CS253424B1 - Agent for the regeneration of demaged tissue - Google Patents

Abstract

Veterinary product to be used to regenerate damaged tissue as granulans and epitalizans, dermatology and antiseptic. The formulation contains 1 wt parts 0.025 to 0.050 wt of the purified flavonoid complex propolis, 0.020 to 0.050 parts by weight pantothenic acid, 0.0003 to 0.010 % by weight of divalent zinc; podium excipients of the pharmaceutical form type. The formulation is preferably used for the exterior application directly as a solution, spray or ointment in traumatology, on early surgery after the rubble, at castration of pigs, at various dermatitis, otitis, gingivitis, periodontitis and tonsillitis.

Description

The invention relates to a composition for the regeneration of damaged tissue such as granulants and epithelizants, as well as a dermatological and antiseptic in veterinary medicine.

In the traumatology of wounds in surgical-orthopedic practice, a large number of medicinal products are used. Natural factors that interfere with the process of wound healing speed include, in addition to oxygen, vitamin C and amino acids, the natural product of bees - propolis, pantothenic acid and scar, although the mechanism of their action while so far! is not known.

Most of all bee products have recently been studied as to the origin, production, composition and therapeutic effects of propolis, both in the field of human and veterinary pharmacology. Propolis is generally attributed to antibacterial, anti-inflammatory, regenerative and keratoplastic effects. The pharmacological spectrum and efficacy of propolis is greatly expanded in conjunction with other active scavengers.

Propolis is a bituminous substance obtained and processed by bees from the extracts of buds, leaves and bark of some deciduous and coniferous trees. Bees use propolis as a water repellent, as a preservative and also for its phytoinhibitory effect.

The development of propolis characteristics is closely evident with the development of analytical and physico-chemical methods in the first and second half of our century. The composition of propolis is variable. It is generally reported to contain about 30% waxes, 50 to 60% resins and balsams, 10 to 12% essential oils, and about 5% pollen and mechanical impurities.

The richest component of propolis is represented by flavonoids, of which more than 20 have been described in propolis so far and are the most studied because of their antimicrobial activity.

Lejeune B. et al. 56, IV-V, 1984} have identified those flavonoids as the main representatives of the active ingredients of propolis that have been qualitatively and quantitatively demonstrated in all samples of native propolis from different geographical areas. These are: pinocembrin, quercetin, chrysin, galangin, and toctochrysin.

Among the biological properties of propolis, the greatest interest was in its autibacterial and antifungal effect. From the results achieved, it is possible to generalize that gram-positive bacteria are particularly sensitive to propolis, while! Which gram-negative react less. Acid-resistant bacteria and fungi are also susceptible to propolis (Lindenfelser, L. A., Antimicrobial activity of propolis. Am. Bee, J. 107, 3, 90-92, 130-131, 1967). Propolis extract has also been found to potentiate 10 to 100 fold the effect of antibiotics - penicillin, streptomycin, tetracycline and neomycin on Staphylococcus aureus and Escherichia coli (Kivalkina VP et al. 2nd International Symposium, Bratislava, 1976, 98-102).

Furthermore, propolis has been found to strongly activate liver cell mitosis and also to increase their metabolic activity (Scheller S. et al., BiologiGal properties and clinical application of propolis. Arzneim. Forsch., 27, 4, 1977, 889-890).

The rich presence of flavonoids in propolis and the knowledge of the cytotoxic activity of some methoxy flavonoids led to the detection of the cytostatic activity of some propolis extracts in vitro on 1'human KB and Hela cell cultures. Diethyl ether extract has been shown to be cytotoxic extract (Ban J. et al .: Cytostatic effects of propolis in vitro. Acta Pharm. Jugosl., 33, 1983, 3 - 4; Wojtaszek M. et al .: Recognition and Research of Cytostatic Storage Fractions eterowej propolis DEEP (Herba Polonica 28, 1982, 1-2).

