AP476A - Eliminating maximum adjacent cut specification restrictions for telescoping pins - Google Patents
Eliminating maximum adjacent cut specification restrictions for telescoping pins Download PDFInfo
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- AP476A AP476A APAP/P/1993/000492A AP9300492A AP476A AP 476 A AP476 A AP 476A AP 9300492 A AP9300492 A AP 9300492A AP 476 A AP476 A AP 476A
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/503—Pyridazines; Hydrogenated pyridazines spiro-condensed
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- 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
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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Abstract
A pharmaceutical composition comprising a plurality
Description
TREATMENT CF DISEASE EMPLOYING HYALURONIC ACID AND NSAIDS.
FIELD QE. INVENTION
This invention relates to the treatment of disease and conditions of the skin and exposed tissue. In some embodiments this invention finds application to the treatment of a disease or condition of the skin and exposed tissue including basal cell carcinoma, squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and tumours in the skin, genital warts (condyloma acuminata), cervical cancer, HPV (Human Papilloma Virus) including HPV (Human Papilloma Virus) on the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet, actinic keratoses lesions, liver spots, fungal lesions, and other such types of lesions, and hair loss on the head of a pregnant women.
This invention also relates to compositions and formulations suitable for use in such treatments, the use of such formulations in such treatments, methods of such treatment, and the delivery of drugs for such treatments.
BACKGROUND OF ...THE. . INVENTION
Basal cell carcinoma is presently treated by surgery. Each lesion, together with all surrounding and underlying tissue (dermis, epidermis, and subdermis), is cut out. In some instances, surgery, while necessary for the patient's welfare, puts the patient at risk in some other respect (for example, the removal of a lesion on a patient's temple (resection) may jeopardize the patient's health). Squamous cell tumours are also treated the same way as are other forms of cancer in the skin
AP/P/ 9 3 / 0 0 4 9 2
BAD ORIGINAL ft and exposed tissue. Furthermore, other conditions and diseases of the skin and exposed tissue are treated in the same way or in ways that cause discomfort to the patient, for example melanoma, genital warts, cervical cancer, HPV (Human Papilloma Virus).
Actinic keratoses lesion is dealt with similarly. Liquid nitrogen is also used to remove the lesion.
These diseases and conditions are usually found in the epidermis (at least for the most part, extending into the dermis and upwards through the Stratum Corneum).
Hyaluronic acid is a naturally occurring glycosaminoglycan. Its molecular weight may vary from 50,000 daltons upwards, and it forms highly viscous solutions. As regards the actual molecular weight of hyaluronic acid in natural biological contexts, this is still a matter of much uncertainty; when the molecular weight of hyaluronic acid is to be determined, different values are obtained depending on the assay method employed, and on the source, the isolation method etc. The acid occurs in animal tissue, e.g. spinal fluid, ocular fluid, synovial fluid, cockscombs, skin, and also in some streptococci. Various grades of hyaluronic acid have been obtained. A preparation with an allegedly high degree of purity and alleged to be entirely free from side effects, is a noninflammatory form described in U.S. Patent No.4, 141,973; this preparation is said to have a molecular weight exceeding 750,000 dalton, preferably exceeding 1,200,000 dalton and is suggested for therapeutic use in various articular conditions. Applicants believe that hyaluronic acid claimed in this patent is sold under the trade mark Healon.
AP/P/ 93/00492
BAD ORIGINAL ft
United States Patent 4,801,619 relates to hyaluronic acid,having a molecular weight of about 3 X 105 dalton or more, administered intra-articularly which is prone to decrease the proteoglycan content of synovial fluid to almost normal levels. According to this patent, this indicates a positive effect on the proteoglycan metabolism of a joint. According to the patent, this is applicable both to inflammatory conditions and to degeneration caused by treatment with symptomatics, such as corticosteroid preparations. It is thus clear that a sufficiently high molecular weight of the hyaluronic acid is alleged to counteract side effects that might be caused by corticosteroids or other symptomatics producing similar effects. When corticosteroids are applied, the amount of hyaluronic acid in the synovial cavity will, according to the patent, increase substantially and, according to the inventors, their hyaluronic acid preparations have a very positive efface on such clinical symptoms as pain, swelling, and lameness.
The patent states that the objectives of the invention are attained by intra-articular administration (injection) of an effective amount of hyaluronic acid with a mean molecular weight exceeding 3 X 106 dalton, preferably exceeding 4 X 10s dalton; usually the molecular weight will not exceed 7 X 106 dalton. The dosage of hyaluronic acid administered is stated to be preferably within the range of 5mg-80mg. The amount of solution given at each administration is generally less than 60 ml, e.g. less than 20 ml. of an aqueous solution of the acid or its salt. It is convenient to administer the acid dissolved in water (<2% w/w, buffered to physiological pH), for instance in the form of
AP/P/ 93/00492
BAD ORIGINAL ft a water-soluble sodium salt. The exact amount will depend on the particular joint to be treated.
The Merck Index Specifies that Hyaluronic Acid has a Molecular Weight within the range pf 50,000 to 8 X 106 depen ding on source, methods of preparation, and methods of determination. The Merck Publication teaches hyaluronic acid as a surgical aid (ophthalmological).
United States Patent 4,808,576 purports to teach that hyaluronic acid, an agent well known for reducing the sequelae of trauma in mammalian joint tissue when injected directly into the traumatized joint tissue, will be carried to such traumatized tissue by the mammal's natural processes if applied at a site remote from the traumatized tissue. Thus, hyaluronic acid in any therapeutically acceptable form can, according to the Patent, be administered by the typical remote routes including intravenous, intramuscular, subcutaneous, and topical.
This, the patent alleges, makes the utilization of hyaluronic acid much more convenient and attractive. For instance, the treatment of arthritis in horse or human joints with hyaluronic acid, according to the patent, no longer requires more difficult intra-articular injections.
United States Patent 4,725,585 relates to a method of enhancing or regulating the host defence of a mammal by administering to a mammal a therapeutically effective amount of hyaluronic acid.
At column 1, lines 43 - 46, the patent provides that the invention was based on the unexpected discovery that administration of hyaluronic acid to mammals results in a considerable increase in the defence.
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The hyaluronic acid employed in the patent was Healon (t.m) provided by Pharmacia A3, Uppsala, Sweden (Pharmacia A3 is also entitled to the benefit of United States Patent 4,141,973). The patent provides at column 4, line 19 that because a patient’s infections had been hard to treat, instead of just hyaluronic acid being administered to the patient to increase the patient’s defence, the patient was given hyaluronic acid and an antibiotic. While one reading the patent may conclude that the antibiotic was given in combination with hyaluronic acid, in fact because the hyaluronic acid was administered subcutaneously and because the patient was a heart patient, one skilled in the art would understand that any antibiotic administered, while possibly administered simultaneously with the administration of the hyaluronic acid, was definitely administered separately intravenously (probably) or intramuscularly (less probably). Thus, the hyaluronic acid administered, according to the teachings of this patent, was administered in order to prevent possible development of infections (increase the host's defence) and not for any other reason.
United States Patent 4,636,524 discloses cross-linked gels of hyaluronic acid, alone and mixed with other hydrophilic polymers and containing various substances or covalently bonded low molecular weight substances and processes for preparing them. These products are alleged to be useful in numerous applications including cosmetic formulations and as drug delivery systems.
The patent further states that as hyaluronic acid is known to be a biologically tolerable polymer in the sense that it does not cause any immune or other kind of response when
AP/P/ 93/00492
BAD ORIGINAL ft introduced into a human body, the cross-linked hyaluronic acid gels can be used for various medical applications. The crosslinked gels modified with other polymers or low molecular weight substances, it is alleged, can be used as drug delivery devices. For example, the inventors are alleged to have found that heparin introduced in a cross-linked hyaluronic acid gel retained its antithrombogenic activity.
The inventors also allege that they have also found that cross-linked gels of hyaluronic acid can slow down the release of a low molecular weight substance dispersed therein but not covalently attached to the gel macromolecular matrix.
Unites States Patent 4,736,024 purports to teach new medicaments for topical use containing:
(i) an active pharmacological substance or a mixture of pharmacological substances, either active or suitable for topical administration and (ii) a topical vehicle which comprises hyaluronic acid or a molecular fraction of hyaluronic acid or a salt of the same with an alkaline metal, an alkaline earth metal, magnesium, aluminium, ammonium, or a pharmacological substance optionally together with additional conventional excipients for pharmaceutical preparations for topical use.
Applicants are also aware of published Japanese Patent
Document 61000017, dated 86/01/06, whose English abstract of disclosure states that the Japanese Patent Document relates to the use of hyaluronic acid or cross-linked hyaluronic acid or their salts as the active ingredient for inhibiting carcinoma metastasis .
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According to the purported abstract of the patent, more that 1.0% of hyaluronic acid is dissolved in alkaline aq. soln, and pref. more than 50% of H20 sol. org. solvent, eq. alcohol, acetone, dioxane, against total soln, is added. Preferably the pH is 12-14. Then a multifunctional epoxy cpd. is added and reacted at 10-60 deg. C, pref. at 20-40- deg. C for 24 hrs. Cross-linking ratio of crosslinked hyaluronic acid or its salt is regulated by changing mol ratio of hyaluronic acid or its salt and multifunctional epoxy cpd.. Pref. hyaluronic acid used has intrinsic viscosity 0.2-30,m.w. 4000-2000000. The hyaluronic acid is allegedly used in several dosage forms. The clinical dose for an adult is alleged to be normally, as hyaluronic acid or cross-linked hyaluronic acid, 25mg-5 g/day (p.o.) and 10 mg-2.5 g/1 dose (inj). The abstract alleges that the advantage is that the hyaluronic acid has no side effects as may other anti-cancer drugs and has an analgesic and a tissue restoration effect.
European Patent Application 0295092 purports to teach a vehicle together with fragments of hyaluronic acid for delivering of the fragments of hyaluronic acid into the skin to reach the dermal layer of the skin to increase the development of blood vessels for stimulating hair growth or regrowth. The preferred fragments of hyaluronic acid are polysaccharides containing from 7 to 25 monosaccharide units. The patent provides that it is apparent that the larger the fragments of hyaluronic acid, the greater the difficulty there is in delivering the fragments to the dermal layer of the skin, unless there is also present in the composition a means for enhancing the activity of said fragments.
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The combination may thus include a means for enhancing the activity of the fragments of hyaluronic acid, especially to improve their penetration through the skin following topical application. Some activity enhancers, it is alleged, also function as vehicles for the fragments of the hyaluronic acid.
Some activity enhancers are also alleged to possess the ability to stimulate or increase hair growth. Minoxidil is asserted among others to be such an activity enhancer. Thus both the fragments of hyaluronic acid and minoxidil are alleged to stimulate hair growth both delivered by a vehicle'.
European Patent Application 0179442 asserts that where free radicals are formed in considerable quantities, hyaluronic acid is broken down or degraded before the hyaluronic acid has given the desired effect.
Canadian Letters Patent 1,240,929 teaches the combination of chondroitin sulfate compound and a hyaluronate to protect both human and animal cell layers and tissue subject to exposure to trauma.
European Patent Application 0208623 purports to teach hyaluronic acid as une augmentation de l’activite de certaines proteases. It also purports to teach the use of hyaluronic acid for treating connective tissue diseases, including malignant tumours and cardiovascular disorders.
European Patent Application 270317 purports to teach the combination of an antiviral agent lacking inhibitory action and a compound [for example, hyaluronic acid] possessing cell fusion inhibitory activity and/or virus-adsorption inhibitory activity for treating disease carried by a virus.
