Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • 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
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention addresses the use of pharmaceutical composition for topical corticosteroid and/or hormonal steroids in association with proteolytic diffusing enzyme, whether or not in the presence of non-hormonal anti-inflammatory agents, for treatment of phimosis.
• the invention scope includes the pharmaceutical industry, prescription compounding services, and physicians.
• Phimosis is more often suspected than actually found. What most frequently happens is an adhesion of the prepuce and the glans, which will detach normally from each other over time. Typically, the prepuce will not retract at birth, but this condition is often resolved within the initial four years of age. As the penis gets larger, epithelial debris will build up under the prepuce and eventually separate the prepuce from the glans. In countries where circumcision is not performed commonly, treatment is seldom found to be necessary. Spontaneous improvement comes with maturity.
• Phimosis is a vague term used commonly, and it generally means a condition in which the penis skin cannot be retracted. Rickwood described as true phimosis the presence of a whitish sclerotic ring keeping the prepuce from retracting. Studies conducted in the United Kingdom show that physicians are not trained to distinguish the normal development of preputial adhesions from pathologic phimosis. This indicates that normal development is improperly classified as phimosis. As a result, a large number of unnecessary circumcisions is performed.
• Another article also describes infant treatment using topical application of 0.05 percent betamethasone cream: Conservative Treatment of Phimosis in Children Using a Topic Steroid by Orsola A, Caffaratti J, Garat JM, Urology (Online), 56 (2): 307-10, 2000 Aug l.
• steroids for topical phimosis treatment there is a number of types of steroids, in the form of 0.5 percent betamethasone creams, 1 and 2 percent hydrocortisone, and 0.05 percent betamethasone, 0.05 percent clobetasol, corticoid together with HCG injection, 0.05 percent betamethasone, 0.1 percent strogen; 1 percent hydrocortisone, etc.
• Kirikos et al (Kirikos CS; Beasley SW and Wood AA, The Response of Phimosis to Local Steroid Application, Pediatric Surgery, 1993, 8:329-332), showed improvement in around 80 percent using 2 percent hydrocortisone. There are no reports of local or systemic adverse effects (the corticoid absorption surface is as small as 0.1 percent of the body). These studies involved groups of patients with median of age around 6 years (2-15 years).
• the invention is intended to develop a new composition for topical treatment of phimosis to help the prepuce detach from the glans by impacting the depolymerization of the hyaluronic acid of the conjunctive tissue between both structures, so that a reduction can be achieved in the resolution time, side effects, effectiveness, and total treatment costs by using corticosteroids either or not associated with hormonal steroids, or non-steroidal anti-inflammatory agents and proteolytic diffusing enzymes.
• This invention resulted in resolved phimosis in 90 percent of the patients between 1 and 30 years of age. Therefore, a patient - who in most cases is a child - is not exposed to the surgical trauma/risk.
• the prepuce skin remains integral, and the sensory and psychological functions are preserved.
• composition for topical application using corticosteroids and/or hormone steroids in association with proteolytic diffusing enzyme helps the prepuce detach from the glans by impacting the depolymerization of the hyaluronic acid of the conjunctive tissue between both structures, thus yielding unusual results.
• This invention resulted in phimosis resolution in 90 percent of the patients aged 1 to 30 years. Therefore, patients - mostly children - are not exposed to the surgical trauma/risk.
• the prepuce skin remains integral, and the sensory and psychological functions are preserved.
• This new invention is aimed at the treatment of phimosis in both children and adults using topical corticosteroid application in association with diffusing enzyme to prevent circumcision (surgical treatment), with better (90 percent) results in relation to the topical use of either steroidal or non-steroidal anti-inflammatory agents.
• the association with the enzyme helps the prepuce detach from the glans by impacting the depolymerization of the hyaluronic acid of the conjunctive tissue between both structures, thus accentuating the local anesthetic and leading to the lysis of the adhesions between the prepuce and the glans, with better results than those obtained with the existing treatment of phimosis.
• the association of corticosteroid with diffusing enzyme has proved more effective than all existing treatments and is an innovative therapy for both adult patients and pediatric ones.
• the Applicant developed a pharmaceutical composition for treatment of phimosis using topical corticosteroid characterized by including around 0.025 to 5 percent in weight in relation to the total weight of the mixture composition of one or more corticosteroids and/or hormone steroids, whether or not associated with non- hormonal anti-inflammatory agents, and around 25 UTR to 4000 UTR/g of one or more proteolytic diffusing enzymes in proper medium, under different pharmaceutical forms, accompanied with additives known to the technical man.
• Usable corticoids may be chosen from, for example, the group:
• Betamethasone hydrocortisone, cortisone, hydrocortisone acetate or buteprate or butyrate or valerate, clobetasol or clobetasol propionate, propionate or dipropionate or valerate or phosphate or acetate and other esters of betamethasone, alclometasone dipropionate, deoxymetasone, clocortolone pivalate, diflorasone diacetate, fluocinolone acetonide, flurandrenolide, metilprednisolone acetate, mometazone furoate, diflorasone diacetate, amcinonide, fluocinonide, halobetazole propionate, desonide, triamcinolone acetonide and mixtures thereof, etc.
• 0.5 to 3 percent in weight should be used in relation to the total weight of the mixture of one or more corticosteroids such as those of the betamethasone family, or 2-phenyl-l,2-benzisoselenasol-3(2H)-one and its by- products.
• corticosteroids such as those of the betamethasone family, or 2-phenyl-l,2-benzisoselenasol-3(2H)-one and its by- products.
• Betamethasone is a synthetic fluorinated corticosteroid in the form of a white or almost white crystalline powder, water-insoluble, and partially alcohol-soluble. It is used for this type of application, ideally in the form of ester such as valerate, propionate, dipropionate, phosphate, or acetate.
• Hormonal steroids may be used in association with the composition's components such as testosterone.
• FIG 1 shows the structural formula of betamethasone in its particularly usable form: Betamethasone valerate.
• the steroidal agent may be alternatively used associated with one or more non-hormonal anti-inflammatory agents such as those chosen from the group: Diclofenac, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, ketoprofen, piroxicam, flurbiprofen, oxaprozin, etc.
• diclofenac is used.
• one or more proteolytic diffusing enzymes of about 25 to 4000 UTR/g are used, ideally within around 75 to 2000 UTR/g, such as hyaluronidase.
• Hyaluronidase is prepared commercially using bovine or ovine testicles, or biotechnological processes, and is marketed in the form of sterile or nonsterile yophil.
• Hyaluronidase depolymerizes the hyaluronic acid present in the interstitial substances of tissues, particularly the skin and synovial fluid.
• the hyaluronic acid consists of a chain of glycuronic-N-acetylglycosamine units polymerized by stable glycoside links, which are split by hyaluronidase. The resulting decreased viscosity contributes to diffusing the substances through the tissues.
• Hyaluronidase may be added to parenteral fluids such as saliva, glucose, lactate, and plasma to accelerate absorption and reduce local tissue distension.
• parenteral fluids such as saliva, glucose, lactate, and plasma
• the absorption in traumatic edema or post-surgical regions, or hematoma may be accelerated by infiltration of hyaluronidase and use of a garrote.
• the inflammation caused by accidental spilling of irritative solutions may be diminished.
• the composition may be applied using gel, ointment, cream, aerosol, or any other form of topical application.
• EXAMPLE 1 A prospective study was conducted with 100 male patients with phimosis diagnosis. Thirty-nine patients were between 1 and 5 years (3.25 years average) - group 1, and 61 between 6 and 30 years (12.49 years average) - group 2. No case referred topical or surgical treatment background, nor local inflammatory process. All patients were treated with topical compound made of 0.2 percent betamethasone added with 150 UTR hyaluronidase prepared in the form of ointment. The patients were directed to use the ointment once or twice a day until process resolution, but not longer than 12 weeks.
• the product was applied by the patient, or the parents if infants, to the fibrotic ring, then the prepuce was retracted slightly. Caution was taken to prevent the retraction from causing the patient pain or bleeding. The treatment was found effective in the cases of complete phimosis resolution following the aforementioned period.
• the mean time of medication usage was 38 days for the group between 1 and 5 years and 42 days for the group between 6 and 30 years.
• EXAMPLE 2 A topical cream was prepared including: Betamethasone 0.2 percent (in weight in relation to mass%)
• PATIENT 1 Patient 18 months of age with phimosis diagnosis, treated earlier with 0.05 percent hydrocortisone ointment with no results. The treatment began with the aforementioned association applied twice a day for four weeks with complete symptomatology resolution.
• PATIENT 2 Patient 16 years of age, pubescent, and presenting phimosis. The same treatment was administered for 8 weeks, with appropriate resolution at the sixth week. This is an evidence of its utility at higher age ranges. PATIENT 3
• the treatment began with the instruction that for secondary phimosis it could take as long as 12 weeks.
• the treatment was effective after 10 weeks using the ointment.