In relation to immunological processes, Kivalkina V. P. (Effect propolisa dlja immunologically denotes reactivity. In: 22. Int. Beekeep. Congr. Sumn., 1969, 136) enhancement of immunological activity in experimental animals using Salmonella enteritis antigen in propolis / polyethylene glycol mixture. In particular, an increased population of B and O lymphocytes points to the adjuvant properties of propolis.

In addition, the known and exploited effect of propolis on the treatment of superficial injuries is based on its antimicrobial effects and regenerative sepsis.

The first propolis medicinal products are in the 12th century for the treatment of other oral and throat inflammations and for dantal purposes. But only the 20th century has been investigating the pharmacological efficacy of propolis in relation to its composition.

Good therapeutic results with stick propolts obtained in experiments already in veterinary medicine. Thus, Sutta J. et al. (Experimental and clinical experience in the treatment of wounds in domestic animals by topical application of propolis alcohol solution. Folia veter., 18, 1-2, 143-147, 1974) investigated the effect of propolis extract on healing experimentally with the treatment of wet skin inflammation as well as dermatltide. of Roses etiology in dogs (Sutta J. et al .: Experimental and clinical experience in the treatment of wounds of domestic animals by topical application of propolis alcohol solution. In: Proceedings of Ref. I. International Propolis Symp., Bratislava, 1972, 53-57). The author points to the intensive epitalizing effect of propolis. Good experience with propolis is reported by Orság A. et al. (Experience with the use of propolis in traumatology of the locomotor system in cattle. In:

Zborník ref. II. medzinár. Symp. on Propolis, Bratislava, 1979, 229-231] in skin and subcutaneous tissue injuries, pressure sores and excorations. Stojko A. and Furewicz A. J. f Progress of propolis ecstract in otitis externa therapy in dogs. Medycyna wet., 36, 1980, 110-113 J laboratory and clinically investigated the effect of propolis extract on dogs with external ear canal inflammation while investigating bacteriological culture findings. The results were 90% very good.

Pantothenic acid has a specific effect on goat and mucous membranes. It improves granulation, accelerates epithelization and thus promotes wound healing. These findings led to its clinical use, respectively. exploiting the properties of its selenium and panthenol alcohol,

In 1959 experiments by Stuttgart and Krause (Die Perkutane Absorption of Tritium Markierten Panthenol bei Mensch und Tier. Arch. Klí. Exp. Derm., 209, 1959, 578-580) with tritium-labeled panthenol proved that panthenol was very well resorbed by goat both humans and animals. In fact, panthenol is provitamine, which as a primary alcohol in the body is oxidized to pantothenic acid. Pantothenic acid functions in the body as a prosthetic group of coenzyme A, which has an important role in the overall metabolism and is an essential catalyst in the acetylation processes and the synthesis of protein polypeptides. It is a substance required for normal tissue function. Its deficiency leads to metabolic disorders, which manifest themselves as a disruption of the epithelium and a decrease in the resistance of the mucous membranes to infections.

Dworacek H. (Bepanthen ais Hautscbutz bei Rontgenschadigungen. Strahlentherapie 41, 1953, 643-646) treated the skin after irradiation with X-ray massage containing 5% panthenol and later used panthenol spray formulations. Matanic V (Die Behandlung der Geschwure der Epidermis mit Panthenol Jenapharm. Zschr. Arztl. Fortbild., 65, 1962, 680-682) compared the effect of panthenol in the diagnosis of ulcera cruris. Similar Combes and Zuckerman (Panthenol. Its topical use in cutaneous ulcerations. J. of Invest. Dermatol., 16, 1951, 379-381) speak of exceptionally good healing and promote the tolerance of panthenol ointment in pyoderma and ulcerations of various episodes. In addition, they recommend the use of panthenol-containing preparations in burns, infected surgical wounds and pressure sores. They conclude that panthenol alleviates soreness, reduces erythema response and wound secretion, while accelerating epithelization and tissue separation. Very good experience with the use of Panthenol-spray produced by Jenapharm in the GDR is described by several authors. Becker and Flex (Uber die Anwendung des Panthenol Spray Jenapharm bei der Behandlung von Oberflachenwunder der Haut. Zschr. Arztl. Fortbild., 60, 1966, 808-812) used this preparation in the treatment of grade 1 to 3 burns, except tobo in the treatment of skin damage of various origins. Huth W. (Die Behandlung von Wunden verschiedener Genese mit dem Panthenol Spray Jenapharm. Zschr. Arztl. Fortbild., 65, 1967, 680-682) used Panthenol Spray in the treatment of burns, acid burns and ulcers and insollation by UV rays.