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United States Patent 4,840,941 purports to teach the use of an effective amount of hyaluronic acid as the active agent for the treatment of retroviruses in association with a pharmaceutically acceptable carrier, diluent, or excipient.
United States Patent 4,851,521 and European Patent Application 0265116 both describe hyaluronic acid fractions, the making thereof and cross-linked esters of hyaluronic. United States Patent 4,851,521 describes esters of hyaluronic acid incorporated into pharmaceutical preparations as the active ingredient and as vehicles for ophthamological medicines for topical use (See column 11, lines 35 to 42; and column 12, lines 62 to column 13, line 3) and in suppositories for a systemic effect due to the effect of transcutaneous absorption, such as in suppositories.
The patent provides at column 13, lines 5 to 31:
The | vehicling action of the | : hyaluronic | esters | |
also | applies to | associated | medicaments | of the |
type | mentioned | above in | which the | active |
substance acts not only topically or by nasal or rectal absorption, for example by nasal sprays or preparations for inhalation for the oral cavity or the pharynx, but also by oral or parenteral route, for example by intramuscular, subcutaneous or intravenous route, as it favors absorption of the drug into the application site. The new medicaments can therefore be applied, apart from in the fields already mentioned, in practically all sectors of medicine, such as internal medicine, for example in pathologies of the
AP/P/ 93/00492
BAD ORIGINAL ft cardiovascular system, in infections of the respiratory system, the digestive system, the renal system, in diseases of an endocrinological nature, in oncology, in psychiatry etc., and may also be classified therefore from the point of view of their specific action, being perhaps anesthetics, analgesics, anti-inflammatories, wound healers, antimicrobics, adrenergic agonists and antagonists, cytostatics, antirheumatics, antihypertensives, diuretics, sexual hormones, immunostimulants and immunosuppressants, for example, one of the drugs having the activity already described for the therapeutically active alcohols to be used as esterifying component according to the present invention, or for the therapeutically active bases used for the salification of the free carboxylic groups.
There have been extensive studies to determine the defect in immune function that allows a tumour cell to develop. It was postulated initially by Jerne, and subsequently by Burnett, that the immune system's major role was that of immunological surveillance to destroy abnormal cells. The concept of surveillance, while somewhat simplistic, remains an accepted concept for the elaborate mechanism of immune recognition and function that is present in the higher species mammals .
It has then been postulated that tumours develop because of local or generalized immune suppression. However, as pointed out by Moller, if general immune suppression occurs, it
BAD ORIGINAL ft is only certain types of neoplastic disorders that develop, mainly those of the lympho-reticular system. This observation is generally correct and represents a major challenge to the immune surveillance theory unless a specific reason can be shown as to why the individual cancer cell can develop plus individually evade the immune system.
It was demonstrated experimentally in 1974 that defects of macrophage function may exist in neoplastic disease.
The initial experiments found suppressor cells to be part of the immune system; these were either of the T-cell type of the macrophage cell system. There was presence demonstrated in neoplasia, chronic bacterial infection, recovery from massive injury and chronic fungal infection.
There has been repeated demonstration in experimental animals that the macrophage cell function is altered in neoplastic disease. The macrophages in the animal's systems appeared blocked in their function. Generally when removed from the in vivo situation, washed in saline and cultured, they perform normally. This block has been shown to be related to the excessive production of prostaglandin by neoplastic tissue or by the macrophage itself. Similarly, the N.K. cells (which are said to be primitive or immature macrophages and which may be involved in cancer defence) are also blocked.
In the basic research efforts in the latter '70s and
AP/PZ 93/00492 the early ’80's, there existed considerable confusion as to what role immunotherapy should take in cancer. Activation or hyping of macrophages was thought to be important. However, in an examination by Romans and Falk of peritoneal macrophages obtained from patients with neoplastic disease, there was
BAD ORIGINAL ft definite evidence that these macrophages were already activated yet were co-existing with cancer cells and not causing their destruction .
It has recently been shown by several independent investigators that the malfunction of macrophages or the putitive block is due to excessive prostaglandin and that this can be altered in tissue culture by corticosteroids, ASA, and the non-steroidal anti-inflammatory drugs, i.e. indomethacin and naproxen (Naprosyn™) . Again, it was repeatedly demonstrated that in animal tumours these substances could alter the response to neoplastic cells and that various combinations of these substances employed with immune enhancing agents could produce very credible success in eliminating experimental tumours. Lala and co-workers combined Indomethacin therapy with Interleukin 2 and showed that this could effect a cure with experiment neoplasm.
There were continued problems with the use of any of these agents in the actual human in vivo experience. All of the non-steroidal anti-inflammatory agents (NSAID) produced major toxicity in terms of gastro-intestinal, neurological, and other areas. Thus, the basis of the present approach is that, under general circumstances, with the use of these agents in human disease in sufficient amounts, the drug will penetrate to any pathological tissue to alter therapeutically local prostaglandin production. While intravenous preparations of Indomethacin (and now of other agents) exist, using these drugs alone produces prohibitive side effects in human subjects. Therefore, only insufficient amounts can be brought into the body to effect more than occasional responses in neoplasm.
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However, the majority of the evidence is present to indicate and therefore, it can be postulated that the basis for neoplastic development and how the initial cell sneaks by the immune surveillance mechanism relates to its production of prostaglandin. One need postulate only one mutation to alter the amount of prostaglandin synthesis produced by cells when they become malignant to establish a mechanism of blocking out the initial cell in any immune reaction, i.e. the macrophage. It therefore became essential to develop a combination of NSAIDs for clinical use to produce a major improvement in response in neoplastic disease and other conditions where excessive prostaglandin synthesis represents the basis of the pathogenesis of this disease state, i.e. arthritis and various others of the so-called connective tissue inflammatory disorders and/or auto15 aggressive diseases.
See also:
1. Modulation of Immunity in Cancer Patients by Prostaglandin Antagonists, Immunity to Cancer II. Alan R. Liss,
Inc .; and
2. Goodwin, J.S., (1981) Prostaglandin E and Cancer
Growth Potential for Immunotherapy with Prostaglandin Synthesis Inhibitors, Augmentive Agents in Cancer Therapy, Raven Press,
New York.
United States Patent 4,711,780 teaches a pharmaceutical composition comprising Vitamin C, a zinc salt, and a sulfur amino acid for treating surface epithelium for epithelium regeneration. Hyaluronic acid may be added for applications in the reproductive tract to block the passage of toxins into the blood system.
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U.S. Patent 4,937,254 (Ethicon) teaches combinations of hyaluronic acid and salts thereof with NSAIDS for the prevention of adhesions after surgery.
Because of the side effects of the use of nonsteroidal anti-inflammatory drugs (major toxicity in terms of gastro-intestinal, neurological, and other areas),use thereof should also be restricted (if possible) to the area of use without delivery to other areas which are not in need of treatment. Thus, if useful amounts of the non-steroidal antiinflammatory drugs or for that matter any drugs could be delivered to a site in need thereof without carriage of substantial amounts away from the site to be treated, thereby accumulating an amount of the drug at the site to be treated for a prolonged period of time, then the use of the drug for example a non-steroidal anti-inflammatory drug at a site may have many other useful applications.
SUMMARY OF THE INVENTION
Applicants have now developed compositions, (combinations and formulations) which are topically applied to the skin and/or exposed tissue of a human and which are quickly transported in dosage amounts percutaneously (intracutaneously) at a site in need of treatment, (site of pathology and/or trauma) best targeting the epidermis and subsequently remaining (accumulating) at the site for a prolonged period of time. The compositions subsequently clear through the lymphatics thereby bringing dosage amounts of the compositions to the lymphatics for the treatment of disease and conditions in the lymphatics.
These compositions, (combinations and formulations) employ, combine, or incorporate (as the case may be) a plurality
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of effective non-toxic dosage amounts, etch dosage amount comprising an effective non-toxic dosage amount of a drug for example a drug which inhibits prostaglandin synthesis for example an NSAID and an effective ncn-toxic dosage amount of a form of hyaluronic acid (preferably hyaluronic acid or salt thereof) for the transport of the drug to the site of the pathology and/or trauma. Suitable dosage amounts of the composition may be removed from a container (for example a tube or jar) and administered (for example, applied).
Thus according to one aspect of the invention these pharmaceutical compositions (combinations and formulations) comprise a plurality of effective non-toxic dosage amounts for administration to the skin and/or exposed tissue of a human in need of treatment, each such dosage amount comprising a therapeutically effective non-toxic (to the patient) dosage amount of a drug to treat a disease and/or condition for example a drug which inhibits prostaglandin synthesis, preferably being a non-steroidal anti-inflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and an effective non-toxic dosage amount (for example in excess of 5 mg per cm2 (square centimeter) of skin or exposed tissue to which the dosage amount of the composition is to be applied) of hyaluronic acid and/or salts thereof (for example the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid (preferably hyaluronic acid and/or salts thereof) to transport (to faciliate or cause the transport of) the drug to the site of the pathology and/or trauma of the disease or condition. These
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BAD ORIGINAL compositions may be applied topically to treat diseases and conditions of the skin and/or exposed tissue at the site of the trauma and/or pathology, (for example, basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours in the skin, genital warts (condyloma acuminata) , cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women) . The results of the treatment with suitable dosage amounts taken from these compositions (combinations and formulations) have been in some instances quite dramatic - difficult situations have been successfully treated and resolved.
Furthermore, application of the dosage amounts of the compositions, combinations and formulations are, systemic independent (there is a lack of a blood level of the drug for example NSAID), are quick to penetrate into the skin to the site of the trauma and/or pathology because the effective dosage amount of the form of hyaluronic acid transports (facilitates or causes the transport of) the drug (for example NSAID) particularly to the epidermis where the composition, combination or formulation accumulates and remains for prolonged periods. The compositions subsequently clear through the lymphatics and are available for the treatment of disease and conditions of the lymphatics .
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BAD ORIGINAL ft
In this regard effective auouats of the fern of hyaluronic acid exceeds in the order of about 5 mg per square cm. (cm2) of the area of for example the skin and/or exposed tissue to which the dosage amounts of the composition is to be applied.
Thus, according to another aspect of the invention, Applicants have provided topically applicable percutaneous (intracutaneous) penetrating (best targeting the epidermis) systemic independent acting (not acting essentially through the blood) pharmaceutical compositions (combinations and formulations) comprising a plurality of dosage amounts each comprising, together with pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and to assist to resolve diseases and conditions of the skin and exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours in the skin primary and metastatic melanoma in the skin, genital warts (condyloma acuminata) , cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women), non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, preferably a non-steroidal anti-inflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and an effective non-toxic amount of hyaluronic acid
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BAD ORIGINAL ft and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) to transport (facilitate or cause the transport of) the drug (for example NSAID’s) rapidly to the site in the skin (for example epidermis) and/or exposed tissue of the disease or condition into the tissue to remain there for a prolonged period of time to assist to treat and assist to resolve the disease or condition for example by blocking prostaglandin synthesis.
