Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/05—Dipeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the invention is referred to the field of biologically active compounds and may be used to produce vulnerary medicinal preparations for treatment of skin damages, wounds, burns and skin diseases, method of its production.
• Cutaneous scarring Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation. J Am Acad Dermatol. 2012, Vol.66(1), P.1-12.; Elliot D, Sierakowski A. The surgical management of painful nerves of the upper limb: a unit perspective. J Hand Surg Eur Vol. 201 1 Vol.36(9),P.760-770). However, it should be noted that in this case the efficiency of proposed therapy depends not only on correct choice of medicinal preparation, but also on the form in which it should be applied (Endorf FW, Ahrenholz D. Burn management. Curr Opin Crit Care. 201 1 Vol. 1 (6), P.601-605).
• Nonsteroidal anti-inflammatory preparations reduce exudation, suppress tissue proliferation, analogize and reduce temperature. Their disadvantage is high toxicity.
• Steroidal anti-inflammatory preparations are similar to glucocorticoids. By the efficiency of anti-exudate effect they predominate over nonsteroidal antiinflammatory preparations several times, but they do not have analgetic and antipyretic action, and in case of long-term application they cause disorder of endocrine profile of the organism. Also antimicrobial preparations are applied, but they facilitate allergization of the organism, development of stabile wound microflora and dysbacteriosis.
• enzyme preparations proteinase, trypsin, chymotrypsin, amino acids and other
• Complex action on wound is provided by medicinal preparations of vegetable origin by virtue of content of the complex of flavonoid compounds and vitamins, but they do not have analgetic action (Mendonca Machado N, Gragnani A, Masako Ferreira L. Burns, metabolism and nutritional requirements. Nutr Hosp. 201 1 Aug;26(4):692-700; Lloyd EC, Rodgers BC, Michener M, Williams MS. Outpatient burns: prevention and care. Am Fam Physician. 2012 Vol.85( 1 ), P.25- 32).
• Vulnerary and anti-inflammatory preparations in a form of creams and ointments containing active agent, oily base (mixture of lanolin and vaseline) and additives are well-known.
• vaseline-lanolin base in these medicinal preparations prevents normal gas exchange reducing wound healing activity of the preparation, especially in case of smoldering processes (Profyris C, Tziotzios C, Do Vale I. Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation. J Am Acad Dermatol. 2012, Vol.66(l ), P. l -12.).
• Efficient forms of vulnerary preparations are gels.
• Polysaccharides such as galactomannan or glucomannan or alginic acids or alginic acid salts or agar-agar or hyaluronic acid or gelatin or pectin or aerosol or zeolites or collodion or 1,2 propylene glycol, may be used as gelatinization agents (Elliot D, Sierakowski A. The surgical management of painful nerves of the upper limb: a unit perspective. J Hand Surg Eur Vol. 201 1 Vol.36(9),P.760-770).
• Vulnerary medicinal preparation "Methyluracil liniment" (RF patent No. 2007997, prior, dated 08/07/92, A 61 K 9/06) containing ⁇ -form of methyluracil as an active agent, and castor oil as a base, is well-known.
• the preparation has increased wound-healing activity due to high bioavailability of the pharmaceutical form.
• the active agent in this medicinal preparation does not have anticontagious and interferon inducing properties, which does not allow healing of infected wounds.
• the object of this invention is to create the preparation devoid of abovementioned disadvantages; herewith the technical result achieved during implementation of this object consists in production of efficient anti-inflammatory, vulnerary and analgetic preparation for external use.
• dipeptide with general formula Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC2H5 as an anti-inflammatory, antibacterial, vulnerary, regenerative, analgetic and burntreating preparation, as well as the pharmaceutical form containing dipeptide with general formula Tyr-Pro- X where X- OH, N3 ⁇ 4, OCH3, OC2H5 as active agent, applied as anti-inflammatory, antibacterial, vulnerary, regenerative, analgetic and burntreating product, is claimed;
• preferable but unessential embodiments of the pharmaceutical form provide its embodiment in a form of one of the following pharmaceutical forms: ointment, gel, liniment, spray, suppository, plaster, orally disintegrating tablets and drops.
• Example 7 For 100 plasters: 5 g of the substance with peptide structure Tyr-Pro-X where X - OH, NH2, OCH 3 , OC 2 H 5 are introduced into the mixture consisting of 9.72 g of poli(DL-lactide) and/or poly(DL-lactide-co-glycolide) with molal weight 50,000 Da and correlation 50:50 with 1.0 g of stabilizer (sodium benzoate) in 60 ml of chloroform. The mixture is thoroughly stirred and poured in a thin layer, after that it is dried with warm air up to complete elimination of organic solvent. Obtained film is combined with tissue base. The preparation is used as a plaster containing 1 -50 mg of the substance of peptide nature Tyr-Pro-X where X - OH, NH 2 , OCH3, OC2H5.
• Example 8 For 100 orally disintegrating tablets: tablets were produced by means of direct compression of the mixture containing 1 g of the substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH3, OC2H5, and 20 g of combined filler "Ludiflash" on the tableting press.
• Example 9 For 100 orally disintegrating tablets: tablets were produced by means of wet granulation of the tableting mixture containing 1 g of the substance with peptide structure Tyr-Pro- X where X - OH, NH 2 , OCH 3 , OC 2 H 5 and 20 g of combined filler "Ludiflash".