Zeibig H. (Experience with Panthenol Foam Spray Jenapharm in Sports-Medical and Clinical Practice, Bas Deutsche Gesundheitswesen 23, 1963, 2,147-2148) reported on the experience of sports-medical practice. All authors evaluate panthenol as a very good therapeutic agent for superficial skin injuries.

The effect of zinc on the quality and speed of healing of natural and experimental wounds in humans and animals has been studied by many authors. Zinc oxide, zinc sulphate or zinc stearate are used to accelerate wound healing in different mixtures and dusting, and it is likely that some of the zinc is adsorbed through the goat and especially through the injured tissue.

Strain et al. (Zinc studies in skin repair. Surg. Forum, 11, 1969, 291) reported that dietary supplementation with zinc with methionine significantly improves and accelerates wound healing in rats. The high content of zinc ions in rado dehydrogenases (glutamate dehydrogenase, lactate dehydrogenase), in - d 'e, carboanhydrase and other enzymes speak. on the importance of zinc in the wound healing process. The lack of this trace element wounds healing, but the mechanism of this effect is unknown with certainty (Schilling: Wound healing. Physiological Rewiews 48, 1968, 374-423; Musil: Fundamentals of Biochemistry of Disease Processes, Avicenum, Prague, 1981, 286).

In rat experiments, Rahmat et al. (J. J. Surg. 61, 1974, 271-273) found that there was a significant difference in the length of healing of experimental wounds in zinc deficient animals, but that histologically no differences were found between experimental and control animals. groups. Authors in agreement with others, eg. Ober-Iaes et al. Am. J. Surg., 121, 1971, 566-568, suggests that the slowing of wound healing may be due to a deficiency in zinc-dependent enzyme activity.

Recently, local absorption of zinc from wounds treated with zinc salts has been the subject of recent work by Halmans (Local absorption of zinc from wounds treasure wound defferent concentraions of zinc sulpha. Acta Dermatovener., / Stockholm / 58, 1978, 413 419; Acta Dermatover, (Stockholm, 58, 1978, 251-253), which applied zinc sulfate locally to the wound. Andermann and Diets (The bioavailabi253424 liters and pharmacokinetics of three zinc salts: zinc pantothenate, zinc sulphate and zinc orotate. Eurapean J, Drug Metabolism and Pharmacokineteics, 7, 1982, 233-239) applied parenterally and orally pantothenate, zinc sulfate and orotate. . The conclusions from these papers speak of increasing the concentration of zinc in serum and liver depending on the concentration of applied salt on the wound. The pharmacokinetic study demonstrated the biological equivalence of two soluble zinc salts: pantothenate and sulfate. The plasma concentration of insoluble zinc orotate showed lower levels and a slower absorption phase after oral administration. The work also draws attention to the fact that there is no correlation between the solubility of these zinc salts in vitro and the parameters found in vivo.

Dermatological preparations based on zinc (most often in the form of zinc oxide) are official components of pharmacopoeias (ČsL 3), but they are also abundant among mass-produced medicinal products intended for human and veterinary medicine (Pityol Spofa, Unguentum zinci oxidati —- etc.).