Effective dosage amounts of the form of hyaluronic acid to facilitate or cause the transport of the drug into the skin and/or exposed tissue by the form of hyaluronic acid exceeds about 5 mg. - 10 mg. in the dosage amount administered (applied and rubbed in) for each 1 cm2 of skin and/or exposed tissue area of the disease or condition (for example basal cell carcinoma) to which the dosage amount is applied. The dosage amount applicable will depend upon the surface area of the skin and/or exposed tissue in which the condition or disease exists. Thus if the disease or condition occupies about .5 cm2, in excess of about 21/2 mg of the form of hyaluronic acid would be used (applied and rubbed in). In the same way if the area is 2 cm2, the amount of the form of hyaluronic acid preferably exceeds about 10-20 mg of the dosage amount of the formulation or composition applied. Preferred forms of the hyaluronic acid (for example hyaluronic acid and the sodium salt thereof) have molecular weights less than about 750,000 daltons (for example about 150,000 to about 225,000 daltons) to transport the medicine in the skin and/or exposed tissue. While higher
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BAD ORIGINAL ft molecular weights of the hyaluronic acid and forms thereof may be used to penetrate the skin and/or exposed tissue and transport the medicines or drugs, where the molecular weight of the hyaluronic acid chosen for use is very large, it is preferred that the form of hyaluronic acid is autoclaved, to break down the hyaluronic acid to fragments of lesser molecular weight or if feasible diluted to permit administration and ensure no coagulation on or in the skin. Where the molecular weight of the form of hyaluronic acid being employed is large, the concentration of the form of the hyaluronic acid in the composition may for example be reduced (for example to less than about 3%) dependent on the molecular weight.
The blockage of prostaglandin synthesis by the transported drug (for example NSAIDS) then unblocks the macrophages and permits the macrophages of the patient proximate the lesion (for example, the basal cell carcinoma) to destroy the lesion or condition. Treatment by dosage amounts of the composition (formulation and/or combination) eliminates the condition without recurrence, even where the lesion has recurred a number of times after unsuccessful treatments according to the prior art.
Other non-steroidal anti-inflammatory drugs (NSAIDS) may be used such as other propionic acid derivatives, Ibuprofen, acetylsalicylic acid, piroxicam and flunixin.
When dosage amounts of such compositions, combinations and formulations are applied to the site of the disease or condition for example the basal cell carcinoma of the patient suffering from the basal cell carcinoma, over a period of time
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BAD ORIGINAL ft (for example, for a period of 2-4 weeks 3 times daily) the basal cell carcinoma is completely resolved and disappears.
Thus according to another aspect of the invention there is provided a pharmaceutical composition from which dosage amounts may be taken for application to the skin and/or exposed tissue, the pharmaceutical composition comprising in a form for application to a human a plurality of dosage amounts of medicine and/or therapeutic agent to treat a disease or condition in a human and a plurality of dosage amounts of hyaluronic acid and/or salts and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid such that when dosage amounts of the pharmaceutical composition are taken from the composition, the amount of the medicine and/or therapeutic agent comprises an effective nontoxic dosage amount cf the medicine to treat the disease or condition in the skin and/or exposed tissue in a human and the amount of the form of hyaluronic acid in the dosage amount is present in an effective amount to transport (facilitate or cause the transport of) the medicine and/or therapeutic agent intradermally (percutaneously, intercutaneous1y, intracutaneously) into the skin (preferably to the epidermis and dermis) and/or exposed tissue of a human to the site of a pathology and/or trauma. The effective amount of the form of hyaluronic acid has a molecular weight and concentration to transport the medicine (drug) and/or therapeutic agent to the site of trauma and/or pathology in the skin and/or exposed tissue. In this regard the preferred amount of the form of hyaluronic acid in each dosage amount exceeds 5 mg./cm2 and preferably the molecular weight is less than about 750,000
BAD ORIGINAL 0 daltons, (in one embodiment about 150,000 to about 225,000 daltons) in some embodiments with a concentration of between about 1 and 3%, preferably concentrations of between about 2 to about 3% by weight. Where forms of hyaluronic acid are used having greater molecular weights, they are preferably cleaved and/or diluted to smaller concentrations, to facilitate or cause the transport of the medicine and/or therapeutic agent.
According to another aspect of the invention there is provided a pharmaceutical composition (for example a gel or cream) from which dosage amounts may be taken and applied to the skin to treat a disease or condition in humans, for example as discussed above, the pharmaceutical composition comprising:
(1) | a medicinal | and/or | therapeutic | agent | suitable |
for treating | a disease or | condition | in the skin and/or | exposed | |
tissue in | humans, for | example | a drug | which inhibits | |
prostaglandin | synthesis (for example | an NSAID); | and | ||
(2) | hyaluronic | acid and/or salts | thereof | and/or | |
homologues , | analogues , | derivatives, complexes, | esters , |
fragments, and sub-units of hyaluronic acid, in a form suitable for administration to the skin and/or exposed tissue in humans; characterized in that an effective non-toxic dosage amount comprising components (1) and (2) taken and administered from said composition (i) is available in the skin and/or exposed tissue upon administration to treat said disease or condition in humans by penetration at the site to be treated to the site of trauma and/or pathology, and (ii) comprises an effective nontoxic dosage amount of component (2) effective to transport (facilitate or cause the transport of) component (1) immediately upon administration percutaneously into the skin (preferably the
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epidermis) to the site to be treated for example the site of trauma and/or pathology where it remains for a prolonged time, accumulating there and from which it is discharged via the lymphatic system.
Therefore according to another aspect of the invention a pharmaceutical composition is provided comprising:
(1) a medicinal and/or therapeutic agent which for example inhibits prostaglandin synthesis in a therapeutically effective amount to treat a disease or condition of the skin and/or exposed tissue;
and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, characterized in that said composition 15 (a) is in a dosage form (for example a gel or cream) which is suitable for administration to the skin and/or exposed tissue;
and (b) is in such an amount and in such form that (i) component (1) is in an effective dosage amount to treat said disease or condition by penetration at the site of the skin and/or exposed tissue to be treated for example the basal cell carinoma and other lesions; and (ii) component (2) is immediately available to transport (facilitate or cause the transport of) component (1) to the site of trauma and/or pathology to be treated, percutaneously into the skin (or exposed tissue) where the composition resides and accumulates for a prolonged period, and which component (2) is in an effective non-toxic dosage amount to transport (facilitate or cause the transport of) component (1) upon administration,
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BAD ORIGINAL ft
2.3 percutaneously into the skin or exposed tissue to the site of the trauma and/or pathology. Preferably the form of hyaluronic acid in the composition comprises hyaluronic acid and/or salts thereof. An effective amount of the form of hyaluronic acid exceeds about 5-10 mg per square centimeter (cm2) of skin and/or exposed tissue to which it is to be applied.
According to another aspect of the invention there is provided the use of:
(1) a medicinal and/or therapeutic agent for example which inhibits prostaglandin synthesis, and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, in the manufacture of a pharmaceutical composition for treating a disease or a condition (for example those discussed above) of the skin and/or exposed tissue in a therapy wherein dosage amounts taken from the composition each comprise:
(1) a therapeutically effective amount of said medicinal and/or therapeutic agent and (2) a therapeutically effective amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, the pharmaceutical composition being characterized in that for each dosage amount taken from the pharmaceutical composition, the amount of component (2) is immediately available to transport component (1) percutaneously to the site of trauma and/or pathology for example into the epidermis where the composition accumulates and remains for a prolonged period, at the site of the skin or exposed tissue to
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BAD ORIGINAL ft be treated, and component (2) is in an effective non-toxic amount to transport (facilitate or cause the transport of) component (1) into the skin or exposed tissue (for example into the epidermis). Preferably component (2) is hyaluronic acid and/or salts thereof and preferably the dosage amount of component (2) in the amount of the composition taken from the composition (to be taken from the composition) and applied to the skin or exposed tissue is a dose amount greater than about 5-10 mg per cm2 of skin and/or exposed tissue to which the dosage amount is to be applied.
The pharmaceutical composition will normally include pharmaceutically compatible excipients to provide a form for ease of administration to the skin and/or exposed tissue for transport into the epidermis. For example a suitable dosage amount of a gel may be squeezed from a tube as a ribbon of gel X cm long (which dosage amount (in the form of the ribbon X cm long) contains the effective non-toxic dosage amounts of the drug and form of hyaluronic acid. Or a dosage amount of cream packaged in a jar may be scooped from the jar by a measuring device or by two fingers in a suitable amount (for example in a spoon containing a premeasured volume or an amount about half the length of the fingers) . Each of the dosage amounts selected comprises the effective amounts of drug (for example NSAID) and effective amount of the form of hyaluronic acid (for example hyaluronic acid and/or salts thereof). In this way the patient may squeeze or scoop or what have you the appropriate dosage amount and apply (rub in) the dosage amount onto the skin and/or exposed tissue for transport into the epidermis .
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Thus, according to another aspect of the invention, a method of treating a disease and/or condition of the skin or exposed tissue, for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours in the skin, genital warts (condyloma acuminata), cervical cancer, HPV (Human Papilloma
Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women, in a human is provided comprising administering topically to human skin and/or exposed tissue an effective non-toxic dosage amount of a composition comprising, together with pharmaceutical excipients suitable for topical application to the skin and/or exposed tissue, for example in the form of a gel or cream (to give the composition definition and form so that specific dosage amounts are easily selected or taken for administration (for example squeezed from a tube or scooped from a jar and rubbed into the skin or exposed tissue), a therapeutically effective (to treat and to assist to resolve the disease or condition for example basal cell carcinoma or other lesion), non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, for example a non-steroidal anti-inflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium
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salt’; -.nd/or homologues, analogues, derivatives, ctm.p_exes, este:s. fragments, and/or sub-units cf hyalure.lie aura (pre:erably hyaluronic acid and salts thereof) to transport {facilitate or cause the transport of) the drug (for example NSAII) into the skin or exposed tissue to the sire of the dise< S€ or condition to be treated percutaneously, (to the sire of t :a :ma and/or pathology), for example into the epidermis, when. .he form of hyaluronic acid and medicine accumulates and rema .n ; for a prolonged period of time thereby for example bloc’.ii.g prostaglandin synthesis in the skin or exposed tissue. The ferm of hyaluronic acid is then cleared through the lymp..atics (lymphatics system) .
Thus, according to another aspect of the invention, the :r:atment may employ the use of the composition, formulation or combination for the treatment of the diseases and conditions aforesaid as for example by applying dosage amounts of she composition, formulation or combination a number of cirn.-s daily (for example, 3 times daily) for a period of time, for example, 2-4 weeks to clear the disease, lesion or condition. hath dosage amount applied will depend upon the size of the lesion or conc.ition on the skin or exposed tissue. For example, a suitable dosage amount may include 5-10 mg. of the form, of hyaluronic acid per 1 cm2 skin area or exposed tissue area.
One such formulation may comprise 3% (by weight) dicloienac in a 21/z% (by weight) hyaluronic acid (sodium hyaluronate - molecular weight 661,600) gel formulation, with the excipients being glycerine (5%), benzyl alcohol (3%) (acting in mart as a solubilizer and preservative), and sterile water (the balance) in a 50 gm. tube of the composition (a plurality
6 V 0 0 / £ 6 /d/dV
BAD ORIGINAL ft of dosage amounts) whose tube O.D. (outer diameter) of the opening through which the gel formulation is discharged from the tube is 8 mm and whose I.D. (inner diameter) of the opening is 4 mm. Therefore a ribbon 2-3 cm in length, squeezed from a tube gives about 5 mg-71/2 mg of hyaluronic acid for application to a skin or exposed tissue surface area of l-l’’/.cm2 with an effective dosage amount of diclofenac. While greater amounts squeezed from the tube, may be applied, the application of substantial excessive dosage amounts to the skin and/or exposed tissue may saturate the skin or exposed tissue and thus the epidermis. (There is therefore no more room for the composition to pass between the cells and therefore further applications at that time will not provide additional benefit) . Where pain relief is also required additional dosage amounts, for example in excess of about 10 mg. of the hyaluronic acid taken from the same pharmaceutical composition applied per/cm2 of surface area of the skin or exposed tissue may be required to be applied.
