro-8-oxo-l, 3-dioxolo / 5,5-g7kinolin-7-carboxylic acid / 1500 g of polyvinylpyrrolidone and 1,500 g of ^this bt Arina were mixed, and the mixture It is granulated with a 1: 1 mixture of water and isopropanol. The granulate was squeezed and mixed with 37 kg of PGF? -? - cyclodextrin inclusion complex and 10 kg of polyvinylpolypyrrolodone. The resulting mixture was compressed into 1.5 g tablets. / Each tablet contains 370 mg of PGF-β-cyclodextrin inclusion complex and 1.0 g of oxolinic acid.

Example 4

Combination tablets / for uterine cavity /

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1000 g of polyvinylpyrrolidone and 1000 g of stearin are dissolved in isopropanol. A solution of 500 g of PGF 1 _{R in} 6 kg of a 1/3 molar solution of sodium acetate was also prepared. The two solutions were mixed and then 500 kg of oxolinic acid were granulated. The granulate was dried and mixed with 2.5 kg of polyvinylpyrrolidone and finally compressed into 550 mg tablets. One tablet contains 5 mg PGF _{20 <} 5 mg and 5 µp mg oxolinic acid.

Example 3

Intrauterine emulsion preparation

A solution of 53 »9 kg of distilled water and 2.6 kg of sodium acetate is prepared (1 solution). Dissolve 100 g of PGEn.x (solution 11) in 10 liters of solution I.

Sorboxane laurate (1.5 kg) and cetylstearyl alcohol (1.5 kg) were melted at about 50 ° C and the solution I, also heated to 50 ° C, was added. Stirring is continued until cool. At this time, solution II was added. The resulting emulsion is filled in 6 g portions into sterile plastic applicators. / Each 6 g dose contains 10 mg PGF _{2c <} /

Example 6

Intrauterine foam spray

120 g of the intrauterine emulsion formulation prepared in the previous example and 20 g of a 4: 6 dichlorodifluoromethane / dichlorotetrafluoroethane mixture are charged into an aerosol can. Preferably, the nozzle of the bottle is configured so that a plastic tube attachment for introducing the composition into the uterus can be attached thereto. The above foam spray formulation is sufficient for 20 treatments.

Transferring 1 portion of the composition into a 100 cc, wet dip roller, yields the following foam volumes over time;

time foam volume in cra'

0 pero 30 20 minute 50 50 minute 50 70 minute 55 120 minute 65

Foam characterizing the stability of the maximum volume / om 65 ^5/20 ° C is maintained even after four days.

Example 7

Intrauterine effervescent tablets in% ethanol are dissolved in 100 g of PGF ₂ , _X , 265 g of polyvinylpyrrolidone and 209 g of o-ethylstearylalkonol (1 solution).

630 g of sodium lauryl sulfate, 7 x 0 g of sodium isothionate coconut ester, 5 x 76 g of tartaric acid, 200 g of calcium stearate and 100 g of polyvinylpyrrolidone are blended (blend II).

Homogenization of 199 g of stearin, 486 g of lactose, 2487 g of sodium bicarbonate, 131 g of calcum stearate and 77 g of polyvinylpyrrolidone (Mixture III).

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Mixture IIa and III obtained as above are individually granulated with proportional portions of solution I, and the resulting granules are individually dried at 30-40 ° C and finally the dry granules are granulated. The granules obtained after regranulation are mixed and compressed into 1 g tablets. One tablet contains 10 mg PGP ₂ , ·. contains the active ingredient. ;

The lather performance of tablets were examined as follows: ⁵ 100 co-volume measuring cylinder was charged 10 cb 'distilled water, and then dropped into a tablet: The time is measured as a function of the measuring cylinder with the volume of the foam.

The following results are obtained:

time minute foam volume time minute foam volume in cn 'in cn'

1 55 12 103 2 58 35 100 3 56 75 86 4 63 90 72 5 76 105 67 6 83 120 59 7 89 135 55 8 93 160 53 9 96 180 44 10 98 210 32 240 28 THE preparations it is expedient to use such EEY Latvian 10 cc in ⁵ water and then the resulting foamy suspension is syringe into the uterine cavity.

Example 8

Spray preparation

1.00 g of PGF _{2 x} are dissolved in 12.5 S of anhydrous ethanol with gentle heating. The solution is filled into an aerosol flask and 35 g of dichlorodifluoromethane and 20 g of dichloro-tetrafluoroethane are added * and the flask is fitted with a dispensing valve. For better applicability, a metering valve is used on which a plastic tubing can be attached.

The spray formulation prepared in this example is sufficient for large-scale treatment of 100 cattle.