Propolis has a wide range of pharmacological efficacy, but it seems likely that for each indication area a specific treatment of propolis will be needed both in terms of excipients and in addition to its efficacy.

Propolis-based preparation intended for regeneration of damaged tissue, resp. wound healing in veterinary medicine, supplemented with pantothenic acid, zinc and adjuvants for this area of indication, adapted to appropriate dosage forms. The preparation is standardized for flav-onoids, panthenol and zinc. During clinical trials and production, it was adapted into three dosage forms: solutio, spray and unguentum. In this formulation, it is expected to be of use in veterinary medicine in the treatment of orthopedic and surgical injuries, particularly in the granulation and epithelialization stages, such as antiseptic and disinfectant after tail amputation, castration, further for the treatment of dermatitis, otitis, gingivitis, periodontitis and tonsilitis.

The composition according to the invention contains, in 1 part by weight, 0.025 to 0.050 parts by weight of purified complexluflavonoids, 0.020 to 0.050 parts by weight of pantothenic acid, 0.0003 to 0.010 parts by weight of divalent zinc and excipients according to the dosage form.

The composition according to the invention is used for external application directly as a solution, spray or ointment, also using a cotton swab for the preparation of compresses. The solution is applied to the place of attachment by dripping with a dropper or syringe with needle. The spray form is used for application from a distance of 15 to 20 cm, it is desirable to repeat the application 2-3 times after drying to form the cover film. The ointment is applied in a thin layer to the wound with the dressing applied. The tolerance of the product in veterinary medicine is good.

Execution example no. 1

The flavonoids from propolis are obtained by ethanol-ol extraction. Native propolis, cooled to 0-10 ° C and homogenized to a particle size of 1 to 5 mm, is 96% ethanol at 0-10 ° C in a 1: 5 ratio (1 part by weight of propolis and 5 vol. parts of ethanol). The extraction of propolis with ethanol is carried out for 5 to 7 days at 0 to -10 ° C with occasional stirring. After extraction, the ballasts are separated from the propolis solution by filtration or centrifugation. For the uniformity of the contents, extraction is carried out in proportions such that at least 100 liters of extract are obtained. In the homogenized extract, the content of flavonoids is determined and, if necessary, adjusted to a minimum of 15 g per 100 ml of extract - by best concentration of the extract at a temperature not exceeding + 50 PC

The concentrated propolis extract thus obtained, comprising a purified flavonoid complex of 15 g per 100 ml, is mixed with a zinc chloride solution in propylene glycol and panthenol in such a proportion that the finished preparation contains 0.025 parts by weight of the purified flavono20 propolis complex in 1 part by weight. parts of pantothenic acid and 0.0003 parts by weight of divalent zinc and 0.20 parts by weight of ethanol. The mixture was enriched with menthol in an amount of 0.001 parts by weight and supplemented with propylene glycol. After technological inspection, the finished preparation is filled into glass or polyethylene containers.

Execution example no. 2

Native propolis, cooled to 0-10 ° C and homogenized to a particle size of 1 to 5 mm, is quenched with 1: 5 96% ethanol at 15-25 ° C. Extraction of propolis with ethanol takes place for 5-7 days at 15 to 25 PCs in the dark with occasional agitation. After this extraction, the entire contents of the extracted mixture are stored at -20 to -30 ° C for 24 hours. After this time, the extract is filtered or centrifuged at min. —20 ° C to remove ballasts. In case of further loss of ballasts, it is necessary to repeat the process of freezing the extract and separating the ballasts. In the purified and homogenized extract, the flavonoid content is determined and adjusted to min. 15 g per 100 ml of extract by vacuum concentration of the extract. Thus, 254242 extract of propolis containing a purified complex of flavonoids propolis 15 g per 100 ml is mixed with a solution of zinc chloride in propylene glycol and panthenol in such a ratio that part by weight 0.050 wt. parts of the purified propolis flavonoid complex, 0.050 wt. parts of pantothenic acid, 0.0009 wt. % of divalent zinc and 0.20 wt. works of ethanol. The mixture is enriched with menthol in an amount of 0 001 wt. works and supplemented with propylene glycol.