Another formulation may comprise 3% (by weight) diclofenac in a 21/2i (by weight) hyaluronic acid (sodium hyaluronate - molecular weight 679,000) gel formulation (also in a tube) with excipients being benzyl alcohol (1%) (a preservative), methoxypolyethylene glycol 350 (20% by weight) (a solubilizer), and sterile water (the balance).
While the above compositions, combinations and formulations are proposed, provided there is sufficient amounts of the form of the hyaluronic acid (for example, sodium hyaluronate) in the dosage amounts applied to the skin and/or exposed tissue to facilitate or cause the percutaneous (intracutaneous) transport of the drug for example which
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BAD ORIGINAL ft inhibits prostaglandin synthesis, preferably an NSAID (for example, diclofenac) to block prostaglandin synthesis, then the formulations may be of any suitable form, for example, a 1% lotion of hyaluronic acid with NSAID, or a cream or gel or any other suitable form.
Therefore according to another aspect of the invention, there is provided containers (for example tubes and jars) containing compositions comprising a plurality of dosage amounts of the drug and form of hyaluronic acid, each dosage amount comprising an effective non-toxic dosage amount of the drug and an effective non-toxic dosage amount of the form of hyaluronic acid (preferably sodium hyaluronate having molecular weight less than about 750,000 daltons) to transport the drug into the skin and/or exposed tissue. In some embodiments, means are provided to assist the removal from the container of an effective dosage amount of the composition in the container for use to apply to the skin or exposed tissue at the site of trauma and/or pathology to treat the disease and/or condition (for example mouth opening of a tube to control the amount discharged from the tube).
Furthermore, because there is little concern with respect to the toxicity or adverse effects of the use of, for example, the NSAIDs with the hyaluronic acid in the compositions of this invention the NSAID may be combined as needed (after solubilizing (if required) of the NSAID in a suitable solubilizer) with the form of the hyaluronic acid.
Therefore according to another aspect of the invention, percutaneous (intercutanous) delivery of a therapeutically effective dosage amount of a drug (in a
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BAD ORIGINAL ft composition, combination or formulation) and which drug tor example inhibits prostaglandin synthesis, preferably being a non-steroidal drug (NSAID) is provided. In this regard the drug is transported to the site of, on, or in the skin and/or exposed tissue of trauma and/or pathology to treat the disease or condition for example the basal cell carcinoma or actinic keratoses lesion in a mammal (human). The delivery may comprise topically administering (to the skin or exposed tissue site of for example the basal cell carcinoma or other lesion) a therapeutically effective non-toxic (to the patient) dosage amount of a composition comprising a drug for example which inhibits prostaglandin synthesis, preferably an NSAID (nonsteroidal anti-inflammatory drug), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™), and an effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, preferably hyaluronic acid and salts thereof, sufficient to transport, (facilitate or cause the transport of) , the drug for example NSAID percutaneously (to for example the epidermis) to the site of the trauma and/or pathology in for example the epidermis, for example the basal cell carcinoma (or other lesion), to be treated for example to block the synthesis of prostaglandins.
Delivery may be also accomplished by the same amount of the form of hyaluronic acid, of other drugs percutaneously (intercutaneously) to the skin and exposed tissue by application and rubbing in of an effective non-toxic dosage amount of the formulation or composition comprising an effective non-toxic
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BAD ORIGINAL ft dosage amount of the drug and an effective non-toxic dosage amount of the form of hyaluronic acid for the transport of the drug percutaneous ly into the skin or exposed tissue to the epidermis where the dosage amount of the composition is accumulated and remains for a prolonged period of time before the form of hyaluronic acid is cleared through the lymphatics. In this regard the drug may be novantrone (an anti-cancer drug) for administration to a tumour or malignancy in the skin. The novantrone may comprise 10 mg in the dosage amount of the composition and the form of hyaluronic acid may be in excess of about 5 mg of sodium hyaluronic per cm2 of the skin or exposed tissue (about 2.5% of the composition) for the percutaneous transport of the novantrone.
Thus, according to another aspect of the invention, use of a composition, combination or formulation is provided to treat a disease or condition for example basal cell carcinoma (or other lesion), by the application of the composition, combination or formulation, the amount of the composition, combination and formulation administered comprising together with pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and assist to resolve a disease or condition for example, basal cell carcinoma), nontoxic (to the patient) amount of a drug for example which inhibits prostaglandin synthesis preferably a non-steroidal anti-inflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) administered together with, or carried in, an effective dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or
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homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) effective to transport the drug for example the NSAID (to facilitate or cause the transport of the drug for example NSAID) percutaneously into the skin especially the epidermis at the site of the disease or condition for example basal cell carcinoma (or other lesion) to be treated, thereby, if an NSAID, blocking prostaglandin synthesis to enable the macrophages (and N.K. cells) to resolve the disease or condition for example basal cell carcinoma or other lesion.
Applicants postulate that the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid facilitate or cause the transport of the drug for example which blocks prostaglandin synthesis (preferably an NSAID) to the site of prostaglandin synthesis to block prostaglandin synthesis .
Applicants' compositions and dosage amounts of their compositions and the use of their compositions and dosage amounts of their compositions, at the same time, abate pain that the patient is experiencing at the paccinian nerve bundles (superficial nerve bundles) at the site of the trauma and/or pathology on/in the exposed tissue and/or skin.
Thus, according to another aspect of the invention, a method of abating pain in the skin and/or exposed tissue for example suffering a disease or condition (for example those discussed above), and a composition from which dosage amounts may be taken and applied (rubbed in) which is useful for abating
- ---------------- BAD ORIGINAL ft
AP/P/ 9 3 / 0 0 492 such pain are provided, the method comprising administering (rubbing on) an effective dosage amount of the composition to the skin and/or exposed tissue, and the composition comprises a plurality of dosage amounts, each comprising an effective nontoxic dosage amount of an NSAID and an effective non-toxic dosage amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or subunits of hyaluronic acid (preferably hyaluronic acid and salts thereof), for example amounts exceeding 10-20 mg. per square cm (cm2) of skin or exposed tissue to which it is applied, for percutaneous transport of the NSAID by the form of hyaluronic acid into the epidermis proximate the paccinian nerve bundles (superficial nerve bundles at the end of the nerves) to abate pain. Thus, according to another aspect of the invention, compositions are provided for use to relieve pain from which dosage amounts of the composition comprising dosage amounts of the NSAID and form of hyaluronic acid are taken.
By way of example and. to illustrate the facilitation of the delivery or transport of a chemical to a site in a human, when ethyl alcohol is injected directly into a tumour and sonographic (ultrasound) assessment is made, it is not dispersed throughout the tumour. When the ethyl alcohol to be administered into a tumour is carried by hyaluronic acid and/or salts thereof, sonographic assessment of the tumour demonstrates the dispersion of the ethyl alcohol throughout the tumour.
While Applicants postulate that the hyaluronic acid facilitate or causes the transport and delivery, Applicants’ invention may be used as described irrespective of the actual
AP/P/ 9 3 / 0 0 492
BAD ORIGINAL method of operation of the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid.
The combination of hyaluronic acid and salts thereof and other forms with drugs for example that inhibit prostaglandin synthesis, for example NSAIDs, alters their distribution and performance in the skin and/or exposed tissue particularly the epidermis (the combinations and formulations being systemic independent), and produces an unusual targeting for underperfused skin and/or pathological tissue in the skin (site of trauma and/or pathology). The application may be made as required with the amount depending upon the condition of the skin or exposed tissue.
As a major amount of soluble indomethacin may be incorporated into the formulation, or composition, the indomethacin may be solubilized using n-methyl glucamine at a dilution of 5mg/ml of n-methyl glucamine (NMG). This substance is then passed through a 22 micron Milipore filter to produce sterility. This material is non-toxic at 16 fold the therapeutic dose in animals (with hyaluronic acid) and for this reason was considered appropriate to be used in human conditions. Thus, Indocid™ solubilized in NMG may be administered with hyaluronic acid topically for percutaneous penetration at, for example, varying doses. The solution of indomethacin and NMG may be mixed with, for example, ’’LifeCore™ hyaluronic acid in dosage amounts discussed above. This produces an appropriate mixture and can be administered safely.
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BAD ORIGINAL £
When the NSAID, for example indomethacin (dissolved in n-methyl glucamine) or other NSAID, is applied topically in an effective dosage amount from a composition or formulation also including the effective dosage amount of the form of hyaluronic acid, no major toxic side effects occur, such as gastrointestinal distress, neurological abnormalities, depression, etc., even at elevated amounts of indomethacin (if necessary). (This may be in part because of the clearing of the hyaluronic acid through the lymphatic system from the site). In addition, the responses that have been observed are dramatic when the drug for example NSAID (for example diclofenac) is combined with hyaluronic acid, demonstrating clearly that the combination is now targeting to the site of pathology or trauma, or pathological tissue. Furthermore, patients using the formulations and combinations of drug (for example NSAID) hyaluronic acid (sodium hyaluronate) (for example, diclofenac or indomethacin and hyaluronic acid), experience dramatic relief of pain immediately.
Thus, Applicants believe that the use of the NSAID, for example with hyaluronic acid (sodium hyaluronate), deblocks the macrophages (and N.K. cells (Natural Killer Cells) thought to be immature macrophages) by preventing enzymatic production of prostaglandin which blocks macrophage (and N.K. cell) functioning. The hyaluronic acid (and salt and other forms) not only enhances the activity of the drug (NSAID) but also reduces any side effects and toxicity that is associated with the use of the prostaglandin synthesis inhibitors. When effective dosage amounts of compositions, formulations and combinations containing effective dosage amounts of the drugs for example,
AP/P/ 9 3 / 0 0 492 (NSAIDs (for example, diclofenac)) and effective dosage amounts of, for example, hyaluronic acid or the sodium salt thereof, are applied to for example the tumour lesion (for example basal cell carcinoma) or other condition (for example, actinic keratoses lesion) for a period of time (for example, 3 times daily for 2-4 weeks), the carcinoma and lesions, as the case may be, disappear .
Applicants also postulate that when the combination or formulation is applied to the disease or condition (for example, basal cell carcinoma or actinic keratoses), the hyaluronic acid passes between the cells (in the stratum corneum and epidermis to the dermis depending on amounts) to the areas of trauma and/or pathology deficient in hyaluronic acid (or forms thereof), transporting, taking, drawing, carrying or pulling the NSAID with it to the sites of prostaglandin synthesis, penetrating to inhibit prostaglandin synthesis until the space between the cells is saturated. The NSAID now being proximate the Paccinian nerve bundle (superficial nerve bundles at the end of the nerves) gives pain relief. The macrophages (which had been previously blocked) are unblocked and act to destroy the disease or condition for example basal cell carcinoma, actinic keratoses lesion, or other disease or lesion. Furthermore, the effective non-toxic dosage amount of the composition, combination or formulation, comprising the effective dosage amount of the form of hyaluronic acid and the effective dosage amount of NSAID passing through the stratum corneum to the epidermis and to the dermis (if a sufficient amount of the form of hyaluronic acid is present), passes into the skin, accumulating and staying longer in the skin at the site of the
AP/P/ 9 3 / 0 0 4 9 2
A
BAD ORIGINAL trauma and/or pathology. Therefore, after having had an immediate effect at the site of trauma and/or pathology (for example, relieving pain and acting on the basal cell carcinoma, actinic keratoses and other disease, condition or lesion), the NSAID-hyaluronic acid combination continues to accumulate at the site in need of treatment and thereafter clears through the lymphatic system.
Thus according to another aspect of Applicant's invention, Applicants’ compositions, formulations and combinations quickly penetrate on application through the stratum corneum into the epidermis (to the dermis) by the form of hyaluronic acid transporting the NSAID, to the site of trauma and/or pathology where the amounts applied accumulate and remain for a prolonged time for treatment.