Claims (10)

Patent claims CLAIMS 1. A method for the preparation of a PGF-containing pharmaceutical composition for veterinary use, in particular for dilating the uterine mouth of a mammal and / or treating uterine stenosis, characterized in that 3-30 mg of free or β-cyclodextrin-enclosed PGFg / 0-1 g of buffer material 0-1 g of non-ionic pulp, 0-1 g emulsifier, 0-5 g chemotherapeutic and / or antibiotic, -8182.762 0-0.1 g of protective colloid, 0-0.1 g of lubricant, 0-0.5 g disintegrant, 0-0.5 g foam stabilizer, 0-0.1 g of wetting agent, 0-1 g of solid organic acid, 0-0.1 g sugar and \ Sodium hydrogen carbonate 0-1 is converted into a homogeneous mixture, tabletted to form rna d tablets in a manner known per se, or mixed with up to 15 g of water and up to 0.3 g of ethanol to form an emulsion, or as a spray blast, emulsion preparations; of the propellant is aerosolized with up to 5 δ propellant gas, with the restriction that the PGF _2x content, free or in the 0-cyclodextrin, in each case may not exceed 25% by weight of the total composition. / Priority: 1980. II. 2. A process for the preparation of a pharmaceutical composition containing PGF _2X for veterinary use, in particular for expanding the mammalian uterus and / or treating uterine inflammation. 3-30 mg of free or Q-cyclodextrin-encapsulated PGF _2x , 0-1 g buffering agent, 0-1 g of non-ionic thickener, 0-1 g emulsifier, 0-5 g chemotherapeutic and / or antibiotic, 0-0.1 g of protective colloid .... 0-0.1 g of lubricant, θ-0.5 S disintegrant, 0-0.5 g foam stabilizer, 0-0.1 g of wetting agent, 0-1 g of solid organic acid, 0-0.1 g sugar and ' 0-1 g of sodium bicarbonate are converted into a homogenous mixture, and then tableted to produce tablets per se known manner, or preparing ..... ¹ emulsion composition, the mixture is mixed no more than 15 g of water, or an emulsion composition obtained in the preparation of a spray formulation as described above prepared up to 5 propellants into aerosol formulations, with the restriction that the free or Q-cyclodextrin-bound PGFo-art litter should in each case contain up to 25% by weight of the total weight of the formulation * / Priority: 1979 · X 03 · / 3. A process according to claim 2, wherein the buffering agent is sodium acetate, nonionic thickener cetyl alcohol, emulsifier sorboxetane laurate, protective colloid polyvinylpyrrolidone, lubricant stearin or calcium stearate, polypyrrolidone, cetyl stearyl alcohol as foam stabilizer or sodium isothionate coconut spirate ether, sodium lauryl sulfate as wetting agent, tartaric acid as solid organic acid and lactose as sugar. / Priority: 1979 · X · 03 · / A process for the preparation of an emulsion composition according to claim 2 or 3, characterized in that 0.52 g of sodium acetate, 0.3 g of cetyl alcohol, 0.4 g of sorboxane laurate, 0.01 g per dosage unit are prepared. PGF ^ -.- t ® ³ Water (10.8 g) is formulated as an emulsion. / Priority: X.03.1979 · / 5. A process for the preparation of a foam spray formulation according to claim 2 or 3, characterized in that 0.52 g of sodium acetate, 0.3 g of cetyl alcohol, 0.4 g of sorboxane laurate per dosage unit are obtained. 0.01 g of PGFo? 10.8 g water 3, Using 6 g of spray propellant, we prepare it as a foam spray formulation. 6. A process for the preparation of a tablet formulation according to claim 2 or 3, characterized in that 0.37 g of PGF _2x -, i-cyclodextrin in inclusion complex per tablet is 1 g. 5-Ethyl-5,8-dihydro-8-O-OX0-1.3 ”dioxolo / 4,5-g / lll-7-carbonic acid, 0.015 g polyvinylpyrrolidone, 0.015 g stearin and 0.1 g polyvinylpyrrolidone into tablets. / Priority:, 379.x.03 · / The method according to claim 2 or 3, which is conceptual. A process for the preparation of a tablet formulation comprising 0.005 g of PGF-4, 0.5 g of 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo / 4,5-g7quinoline-7 per tablet. carboxylic acid, 0.01 g of polyvinylpyrrolidone, 0.01 g of stearin and 0.025 g of polyvinylpyrrolidone are prepared as tablets. / Priority: 1979.X.O3 · / 8. A process for the preparation of an emulsion composition according to claim 2 or 3, characterized in that 0.01 g of FGF per dosage unit is used _. 0, 0.26 g of sodium acetate. 0.2 g of sorboxetane laurate, 0.15 g of cetyl stearyl alcohol and 5.39 g of water are prepared as an emulsion. / Priority: 1979 · X.03 · / A process for the preparation of a foam spray composition according to claim 2 or 3, characterized in that 0.01 g PGF _{2 x} , 0.26 g sodium acetate, 0.2 g sorboxane laurate per dosage unit, 0.15 g of cetyl stearyl alcohol, 5.39 g of water and 1 g of spray propellant are prepared as a foam spray formulation. / Priority: 1979 · Χ · Ο3 · / Process for the preparation of a foaming tablet according to claim 2 or 3, characterized in that 0.01 g of PGFpx, 0.006 g of sodium lauryl sulfate, 0.0007 g of sodium isothionate coconut fatty acid are produced per tablet. ester, 0.57 g of tartaric acid, 0.03 g of calcium stearate, 0.02 g of polyvinylpolypyrrolidone, 0.02 g of cetyl stearylalkanol, 0.055 g of polyvinylpyrrolidone, 0.02 g of stearin? 0.049 g lactose, 0.25 g sodium bicarbonate are prepared as tablets. / Priority: 1979 · X 03/30 11. A process for the preparation of a spray composition according to claim 1, wherein 1.00 g of PGF 0 is dissolved in 12.5 g of anhydrous ethanol, followed by 35 g of dichlorodifluoromethane and 20 g of dichlorotetrafluoride. Ethane in Spray Preparation · 29 /