Execution example no. 3

The purified and homogenized propolis extract prepared according to Example 1 or 2 is preferably concentrated in a vacuum cdpark at a temperature not exceeding 50 ° C so as to completely remove the ethanol. The thickened propolis extract is then dissolved in castor oil at a ratio of 2: 1 (to two parts by weight of the propolis extract, 1 part by weight of castor oil) and the flavonoid content is determined in the mixture. The thickened propolis extract in castor oil is mixed with zinc oxide and panthenol in such a proportion that the finished preparation contains 1 wt. % 0.025 wt. parts of the purified propolis flavonoid complex, 0.020 wt. % of pantothenic acid and 0.006 wt. works of bivalent zinc. The homogenized mixture is treated with sunflower oil and beeswax in such a proportion as to obtain an oily consistency dosage form.

Evaluation of the efficacy of the preparation of the invention.

Clinical verification of the preparation of the invention was performed under experimental conditions and in veterinary practice at high concentrations of animals by application to sites of excursions and pressure sores in goat locomotion and in veterinary hospitals and treatment rooms.

The evaluation of the preclinical studies followed in experimental animals gave an overview of the effects of the preparation according to the invention in three base forms in traumatology of wounds with substance loss in wound healing per secundam intentionem. All three dosage forms had a positive effect on the rate of wound healing. Positive evaluation under experimental conditions was also achieved in clinical trials under veterinary practice.

The results obtained in the traumatology of wounds are positively evaluated for the effect of the preparation according to the invention on the regenerative ability, with the granulation and epithelialization phases being highlighted in the direction of a faster healing process. its application is particularly advantageous at the stage of reduced wound suppuration. The therapeutic success is evident both in a comparative clinical trial, as opposed to a pure propolis spray formulation, and in a greater number of clinical experimental trials.

Based on the results of the clinical investigation, it is recommended to use the preparation of the invention in veterinary practice for the following diagnoses:

- early (especially superficial, low suppuration - dermatitis, excorations, otitis externa - gingivitis (wider application in dental practice) - application in pigs after tail amputation - application after castration of animals.

The efficacy of the preparation of the invention is documented by the evaluation of clinical efficacy in veterinary practice and by the following graphs and tables:

In FIG. no. 1 is a graphical representation of wound healing with substance loss after application of a bovine animal.

In FIG. no. 2 shows the dynamics of haematological values in the treatment of wounds after application of the preparation in bovine animals.

In table no. 1 shows the results of histopathological examination.

In table no. 2 shows the effect of the preparation in the treatment of surgical diseases of horses in terrain conditions.

In table no. 3 shows the effect of the preparation in the treatment of surgical diseases of bovine animals in field conditions.

In table no. 4 shows the effect of the preparation in the treatment of surgical diseases of dogs under field conditions.

In table no. 5 shows an overview of wound healing in bovine animals following application of propolis spray, a spray formulation of the invention and 3% H2O2.

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Table no. 2

The effect of the preparation in the treatment of surgical diseases of horses in field conditions

P. č. age diagnosis Used product The length treatment result First 2 years Dermatitis in subreg. ph. prox. m. PELV. sin. spray 7 days reformed Second 2 years Dermatitis in subreg. ph. prox. m. PELV. dx. Ointment 7 days reformed Third 1 year Dermatitis in subreg. ph. prox. m. PELV. dx. Ointment 7 days reformed 4th 1 year Dermatitis in subreg. ph. prox. m. thor. dx. Ointment 7 days reformed 5th 2 years Dermatitis in reg. interscapularis et reg. dorsum unguentum + spray 13 days reformed 6th 1 year Dermatitis in reg. interscapularis et reg. dorsum unguentum + spray 13 days reformed 7th 2 years Dermatitis in reg. interscapularis et reg. dorsum unguentum + spray 13 days reformed 8th 2 years Dermatitis in reg. interscapularis et reg. dorsum unguentum + spray 13 days reformed 9th 3 years Vulnus sectum metatars sin. Ointment 16 days reformed 10th 7 years Vulnus sectum pectoralis spray + solution 18 days reformed