Fifteen (15) minutes after application of one of Applicants' formulations, about three times the amount of Applicants' formulation has penetrated into the skin (particularly the epidermis) than formulations and combinations not containing hyaluronic acid or effective dosage amounts of hyaluronic acid, but containing the same drug. Furthermore, the drug and hyaluronic acid accumulate and remain at the site in need of treatment for a longer period of time.
Thus according to another aspect of the invention, non-toxic effective dosage amounts of forms of hyaluronic acid (preferably sodium hyaluronate) and effective non-toxic dosage amounts of a drug may be administered in compositions to sites of trauma or pathology, on/in the skin and/or exposed tissue (for example the epidermis) by the application of the effective non-toxic dosage amount of the composition comprising an
AP/P/ 9 3 / 0 0 4 9 2
effective non-toxic dosage amount of a drug (for example an NSAID) and an effective non-toxic dosage amount of a form of hyaluronic acid (for example sodium hyaluronate) to the skin or exposed tissue whereby the forms hyaluronic acid transport the drug percutaneously to the site of trauma and/or pathology where the composition accumulates and remains for a prolonged period of time thereby retaining the drug at the site of trauma and/or pathology (for example the epidermis) for the treatment of the condition or disease and the reduction of pain.
Thus according to another aspect of the invention,
Applicants have provided compositions (formulations and combinations) (including pharmaceutical excipients suitable for topical application) from which effective non-toxic (to the patient) dosage amounts of a drug (for example an NSAID) to treat and to assist to resolve diseases and conditions of the skin and/or exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours of the skin, gential warts, cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women), and effective non-toxic dosage amounts of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof)
6 7 0 0 / £ 6 /d/dV
BAD ORIGINAL sufficient to transport (to facilitate or cause the transport of) the drug, for example NSAID, are taken for application, to a site in the skin (for example epidermis) or exposed tissue having a disease or condition for percutaneous transport into the skin and/or exposed tissue to accumulate and remain there for a prolonged period of time to for example block prostaglandin synthesis. Thus an effective dosage amount of the composition or formulation or combination penetrates quickly into the skin, for example by the hyaluronic acid transporting the NSAID or causing the NSAID to be transported for example to the epidermis of the skin, accumulates there and remains there for a prolonged period of time, thereby accumulating the drug and forms of hyaluronic acid in the skin (particularly the epidermis).
Thus according to another aspect of the invention, a method of accumulating a drug and a form of hyaluronic acid in skin and/or exposed tissue is provided comprising' topically administering a therapeutically effective non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for topical applications, an effective non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, preferably a non-steroidal antiinflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) (to treat and to assist to resolve the disease and conditions of the skin and exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots and like lesions (found for the most part in the
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9 epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or cu.mours of the skin, primary and metastatic melanoma in the skin, genital warts cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis) , corns on the feet and hair loss on the head of pregnant women), and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) effective to transport (to facilitate or cause the transport of) the drug (for example NSAID) percutaneously to the site in the skin (for example epidermis) or exposed tissue of the disease or condition to accumulate and remain there for a prolonged period of time for example to block prostaglandin synthesis.
According to another aspect of the invention, a method of quickly delivering a drug to the skin or exposed tissue, particularly the epidermis, and maintaining the drug therein for a prolonged period of time is provided, the method comprising topically administering (for example rubbing in) an effective non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and assist to resolve the disease and/or condition of the skin and exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots and like lesions (found for the most part in the epidermis) , squamous cell tumours, metastatic cancer of the breast to the
AP/P/ 9 3 / 0 0 492
BAD ORIGINAL skin, primary and metastatic melanoma in the skin, malignancies and/or tumours of the skin, genital warts, cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women)), non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, preferably a nonsteroidal anti-inflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol™) and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) sufficient to transport (to facilitate or cause the transport of) the drug for example the NSAID percutaneously to the site of the trauma and/or pathology in the skin (for example epidermis) or exposed tissue, for remaining there for a prolonged period of time (for example in the epidermis and dermis) to for example block prostaglandin synthesis. Suitable amounts of the form of hyaluronic acid may comprise in excess of 5 mg. per cm2 in a form which transports the drug (for example molecular weights of the form of hyaluronic acid being less than about 750,000 Daltons or if at substantially greater molecular weights, diluted (to reduce) the concentration or autoclaved or cleaved if required to reduce the size of the molecules.
According to another aspect of the invention, a method of controlling the unloading of a drug from the skin or exposed tissue into the lymphatic system comprises delivering
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BAD ORIGINAL ft (transporting) an amount of drug into the skin or exposed tissue by an effective non-toxic dosage amount of a form of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to the skin (epidermis) or exposed tissue to control the unloading of the drug into the lymphatic system (for example by the application of greater than 5 mg./cm2) of the form of hyaluronic acid.
Thus according to another aspect of the invention a composition is provided which when administered to a human by preferably administration to the skin and/or exposed tissue of a human, unloads its contents into the lymphatic system, the composition comprising an effective non-toxic dosage amount of a drug (for example an NSAID or an anti-cancer drug (Novantrone) and an effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub-units of hyaluronic acid (for example at least about 5-10 mg/cm2 of skin or exposed tissue). Thus the composition is made up of a plurality of such dosage forms (for example a cream or lotion or gel).
Thus according to another aspect of the invention, a new composition for treating diseases via the lymphatic system is provided comprising a plurality of effective non-toxic dosage amounts of the composition, each dosage amount comprising hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or subunits of hyaluronic acid for passing into the lymphatic system and a therapeutic effective amount of medicine for treatment of a disease (which disease may be in the lymphatic system).
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According to another aspect of the invention, the composition may be for application to the skin or exposed tissue .
According to another aspect of the invention, a 5 composition is provided from which effective dosage amounts may be taken and administered, each effective dosage amount of the composition comprising an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub10 units for transporting a therapeutically effective non-toxic dosage amount of a medicine and/or therapeutic agent (for example an NSAID) in the composition into the skin and/or exposed tissue when applied thereto to an area of pathology and/or trauma then into the lymphatic system, the dosage amount being essentially systemic independent such that substantial amounts do not enter the blood system prior to clearing (passing) into the lymphatic system. Preferably the amount of the form of hyaluronic acid in each dosage amount administered is greater than about 5-10 mg./cm2 and the molecular weight is less than about 750,000 daltons.
We have compared the penetration and retention of one of our combinations (formulations) with a control and Voltarol Emulgel in the skin as follows:
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BAD ORIGINAL ft (A)
OUR FORMULATION l°s DICLOFENAC IN 3.0¾ HA GEL__50g/tube
EPDICLO1
LOT XPB 044 Quantity 1500ml
FORMULA | Supplier | Lot | Amount | Percent |
Sterile Water | Baxter | AW45F1 | 1397ml | — |
Glycerin | Life | 1043 | 4 5g(3 6ml) | 3% |
Benzyl Alcohol | Caledon | 02517 | 22.5g(22ml) | 1.5% |
Liquid Wax DICDD | Brooks | 191-175 | 45g | 3% |
Diclofenac Sodium | Prosintex | 9113003 | 15g | 1% |
Sodium Hyaluronate | Skymart | HG-1103 | 45g | 3% |
Mol. Wt. 661, 600 | ||||
PROCEDURE |
- Set up stirring apparatus using a 3 liter stainless steel beaker
Add Water, Glycerin, Benzyl Alcohol and Liquid Wax DICDD, stir and mix for 10 minutes
- Add Diclofenac Sodium and stir for 30 minutas to dissolve
- Add Sodium Hyaluronate and stir for 90 minutes
EILLEU
In a 50 ml aluminum collapsible tube, inside of tube lacquered with a phanolic resin, outside of tube white regular enamel coating;
mm white polypropylene screw on cap with pierce tip
Gels Batch No.s (B) Voltarol Emulgel 060400 10 93 (C) 1% Diclofenac Gel XPBO49 (Control)
AP/P/ 9 3 / 0 0 4 9 2 bad original d
4 (C) CONTROL·
1% DICLOFENAC IN CARAPOL GEL, 50g Jar LOT XPB 049 Quantity 100ml
FORMULA | Supplier | Lot | Amount | Percent |
Sterile Water | Baxter | AW45N5 | 93ml | — |
Glycerin | BDH | 2579 | 3g | 3% |
Benzyl Alcohol | BDH | 23797 | 1.5g | 1.5% |
Liquid Wax DICDD Brooks | L-1424 | 3g | 3% | |
Diclofenac Sodium Prosintex | 9113003 | ig | 1% | |
Carbopol 934 | A&C Chemicals | 910304 | ig | 1% |
PROCEDURE Set up stirring apparatus using a beaker | 400ml stainless steel | |||
Add Water, Glycerin, Benzyl Alcohol, stir to mix thoroughly for 10 minutes | Liquid Wax | DICDD, and | ||
- Add Diclofenac Sodium and stir for 20 | minutes to | dissolve | ||
- Very slowly add Carbopol 934, | avoid getting lumps | |||
Samples | ||||
Cell | Sample | Quantity of gel applied | ||
(mg) | ||||
A | 060400 10 93 | 192 | ||
B | 060400 10 93 | 192 | ||
C | EPDICLO1* | 192 | ||
D | EPDICLO1* | 192 | ||
E | XPB049 | 192 | ||
F | XPB049 | 192 |
AP/P/ 9 3 / 0 0 4 9 2 * - Our Formulation
Skin Type
One piece of skin (Female, 37 years, smoker, breast skin) was used for one sample from each batch. A second piece of skin (no further details available) was used for the second
5 sample from each batch. The skin was stored deep frozen (<20°C) until thawed for this experiment. Full thickness skin was used for this experiment.
Experimental Conditions
Skin permeation cells were prepared containing an exposed skin surface area of 9.6 cm2 and a constantly stirred receptor fluid beneath the skin consisting of 135 ml of ethanol: phosphate buffered saline (25:75 v/v).
Each cell was allowed to equilibrate for 1 hour at 37°C after which the gel was spread evenly over the skin surface at a concentration of 20 mg/cm2). See table above.
The cell was then maintained at 37°C with an air temperature above the skin of 35°C.
hours after application of the gel the experiment was stopped and a portion of the receptor fluid removed. The skin was removed from the cell and any gel remaining on the surface carefully wiped off with dry paper towel followed by paper towel moistened with water. The skin was cut with a scalpel to obtain thin top and thicker lower sections of skin.
This was done in order to obtain layers of skin which approximated the epidermal and dermal layers. Each skin section was weighed and the residual diclofenac extracted with 10ml of fresh receptor fluid using an ultra turrax homogeniser. The homogenates were centrifuged and a portion of the resultant supernatant solutions removed.
The receptor fluid and skin extracts from each cell were assayed for diclofenac content by using a validated reverse phase high performance liquid chromatography (HPLC) method.
AP/P/ 93/0049?
