Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same

• US 5,166,331 A
• Filed: 12/19/1989
• Issued: 11/24/1992
• Est. Priority Date: 10/11/1983
• Status: Expired due to Term

• Current Assignee: Fidia Farmaceutici s.p.a (P.&R. S.p.A)
• Original Assignee: Fidia S.P.A.
• Inventors: Romeo, Aurelio, Lorenzi, Silvana, della Valle, Francesco
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US07/452,681
• Time in Patent Office: 1,071 Days
• Field of Search: 536/55.1, 514/54, 514/912, 514/777, 514/420, 514/576, 424/78, 424/78.05
• US Class Current: 536/55.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0046 Ear
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/12 Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Abstract

Two pharmaceutically useful fractions of hyaluronic acid are obtained comprising a first fraction with a molecular weight between 50,000 and 100,000 which is useful for wound healing, and a second fraction having a molecular weight between 500,000 and 730,000 which is useful for intraocular and intraarticular injections.

In addition, pharmaceutical preparations for topical administration are provided containing a pharmacologically active substance together with hyaluronic acid or a molecular weight fraction thereof. The hyaluronic acid may be in the form of the free acid or may be a salt with an alkali or alkaline earth metal, magnesium, aluminum or ammonium, or in the form of a salt with one or more pharmacologically active substances.

Claims

1. A pharmaceutical composition which comprises as an active ingredient a pharmacologically effective amount of a partial or a stoichiometrically neutral salt of hyaluornic acid or a molecular weight fraction thereof with at least one pharmacologically active substance of a basic nature suitable for topical administration and which is capable of being absorbed intradermally or thorugh the nasal or rectal mucosa, together with an excipient suitable for topical administration.

2. A pharmaceutical composition according to claim 1, wherein said salt is a partial salt wherein a first portion of the acid groups of the hyaluronic acid is salified with at least one pharmacologically active substance suitable for otpical administration.

3. A pharmaceutical composition according to claim 2, wherein a second portion of the acid groups of said hyaluronic acid is salified with an alkali or an alkaline earth metal, magnesium, aluminum or ammonium.

4. A pharmaceutical composition according to claim 1, wherein said salt is a stoichiometrically neutral salt in which all of the acid groups of the hyaluronic acid are salified with a pharmacologically active substance suitable for topical administration, an alkali or alkaline earth metal, magnesium, aluminum or ammonium.

5. A pharmaceutical composition according to claim 1, wherein said hyaluronic acid is a fraction having an average molecular weight between about 30,000 and 730,000.

6. A pharmaceutical composition according to claim 5, wherein said fraction is substantially free of hyaluornic acid having a molecular weight less than 30,000.

7. A pharmaceutical composition according to claim 6, wherein said fraction has an average molecular weight between about 50,000 and 100,000.

8. A pharmaceutical composition according to claim 6, wherein said fraction has an average molecular weight between about 500,000 and 730,000.

9. A pharmaceutical composition according to claim 1, wherein said active substance is suitable for dermatological, otorhinolaryngological, odontological, angiological, obstetrical or neurological use.

10. A pharmaceutical composition according to any one of claims 1, 4, 6 or 7, wherein said pharmacologically active substance is an antibiotic, anti-infective, antiviral, antimicrobial, anti-inflammatory, wound healing, cytostatic, cytotoxic, anesthetic, cholinergic promotor, cholinergic antagonist, adrenergic promotor or adrenergic antagonist agent.

11. A pharmaceutical composition according to claim 1, wherein said pharmacologically active substance is an antibiotic.

12. A pharmaceutical composition according to claim 1, wherein said pharmacologically active substance is an anti-infective, anti-viral or anti-microbial agent.

13. A pharmaceutical composition according to claim 1, wherein said pharmacologically active substance is a wound healing agent.

14. A method for the treatment of ophthalmological conditions which comprises topically applying to the cornea a pharmaceutical composition according to claim 1.

15. A method according to claim 14, wherein said pharmacologically active substance is an antibiotic.

16. A pharmaceutical composition which comprises hyaluronic acid or a pharmaceutically acceptable salt thereof and a non-steroid anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition according to claim 16, wherein said non-steroid anti-inflammatory agent is a member selected from the group consisting of indomethacin, oxyphenbutazone and flurbiprofen.

18. A pharmaceutical composition which comprises hyaluronic acid or a pharamaceutically acceptable salt thereof and a non-steroid anti-inflammatory agent.