• Example 10 For 100 orally disintegrating tablets: tablets were produced by means of dry pelletizing of the tableting mixture containing 1 g of the substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC 2 H 5 and 20 g of combined filler "Ludiflash”.
• the preparation is used in a form of nasal drops containing 0.01 - 10 mg of the substance of peptide nature Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC2H5.
• Example 13 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH3, OC2H5 in the formalin test in order to identify analgetic and anti-inflammatory activity.
• Acute inflammatory response was caused subplantarly (under plantar aponeurises) by means of introduction of 50 mcl of 5% formalin.
• Number of pain reactions was registered (tapping on the floor with a paw, gnawing of a paw, etc.) within first 5- 10 minutes - 1 phase (action on primary pain afferents) and from 30 th to 50 th minute - II phase (pain occurred as a result of inflammatory response) (Bannon et al., 1998).
• Reliable reduction of the number of pain reactions in the test group in relation to the control group was considered to be the criterion for analgetic effect.
• Test specimens (specimen 1 - ointment 5%, specimen 2 - gel 10%) were applied to the paw simultaneously with introduction of formalin in male outbred rats with weight of 200-300 g. Dermatic preparation without active agent was applied to control animals. Obtained results are represented in table 1.
• the preparation for external use containing original substance with peptide structure Tyr- Pro-X where X - OH, N3 ⁇ 4, OCH3, OC2H5 has analgetic and anti-inflammatory action in formalin test.
• Example 14 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where OH, NH 2 , OCH 3 , OC2H5 when molding thermal burn.
• Example 15 Studying of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, N3 ⁇ 4, OCH3, OC2H5 in molding of dermal wound.
• Dermal wound was molded on chinchilla rabbits with weight of 2.8-3.2 kg. In order to mold the wound the area of soft tissues on rabbit hips was shaved, and the incision 1 cm in depth and 5 cm in length was made with lancet. After that the study was performed in three animal groups. In the first (control) group the treatment was not performed. In the second (test) group treatment was performed with the preparation for external use in a form of ointment without active agent produced according to the prototype. In the third (test) group treatment was performed with the preparation for external use in a form of ointment with the concentration of active agent 5.0 % wt.
• the efficiency of preparations in test and control groups was evaluated according to crust rejection time, wound cleansing of purulonecrotic masses, time of granulation tissue onset in the wound and initiation of acentric epithelialization according to dynamics of inflammatory process regress, as well as according to dynamics of wound bacterization.
• Example 16 Study of the preparation for external application containing original substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH3, OC2H5 in the test of neurogenic pain syndrome caused by sciatic nerve transection as a mold of neuropathic pain in order to identify analgetic and anti-inflammatory activity.
• Intensity of autotomies was evaluated according to 11 -point scale: 1 point - damage of 1 claw; 2, 3, 4 and 5 points - damage of 2, 3, 4 and 5 claws; 6 points - damage of maniphalanx of one finger; 7, 8, 9, and 10 points - damage of maniphalanxes of 2, 3, 4 and 5 fingers correspondingly; 1 1 points - damage of instep bones. Pain syndrome development dynamics in rats of test and control groups was observed within 25 days (G.N. Kryzhanovsky et al., 1991).
• Example 17 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, N3 ⁇ 4, OCH3, OC2H5 in the patient E, 68 years old. In the patient pyogenic acne on the face near the nose were diagnosed. The preparation for external use in a form of ointment was applied to all damaged skin areas. On the next day after single application light crust formed; it could be easily eliminated. No traces of wounds remained on the face.
• Example 18 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC 2 H 5 in the patient A, 58 years, with burn.
• the trauma was civilian. Hyperemia, cutaneous edema and big continuous blisters with contents were observed.
• On the next day after application of the preparation for external use in a form of gel significant reduction of hyperemia and almost complete absence of edema and content of blisters were observed.
• the preparation was applied for 5 days.
• Example 19 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC 2 H 5 in the patient T., 56 years old, with burn. The burn of I, II degree of the backside of left forearm in the area of fist, 20 cm 2 , with hot vapor was diagnosed in the patient. The trauma was civilian. Hyperemia, cutaneous edema and big and small blisters with contents were observed. The preparation was applied for 3 days.
• Example 20 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC 2 H 5 in the child S., 6 years old. Hyperemic scabrous plaque 1 cm 2 that remained for 7 days was diagnosed on the right hip of the child in the area of contact with the elastic webbing. On the next day after application of the preparation for external use in a form of ointment the plaque disappeared and never appeared again.
• Example 21 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC 2 H 5 .
• Example 22 Study of the preparation for external use containing original substance with peptide structure Tyr-Pro-X where X - OH, NH 2 , OCH 3 , OC 2 H 5 .
• the patient K. 45 years old. On the left elbow there was a hyperemic plaque 3 cm 2 that remained for long period of time. The patient addressed to medical institution on several occasions, but no results were observed. Two days after single application of the preparation in a form of plaster the plaque disappeared and never appeared again.

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• Health & Medical Sciences (AREA)
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• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
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• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Dermatology (AREA)
• Gastroenterology & Hepatology (AREA)
• Immunology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Epidemiology (AREA)
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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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• 2012
  • 2012-08-03 RU RU2012133274/15A patent/RU2517213C2/ru not_active IP Right Cessation
• 2013
  • 2013-07-19 WO PCT/RU2013/000625 patent/WO2014021737A1/en active Application Filing

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