BAD ORIGINAL ft ge.s_u.liia
Distribution of Diclofenac_14_hoju^s_after application of
Diclofenac Gel
μ? | Skin Weight (g) | μ? | μ9/σ | Skin Weight | ug | ug/g | ||
(Voltarol | ||||||||
Emugel) | ||||||||
060400 10 | 93 | 447 | 0.1363 | 101 | 742 | 1.2449 | 217 | 174 |
060400 10 | 93 | 764 | 0.2445 | 141 | 577 | 1.2351 | 202 | 164 |
Mean | 606 | 660 | 169 | |||||
(Our | ||||||||
Formulation) | ||||||||
EPDXCLO1 | 247 | 0.1535 | 133 | 867 | 1.4663 | 14 8 | 101 | |
EPDICLO1 | 292 | 0.1647 | 145 | 879 | 1.0022 | 86 | 86 | |
Mean | 269 | 873 | 93 | |||||
(Control) | ||||||||
XPB049 | 184 | 0.1275 | 35 | 272 | 1.1324 | 58 | 51 | |
XPB049 | 147 | 0.2068 | 82 | 396 | 1.0893 | 68 | 63 | |
Mean | 16S | 334 | 57 |
Thus having regard to the above and Figures 1', 2' and 3', it is clear that the sodium hyaluronate takes the diclofenac into the skin to the epidermis level (See Figure 1') more rapidly than the Voltarol Emugel or non-hyaluronic acid diclofenac containing control formulation, accumulates it there and retains it there longer. The other formulations permit the NSAID, diclofenac, to pass through the bottom skin portion (dermis) quicker, thereby clearing it from the epidermis and
AP/P/ 93/00492
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- 4 7 dermis, quicker. Furthermore, more cf Applicants' formulation is in the epidermis and in the dermis even after 12 hours.
It is also clear that Applicants’ formulations clear into the lymphatic system not through the blood system. Yet the prior art topical formulations have always tried to drive the formulations through the skin into the blood for treatment of the disease or condition in the area (i.e. systemic action).
Thus, our composition, formulation and combination, (and dosage amounts thereof) penetrate quickly and rapidly at the site of treatment through the upper skin into the epidermis, where the paccinian bundles are located and the NSAID and the form of hyaluronic acid are accumulated and are retained longer, where needed (for example for the treatment of basal cell carcinoma).
Further, the NSAIDs are retained in the area to be treated with the form of hyaluronic acid. In doing so, they preclude prostaglandin synthesis , in effect, deactivating the synthesis or inhibiting the synthesis, of prostaglandins, permitting the macrophages' scavenger cell activity to eliminate the tumour and lesion. Additionally, a rapid onset of pain relief (analgesic effect) is provided (depending on the amount of NSAID and form of hyaluronic acid) usually where in excess of about 10 mg of the form of hyaluronic acid (preferably hyaluronic acid and salts thereof) is administered per cm2 of surface area comprises the dosage amount administered. However, there are no blood levels of the NSAID in the immediate area of treatment. The forms of hyaluronic acid are thus cleared via the lymphatic system. Then the lymphatics pass the forms of hyaluronic acid, Applicants believe, to the blood system. Thus,
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BAD ORIGINAL ft the NSAIDs and forms of hyaluronic acid stay ar the site to be treated for well in excess of 12 - 24 hours, a protracted stay.
Thus, over the period of treatment (for example, applications of effective non-toxic dosage amounts of compositions containing for example effective non-toxic dosage amounts of the NSAIDS and effective non-toxic dosage amounts of the sodium hyaluronate, 3 times a day for 2-4 weeks, transport the NSAIDS to to the epidermis to inhibit prostaglandin synthesis to enable the macrophages to scavenge the tumour cells and eliminate them. The end result is the successful treatment of the disease or condition at the site of trauma and/or pathology of the skin or exposed tissue, for example, the resolution of, the basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours in the skin, primary and metastatic melanoma in the skin, genital warts cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women, with complete disappearance of the disease or condition as the case may be, by topical therapy without resorting to surgery.
One of the formulations which we have employed successfully is a gel formulation comprising 3% diclofenac in 2.5% sodium hyaluronate formulated as follows:
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BAD ORIGINAL rf
Formulation 1 (3000 mi.) | Am-unt Pert | χώ1; | ||
Formula | Suppliar | GOT! | ||
Glycerine | Life | 1043 | 150 g (119 ml) | 5 |
Benzyl Alcohol Caledon | 02517 | 90 g (36 ml) | 3 | |
Diclofenac Sodium | P ros intex | 9113003 | 90 grams | 3 |
Sodium Hyaluronate | Skymark | HG1003 | 75 grams | 2.5 |
(MW 661,660) | ||||
Sterile water | Baxter | AW4455 | 2795 ml. |
balance
Procedure
- set up stirring apparatus using a 4 litre stainless steel beaker
- add water, Glycerine, and Benzyl Alcohol; stir to mix
- add Diclofenac Sodium and stir for 30 minutes
- then add the Sodium Hyaluronate and stir for 90 minutes
- initially, stir at a high torque but avoid splashing; as the gel thickens, stir at a lower torque.
The gel is then packaged in a tube or jar or other suitable container for use. Identification of suitable dosage amounts and how they are taken from the container may be provided with the container - for example squeeze X” cm. of ribbon from the tube; fill spoon or spatula accompanying jar; (the spoon or spatula containing a predetermined dosage amount) then apply and rub into site of trauma and/or pathology (the dosage amount indicated will be such amount of the composition which comprises in excess of about 5 mg. of sodium hyaluronate per cm2 (square centimeter) of skin or exposed tissue to which the dosage amount is to be applied. The amount of Diclofenac Sodium was determined in the same manner (having regard to the dosage amount required).
Another such formulation is:
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Formulation 2
Formula_Supplier_(1Ώ11_Amcuat_Percent
Methoxypolyethylene | Sigma | 34F-0266 | 300 g . | 20 |
Glycol 350 | ||||
Benzyl Alcohol | BDH | 23797 | 15 g. | 1 |
Diclofenac Sodium | Prosintex | 9123012 | 45 g. | 3 |
Sodium Hyaluronate | Skymart | HG 1004 | 37.5 g. | 2.5 |
(MW 679,000) | ||||
Sterile Water | Baxter | AW45R6 | 1200 ml. |
balance
Procedure set up stirring apparatus using a 3 litre stainless steel beaker
- add water, Methoxypolyethylene Glycol 350, and Benzyl
Alcohol and stir for 20 minutes to mix
- add Diclofenac Sodium and stir for 30 minutes to dissolve
- add Hyaluronate Sodium slowly and stir initially at a high speed, but avoid splashing
- after addition, stir at a slower speed for 90 minutes; the slower speed reduces the formation of air bubbles
- the result is a clear, transparent, viscous gel which is put into a container. Once again instructions are given for administration and if applicable measuring devices (to provide a premeasured dosage amount) accompany the container.
Still other formulations are:
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Formulation 3
3% Diclofenac in 2,5 | >% HA Gel | W | Amount | Percen |
Formula | Suoolier | |||
Sterile Water | Baxter | AW45KS | 1200 ml | |
Methoxypolyethylene | Sigma | 34F-0266 | 300G (273 ml) | 20% |
Glycol 350 | ||||
Benzyl Alcohol | 3DH | 23797 | 15G (14 ml) | 1% |
Diclofenac Sodium | Pros intex | 9123012 | 45 g | 3% |
Sodium Hyaluronate | Skymart | HG 1004 | 37.5 g | 2.5% |
MW 679,000
Procedure
25
Set up stirring apparatus using a 2 liter stainless steel beaker,
Add water, Methoxypolyethylene Glycol 350, and Benzyl Alcohol and stir for 20 minutes to mix,
Add Diclofenoc Sodium and stir for 30 minutes to disolve, Add Hyularonate Sodium slowly and stir initially at a high speed, but avoid splashing,
After addition, stir at a slower speed for 90 minutes,the slower speed reduces the formation of air bubbles,
The result is a clear transparent, viscous gel which is poured into jars and tubes. Once again instructions accompany the container and where applicable appropriate devices for providing a premeasured amount of the composition accompany the container.
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Formulation 4
5% IBUPROFEN IM | 3.0¾ HA GEL, 50 ml JAR | |||
E&mula | Supplier | LOT | Amount | Percent |
Sterile Water | Baxter | AW45R6 | 196 ml | — |
Meglumine | Falk | 15684 | 11 g | 5.5% |
Ibuprofen | SDH | 19/241 | 10 g | 5% |
Benzy Alcohol | BDH | 23797 | 2 g | 1% |
Glycerin | BDH | 2579 | 2 g | 1% |
Hyaluronate | ||||
Sodium | Skymart | HG 1003 | 6 g | 3% |
Mol Wt 661,600
PROCEDURE
- Set up stirring apparatus using a 300 ml stainless steel beaker,
Add Sterile Water and Meglumine, and stir for 10 minutes, Add Ibuprofen and stir for 15 minutes,
- Add Benzyl Alcohol, followed by Glycerin and stir for 15 minutes,
Finally, add Hyaluronate Sodium slowly and stir initially at a high torque to mix, but avoid splashing,
- As the gel thickens, stir at a slow speed for 90 minutes.
AP/P/ 93/00492
Fominlat ion .J3
2% PIROXICAM IN 2.5¾ | HA GEL | |||
Formula | Supplier | LOT | Amount | Percent |
Sterile Water | Baxter | AW45R6 | 200 ml | |
Meglumine | Falk | 15634 | 3 g | 4¾ |
Piroxicam | AMS A | 1-010 | 4 g | 2¾ |
Hyaluronate Sodium | Skymart | HG 1003 | 5 g | 2.5% |
MW 661, 600 |
PROCEDURE
Set up stirring apparatus using a 300 ml stainless steel beaker,
- Add 200 ml of sterile water,
- Add 8 grams of Meglumine and dissolve,
Very slowly add 4 grams of Piroxicam and stir for 20 minutes,
- Slowly add 5 grams of Hyaluronate Sodium and stir at high speed,
- Stir for 90 minutes at a slower speed
COMMENTS
- A clear yellowish transparent gel ! AP/P/ 93/00492
BAD ORIGINAL A
Formulation 6.
5% IBUPROFEN CREAM, 50 mi. JAR
OILY PHASE
r uriuu Liquid wax DICDD | Brooks | _ L-1424 | nmuuu u 450 g | rcr LVIIL 15% |
Brookswax D | Brooks | P-490 | 4S0 g | 16% |
Glycerin | BDH | 109109/2578 | 150 o(119 | ml) 5% |
AQUEOUS PHASE | ||||
Sterile Water | Baxter | AW45F1 | 1950 ml | -- |
Meglumine | Falk | 15684 | 150 g | 5% |
Ibuprofen | BKH | 19/241 | 150 g | 5% |
MW 200,00 | ||||
Sodium Hyaluronate | Skymart | OOl | 45 g | 1.5% |
Preservative Suttocide | A,Sutton | SH-107 | _ | _ |
PROCEDURE
A - Add all the ingredients of the oily phase A into a 4 liter stainless steel beaker, melt at 55°c, finally heat to 75% when Aqueous Phase B is ready
B - Into a 3 liter stainless steel beaker, add 1950 ml water, set up, the stirring apparatus, add the Meglumine, stir to dissolve for 10 minutes,
Slowly add Ibuprofen, stir to dissolve for 20 minutes,
Very slowly add Sodium Hyaluronate and stir for one hour to dissolve all the Sodium Hyaluronate,
Finally, heat to 75°C,with stirring for a total time of 30 minutes.
AP/P/ 93/00492
POUR R INTO A, both at a temperature of slowly
- Remove the heat source and stir with a strong vortex for one hour,
- When the temperature has cooled down to 45cC add preservative Suttocide A,
- Continue stirring at a slower speed until the temperature is 35°C,
- At 35cC remove Formulation 7. 1% DICLOFENAC IN 3% | the propeller, HA Gel. 50 ml | pour into 50 ml jars. | ||
iar | Percent | |||
Formula | Supplier | Quantity LOT | 3000ml Amount | |
Sterile Water | Baxter | AW45R6 | 2796ml | -% |
Glycerin | BDH | 2579 | 50g(71ml) | 3% |
Benzyl Alcohol | BDH | 23797 | 45g(43ml) | 1.5% |
Liquid wax DICDD | Brooks | 191-175 | 90 g | A |
Diclofenac Sodium | Pros intex | 9113003 | 30 g | 1% |
Hyaluronate Sodium | Skymout | KG 1004 | 90 g | 3% |
MW 679,000
PROCEDURE
- Set up stirring apparatus using a 4 liter stainless steel beaker.