Table no. 3

The effect of the preparation in the treatment of surgical diseases of bovine animals. cattle in field conditions

P. č. Age Diagnosis Product used Length Treatment outcome

First 6 years Vulnus laceratum cruralis dx. Ointment 21 days reformed Second 5 years Vulnus laceratum mammae Ointment 9 days reformed Third 4 years Vulnus laceratum mammae Ointment 9 days reformed 4th 4 years Vulnus laceratum mammae Ointment 12 days reformed 5th 7 years Vulnus laceratum mammae Ointment 12 days reformed 6th 6 years Status post sec. caesaraea solution 12 days reformed 7th 5 years Pododermatitis purulenta supers. digit. IV. m. PELV. dx. solution 18 days reformed 8th —5 years Decubitus in reg. femoralls lat. prox. sin. Ointment 10 days reformed 9th 4 years Keratitis profunda Ointment 14 days reformed 10th 2,5 years Pododermatitis purulenta Ointment 14 days reformed

superf. digit. IV. m. PELV. sin.

T a b u 1 'k a no. 4

Effect of the product in the treatment of surgical canine diseases used agent in terrain Dížka treatment conditions The result P. č. age diagnosis First 4 years Dermatitis interdigitalis m. PELV. dx. spray 8 days reformed Second 8 years Gingivitis, paradontosis solution - after application, recession of inflammation, recurrence Third 3 years Dermatitis in reg. dorsus spray 10 days reformed 4th 8 mes. Dermatitis madidans in subreg. ph. prox. digit. IV. m. PELV. dx. solution 22 days reformed 5th 2 years Vulnus laceratum thoracalis spray 13 days reformed 6th 2 years Vulnus laceratum femoralis lat. sin. spray ’18 days reformed 7th 3 years Vulnus laceratum and reg. femoralis lat. sin. spray 16 days reformed 8th 2 years Phlegmon in reg. paraanalis spray 11 days reformed

Cont. tab. no. 4

Count ks age diagnosis agent Length treatment The result 20 1 - 10 years Dermatitis madidanS spray 10 - 20 days 30% relapse 6 1-10 years Dermatitis interdigitale spray 10 - 20 days 50% relapse 5 1 - 10 years Otitis externa spray 10 - 20 days 40% relapse 1 4 years Dermatitis erythemat. solution 9 days reformed 1 3 months Dermatitis purulenta solution - unresolved 1 3 years Dermatitis erythemat. solution + + spray 14 days reformed 1 6 months decubitus solution 22 days reformed 1 2 years Dermatitis máddans solution - unresolved 1 2 years Unhealed wound after sec. caesaraea spray purulence unresolved

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Claims (3)

SUBJECT A composition for the regeneration of damaged tissue, dermatological and antiseptics in veterinary medicine, characterized in that 1 wt. the part contains 0.025 to 0.050 wt. % of purified flavonoid propolis complex, 0.020-0.050 wt. % of pantothenic acid, 0.0003 to 0.010 wt. parts of divalent zinc and vehicle over the desired dosage form. 2. The composition of claim 1 INVENTION is that for solution and spray formulations, ethanol and propylene glycol are used as the vehicle in a ratio such that the specific gravity of the formulation is in the range of 0.9940 to 1.0240. 3. The composition of claim 1, wherein the ointment formulation is a vegetable oil and beeswax in a ratio to form a topical gel formulation. 2 sheets of drawings Vefbosf early in the head