Landscapes

• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Dermatology (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (2)

Family

ID=36686652

Family Applications (1)

Country Status (12)

Cited By (1)

Families Citing this family (9)

Family Cites Families (1)

• 2000
  • 2000-12-28 BR BR0006556-0A patent/BR0006556A/pt active Search and Examination
• 2001
  • 2001-12-13 DE DE60121047T patent/DE60121047T2/de not_active Expired - Lifetime
  • 2001-12-13 ES ES01272567T patent/ES2267671T3/es not_active Expired - Lifetime
  • 2001-12-13 JP JP2002554088A patent/JP5095907B2/ja not_active Expired - Fee Related
  • 2001-12-13 WO PCT/BR2001/000154 patent/WO2002053137A2/en not_active Ceased
  • 2001-12-13 MX MXPA03005813A patent/MXPA03005813A/es active IP Right Grant
  • 2001-12-13 EP EP01272567A patent/EP1365766B1/en not_active Expired - Lifetime
  • 2001-12-13 CN CNB01822296XA patent/CN1270719C/zh not_active Expired - Fee Related
  • 2001-12-13 RU RU2003119439/15A patent/RU2279893C2/ru not_active IP Right Cessation
  • 2001-12-13 AU AU2002221365A patent/AU2002221365A1/en not_active Abandoned
  • 2001-12-13 US US10/465,977 patent/US7666858B2/en not_active Expired - Fee Related
  • 2001-12-27 AR ARP010106081A patent/AR032208A1/es unknown

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events