- Add water, Glycerin, Benzyl Alcohol and Liquid wax DICDD and stir to mix thoroughly for 10 minutes
Add Diclofenac Sodium and stir for 30 minutes to dissolve.
- Slowly add Hyaluronate Sodium, stirring at a high torque initially during addition.
- After addition stir at a slower speed for 90 minutes.
- A white opaque viscous gel is formed.
AP/P/ 93/00492
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Εώςίγ·1 ? latieD—i
1% DICLOFENAC IN 3.0% HA Gel. 50 ml tube | ||||
Formula | Supplier | Quantity 1500 ml | ||
LOT | Amount_Percent | |||
Sterile Water | Baxter | AW45F1 | 1397 ml | -% |
Glycerin | Life | 1043 | 45g(36 ml) | 3% |
Benzyl Alcohol | Caledon | 02517 | 22.5g(22ml) | 1.5% |
Liquid wax DICDD | Brooks | 191-175 | 45 g | 3% |
Diclofenac Sodium | Prosintex | 9113003 | 15 g | 1% |
Sodium Hyaluronate | Skymart | HG 1003 | 45 g | 3% |
Mol. Wt. 661,600
PROCEDURE
Set up stirring apparatus using a 3 liter stainless steel beaker .
- Add water, Glycerin, 3enzyl Alcohol and Liquiwax DICDD, stir to mix for 10 minutes.
- Add Diclofenac Sodium and stir for 30 minutes to dissolve.
Add Sodium Hyaluronate and stir for 90 minutes.
AP/P/ 9 3 / 0 0 4 9 2
F£ rmvlation 9
HYANALGESE CREAM (L) ml tube
Quant icy 3000 ml
5 | FORMULA A. Oily Phase | SUPPLIER | LOT | AMOUNT | PERCENT |
Liquid Wax DICDD | Brocks/Amisol | 450g | 15.0% | ||
Brookswax D | Brocks/Amisol | 480g | 16.0% | ||
10 | Glycerine B. Aqueous Phase | Amisol | 150g | 5.0% | |
Sterile Water | Baxter | AW4YA8 | 1950ml | -% | |
Meglumine | Falk | 150g | 5.0% | ||
Sodium Hyaluronate | Skymart | PO1 | 45g | 1.5% | |
15 | MW 207,000 Ibuprofen | BDH | 150g | 5.0% | |
Suttocide A | Sutton | 9. Og | 0.3% |
PROCEDURE
A. - Add all the ingredients of the oily phase into a 4 liter stainless steel beaker, melt at 55°C, finally heat to 75°C when aqueous phase is ready (at 75°C) to pour in.
B. - Into another 4 liter stainless steel beaker, add 1950 ml water.
Set up the stirring apparatus and add the Meglumine
Stir to dissolve with high torque, then slowly add
Ibuprofen
- When the Ibuprofen is dissolved, slowly add Sodium
Hyaluronate
Stir cold for one hour to dissolve all the ingredients
- Finally heat to 75°C and stir thoroughly throughout a 30 minute period
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MIX 3 INTO A
Slowly pour B into A (both at 75°C) with stirring Immediately remove the hot plate (heat) and stir
- Stir with a strong vortex for one hour
- When the temperature is 45°C, add the preservative Suttocide A
Stir for about an hour to cool to 35°C
At 35°C remove the propeller and pour into 50 ml tubes
Pour 50 grams of the cream into each tube
1% BANAMINE IN 2.5% HA GEL (L) XPB 041 Quantity 3000 ml
FORMULA
SUPPLIER_LQI AMOUNT PERCENT
Sterile Water | Boxter | AW4SA2 | 2400 ml | --% |
Sodium Hyaluronite MW 661,600 | Skymart | HE1003 | 7 5g | 2.5% |
♦Banamine, 100 ml vial | Scheing | 0 CNXB13 | 300 ml | 1% |
Banamine. 100 ml vial | Sshsing | Q £14X312 | 2£J_rcL.. 3000 ml | Li |
(50 mg/ml) 600 = 30,000mg = 30 grams Flunixin in 600 ml ♦Banamine contains Flunixin Meglumine (50 mg Flunixin per ml) or 83 mg Flunixin Meglumine
EJRQCELULE
Set up stirring apparatus using a 4 liter stainless steel beaker
- Add water, stir with a strong vortex, then add sodium
Hyoluronate slowly
Then immediately add the Banamine, stir the mixture for 4 hours.
One form of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid,
AP/P/ 93/00492
preferably hyaluronic acid and salts and thereof, suitable for use with Applicant's invention is a fraction supplied by Hyal Pharmaceuticals Limited. One such fraction is a 15 ml vial of Sodium hyaluronate 20mg/ml (300mg/vial - Lot 2F3) . The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight of about 225,000. The fraction also contains water q.s. which is triple distilled and sterile in accordance with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
The fraction of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, preferably hyaluronic acid and salts thereof, may comprise hyaluronic acid and/or salts thereof having the following characteristics:
a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from the group (and preferably all characteristics) consisting of the following:
i) a molecular weight within the range of
150,000-225,000;
ii) less than about 1.25% sulphated mucopolysaccharides on a total weight basis;
iii) less than about 0.6% protein on a total weight basis;
iv) less than about 150 ppm iron on a total weight basis;
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v) less than about 15 ppm lead on a total weight basis;
vi) less than 0.0025% glucosamine;
vii) less than 0.025% glucuronic acid;
viii) less than 0.025% N-acetylglucosamine;
ix) less than 0.0025% amino acids;
x) a UV extinction | coefficient | at | 257 nm | of | |||
less | than | about | 0.275; | ||||
xi) a UV extinction | coefficient | at | 280 nm | of | |||
less | than | about | 0.25; and | ||||
xii) a pH within | the range | of | 7.3-7. | 9 . |
Preferably, the hyaluronic acid is mixed with water and the fraction of hyaluronic acid has a mean average molecular weight within the range of 150,000-225,000. More preferably, the fraction of hyaluronic acid comprises at least one characteristic selected from the group (and preferably all characteristics) consisting of the following characteristics:
i) less than about 1% sulphated mucopolysaccharides on a total weight basis;
ii) less than about 0.4% protein on a total weight basis;
iii) less than about 100 ppm iron on a total weight basis;
iv) less than about 10 ppm lead on a total weight basis;
AP/P/ 9 3 / 0 0 492
v) | less | than | 0.00166% | glucosamine; |
vi) | less | than | 0.0166% | glucuronic acid; |
vii) | less | than | 0.0166% | N-acetylglucosamine |
viii) | less | than | 0.00166% | amino acids; |
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x) a UV extinction coefficient at 257 nm of less than about 0.23;
xi) a UV extinction coefficient at 280 nm of less than 0.19; and xii) a pH within the range of 7.5-7.7
Applicants also propose to use sodium hyaluronate produced and supplied by LifeCore™ Biomedical, Inc., having the following specifications: Characteristics
Appearance
Odor
Viscosity Average Molecular Weight UV/Vis Scan, 19Q-320nm
OD, 260nm
Hyaluronidase Sensitivity
IR Scan pH, lOmg/g solution
Water
Protein
Acetate
Specificat ion
White to cream colored particles No perceptible odor < 750,000 Daltons
Matches reference scan < 0.25 OD units
Positive response
Matches reference
6.2 - 7.8
8% maximum < 0.3 mcg/mg NaHy < 10.0 mcg/mg NaHy
Heavy Metals, maximum ppm | ||||||
As Cd | Cr Co | Cu | Fe | Pb | Hg | Ni |
2.0 5.0 | 5.0 10.0 | 10.0 | 25.0 | 10.0 | 10.0 | 5.0 |
Microbial | Bioburden | None | observed |
Endotoxin
Biological Safety Testing < 0.07EU/mg NaHy
Passes Rabbit Ocular
Toxicity Test
AP/P/ 9 3 / 0 0 492
BAD ORIGINAL .Another form of sodium hyaluronate is sold under the name Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications:
Specifications’ Test
Results
Lot No . | HG1004 |
PH | 6.12 |
Condroitin Sulfate | not detected |
Protein | 0.05% |
10 Heavy Metals | Not more than 20 ppm |
Arsenic | Not more than 2 ppm |
Loss on Drying | 2.07% |
Residue on Ignition | 16.69% |
Intrinsic Viscosity | 12.75 dl/s (XW: 679,000) |
15 Nitrogen | 3.14 % |
Assay | 104.1% |
Microbiological Counts | 30/g |
E. coli | Negative |
Mold and Yeast | Not more than 50/g |
Z6^0Uz£6 /d/dV
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Other forms of hyaluronic acid and/or its salts, and homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in prior art documents provided the form of hyaluronic acid chosen is suitable for transport of the medicine.
The following references teach hyaluronic acid, sources thereof, and processes for the manufacture and recovery thereof which may be suitable.
United States Patent 4,141,973 teaches hyaluronic acid fractions (including sodium salts) having:
(a) an average molecular weight greater than about 750,000, preferably greater than about 1,200,000 - that is, a limiting viscosity number greater than about 1400 cm3/g., and preferably greater than about 2000 cm3/g.;
(b) a protein content of less than 0.5% by weight;
(c) ultraviolet light absorbance of a 1% solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280 nanometers wavelength;
(d) a kinematic viscosity of a 1% solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
(e) a molar optical rotation of a 0.1 - 0.2% sodium hyaluronate solution in physiological
AP/P/ 9 3 / 0 0 492
4 buffer of less than -11 X 103 degree - cn2/nole (of disaccharide) measured at 220 nanometers;
(f) no significant cellular infiltration of the vitreous and anterior chamber, no flare in the aqueous humour, no haze or flare in the vitreous, and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye when one milliliter of a 1¾ solution of sodium hyaluronate dissolved in physiological buffer is implanted in the vitreous replacing approximately one-half the existing liquid vitreous, said HUA being (g) sterile and pyrogen free and (h) non-antigenic.
Canadian Letters Patent 1,205,031 (which refers to
United States Patent 4,141,973 as prior art) refers to hyaluronic acid fractions having average molecular weights of from 50,000 to 100,000; 250,000 to 350,000; and 500,000 to 730,000 and discusses processes of their manufacture.
In order to determine the blood levels in patients using formulations made according to embodiments of the invention, a study of the pharmacokinetic profiles of two topical diclofenac formulations after repeat dosing were undertaken .
One such product was the product Voltarol Emulgel marketed in the United Kingdom by Geigy. The other was a Diclofenac preparation in Hyaluronic Acid.
This was an open, repeat dose, crossover comparison using a randomized balanced block in six healthy volunteers.
AP/P/ 93/00492
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5
The study consisted cf administration with one, two week period in between periods, each period lasting fourteen days. The test articles applied were for the first six days of each period and the seventh day was study day during which the final application is made and blood samples taken.
The approximate duration of the study including pre and post study screening was six weeks.
Doses
Diclofenac (3.0%) with Hyaluronic Acid (2.5%)
Dose: Approximately 2 g, three times daily
Route: Topical (Wl)Voltarol Emulgel, Diclofenac diethylammonium salt 1.16g aqueous gel (Geigy)
Dose: Approximately 2 g, three times daily Route: Topical (Wl)
ADMINISTRATION: to suitable patients
Subjects applied one of the designated test articles topically to the calves and massaged into the skin, in a dose of approximately 2 g per application three times a day for six consecutive days. The size of a 2g dose was prepared by comparison with a silicone example given to each subject.
On the seventh day, the cream was applied once, in the same manner as before, under the supervision of the staff of the Clinical Investigation Unit.
After a washout period of one week the procedure was repeated with the alternate test article.
The following were the results of the tests:
(H = hyaluronic acid formulation) (V = Voltarol Emulgel)
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- 66 PERIOD 1
All concentrations ng ml - 1
SUBJECT TIME POINT (hours)
Q.25 Q.5 1 , 2 3_4 5_5_8 IQ 12
H-l | 10.3 | 7.1 | 6.4 | ND | ND | 5.4 | 6.5 | 5.1 | ND | ND | ND | ND |
H-2 | ND | 5.1 | ND | 5.1 | ND | ND | ND | ND | ND | 5.1 | ND | ND |
ND | ND | ND | 5.5 | 5.2 | ND | ND | ND | ND | ND | ND | ND | V-3 |
ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | H-4 |
ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | V-5 |
ND | ND | ND | ND | ND | ND | ND | 8.4 | ND | ND | ND | ND | V-6 |
ND | = NONE | 1 DETECTED | {>5.0 | ng | ml~l) |
PERIOD.....II
All concentrations ng ml -1
SUBJECT TIME POINT (hours)
0 | 0.25 | . 0.5 . | 1 | 2 | 3 | 4 | 5 | 6 | 3 | 10 | 12 | |
V-l | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND |
V-2 | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND |
H-3 | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND |
V-4 | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND |
H-5 | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND |
HrS | ND | ND | ND | ND | HD | ND | JHD | HD .. | ND | JiD | ____ND. |
ND = NONE DETECTED (>5.0 ng ml-1)
Other tests were undertaken to determine blood levels comparing Proflex (a formulation containing Ibuprofen) and the following formulation containing hyaluronic acid and Ibuprofen. HYANALGESE CREAM (L) X PB 022
- 50 ml tube
Quantity 3000 ml
ECRMULA
AP/P/ 93/00492
A. Oily Phase | SUPPLIER | . LOT | AMOUNT | PERCENT |
Liquid Wax DICDD | Brooks/Amisol | 450g | 15.0% | |
Brookswax D | Brooks/Amisol | 480g | 16.0% | |
Glycerine | Amisol | 150g | 5.0% | |
B. Aqueous Phase | ||||
Sterile Water | Baxter | AW4YA8 | 1950ml | -% |
Meglumine | Falk | 150g | 5.0% | |
Sodium Hyaluronate | Skymart | PO1 | 4 5g | 1.5% |
MW 207,000 | ||||
Ibuprofen | BDH | 150g | 5.0% | |
Suttocide A | Sutton | 9.0g | 0.3% |
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The following were the results (A) PROFLEX
SUBJECT Time after administration (Hours)
Number
. PD | 0 | 0.25 | 0.5 ... | 1 | —2 | 3 | _ | 5 | 6 | 3 | 10 | 12 | |
1 | ND | 0.41 | 0.37 | 0.37 | 0.32 | 0.30 | 0.27 | 0.27 | 0.24 | 0.37 | 0.31 | 0.31 | 0.16 |
2 | ND | 0.12 | C. 12 | 0.03 | 0.11 | 0. 12 | 0.12 | 3 . Z / | 0.09 | 0.09 | 3.03 | ND | 0.05 |
3 | ND | 0.09 | 0.C8 | 0.07 | ND | ND | ND | ND | ND | ND | ND | ND | ND |
4 | ND | 0.12 | 0.14 | 0.16 | 0.11 | 0. 11 | 0.25 | 0.24 | 0.17 | 0.13 | 0.15 | 0.11 | 0.13 |
5 | ND | 0.14 | 0.19 | 0.19 | 0.15 | 0.16 | 0.16 | 0.14 | 0.12 | 0.11 | 0.13 | 0.10 | 0.07 |
6 | ND | Q.ll | 0.09 | 0.09 .. | 0.06 | 0.07 | 0.05 | 0.05 | 0.05 | ND | ND | ND | ND |
Mean | 0.00 | 0.17 | 0.17 | 0.16 | 0.13 | 0.13 | 0.14 | 0.13 | 0.11 | 0.12 | 0.11 | 0.09 | 0.07 |
S.D. | 0.00 | 0.12 | 0.10 | 0.11 | 0.10 | 0.10 | 0.10 | 0.10 | 0.08 | 0.13 | 0.11 | 0.12 | 0.06 |
(B) HYALURONIC ACID AND IBUPROFEN
SUBJECT Time after administration (Hours)
Number
PD 0_Q-25 0.5 1_2_3_4 5 6 8 10 12
1 | ND | 0.11 | 0.11 | 0.12 | 0.08 | 0.C8 | 0.09 | 0.11 | 0. 12 | 0.08 | 0.11 | 0.16 | 0.14 |
2 | ND | 0.22 | 0.21 | 0.26 | 0.17 | 0.24 | 0.24 | 0.25 | 3.23 | 3.19 | 0.19 | 0.20 | 0.14 |
3 | ND | 0.17 | 0.10 | 0.12 | 0.C9 | 0.C8 | 0 . C7 | 3.36 | ND | 3.36 | 0.26 | 0.39 | 0.05 |
4 | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND |
5 | ND | 0.17 | 0.16 | 0. IS | 0.12 | 0.09 | 0.10 | V . i. i. | u . 10 | 3.09 | 0.10 | 0.07 | ND |
5 | 0.07 | 3 . C7 | 0.09 | ND | XD | ND | ND | ND | ND | ||||
Mean | 0.00 | 0.12 | 0.11 | 0.13 | 0.08 | 0.03 | 0.C8 | 0.39 | 3.03 | 3.07 | 0.11 | 0.09 | 0.06 |
S.D. | 0.00 | 0.08 | 0.07 | 0.08 | 0.C6 | 0.08 | 0.08 | 0.39 | 0.09 | 0.07 | 0.13 | 0.08 | 0.07 |
ND None detected <0.05 gg/ml
The above clearly indicates that the blood levels are much less using hyaluronic acid to administer the NSAID.
PRELIMINARY REPORT CNf >3*
A trial was conducted using a gel composition (Number 109) comprising 3% Diclofenac in 2.5% Hylauronic Acid as previously described and a composition containing Diclofenac sodium salt 3% but not including any form of hyaluronic acid. (Number 112) The trial was conducted with 60 patients who were randomly assigned to test preparations number 109 or 112. The trial has not been completed as yet but so far 31 patients have finished the protocol. Patients were diagnosed:
to
GL <
BAD ORIGINAL A
Rheumatoid arthritis of the knee
Myofascial trigger points in the M. trapezius area
Periarthropathies of knee without effusion
Periarthropathies with effusion in the knee joint 5 The 31 patients were aged 22-75 years (27 females, 4 males). All patients were hospitalized. Patients entering the trial were thoroughly examined and type of extraarticular or articular rheumatism assessed.
On day 1 baseline pain was assessed on the 10 cm 10 visual analogue scale (VAS) and pain measurement of the quantititative pain sensitivity using a pressure tolerance meter (PTM) were performed. Then test gel - approximately 2.g - was massaged on to the skin of maximum pain. Gels were applied 3 times daily.
0.5, 1, 1.5, and 2 hours after morning application measurements of pain sensitivity were carried out and values recorded.
This procedure was countinued on day 2, 3 and 4;
measurements (VAS and PTM) of pain severity were done on day 1,
2 and 4 .
Prior of the beginning of the study and at the end on day 4, physician's global assessment, assessment of swelling, tenderness and limitation of movement were recorded.
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As the study is ongoing statistical evaluation is not yet available. For further details see Table 1.
TABLE 1
Composition Composition
Reaction
Good Alleviation of pain
Moderate Alleviation of pain
No Alleviation of pain
109, n = 16 13
112, n - 15 8
From the data recorded we have concluded that the patients to whom composition 109 was administered did better in terms of earlier and longer lasting analgesic effect (up to 4 hours) than the 112 composition especially in patients with myofascial trigger points and with periarthropathies of the knee joints . without effusions. Neither composition 109 nor composition 112 treated patients showed any effect on swelling if any swelling exist at all. Systemic side effects have not been observed; one patient to whom composition 112 was administered showed reddening of the skin on the site of application .
Any intake of system NSAIDS,corticosteroids and other analgesics was not allowed one week before and during the trial.
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- 70 EXAMPLES
The following examples are offered to illustrate uses of Applicants' invention.
Example 1
A male patient had a number of lesions (basal cell carcinoma), including one on his forehead which was a combination of major horny epithelium and some degree of ulceration. After continuous treatment with Formulation 1 10 (several times per day for several weeks of dosage amounts squeezed from tubes as ribbons of composition), the lesions showed epithelialization, no hemorrhagic areas, and no initiated areas (as they were in the past without our treatment) . The horny epithelium and ulceration of the forehead lesion were 15 also gone. The patient had a complete successful response with the formulation. All basal cell carcinoma lesions had been resolved and disappeared. There has been no recurrence.
Example 2
60 year old male tennis player had sore elbow and basal cell carcinoma on forearm proximate sore elbow. Patient tried Formulation 1 to abate pain in tennis elbow. (Dr. Falk was not treating this patient for anything at the time, did not know of the basal cell proximate the elbow and merely offered the formulation for pain relief of the elbow instucting the patient to squeeze a ribbon of the composition and apply and rub into the sore elbow). However, the formulation spilled over onto the Patient's basal cell carcinoma. Patient was planning to have basal cell carcinoma removed surgically by another
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1 doctor, but when the patient returned to see the doctor, the basal cell carcinoma was disappearing (because of spill-over of Formulation 1). Dr. Falk was then advised and treatment was now undertaken by Dr. Falk with direct application of Formulation 1 to the lesion 3 times a day for two additional weeks. After two weeks, the basal cell carcinoma disappeared. There has been no recurrence .
Example 3,
Male, mid to late 40’s had severe basal cell carcinoma on left temple. Doctors recommended its removal by surgery. However, the surgery would have been risky because of the lesion's proximity to facial nerves.
Patient saw Dr. Falk who gave him Formulation 2 to be applied in dosage amounts 3 times daily.
After 14 days, 75% of the lesion was gene. Surgery was postponed and the treatment was continued. Application of dosage amounts of Formulation 2 was continued for an additional two weeks. At the end of the 2- week period, the lesion was completely resolved and disappeared without any surgery being required. There has been no recurrence.
Sxawp.ls.-1
Male, early 40's, had recurrent actinic keratoses lesion on his right temple. Early attempts at removal by third parties involved the application of liquid nitrogen (twice) without final resolution. The lesion kept recurring. The patient was sent to Dr. Falk who treated the lesion with Formulation 1 with applications of dosage amounts 3 times daily
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BAD ORIGINAL ft for 7 days. After 7 days, the lesion was completely resolved with no subsequent recurrence.
Example 5
A male patient suffering from kyphosis suffered from constant back pain. Taking analgesics orally and rubbing back preparations onto his back did little to alleviate the back pain. When NSAIDs in hyaluronic acid (sodium hyaluronate) were applied directly to the back, the back pain eased and disappeared.
With indomethacin (dissolved in N-methyl glucamine) and naproxen both dissolved in hyaluronic acid, the patient experienced some side effects. However, with Toradol™ (the [+/-] form tromethamine salt of ketorolac - a prostaglandin biosynthesis inhibitor and analgesic and anti-inflammatory, the back pain eased and disappeared for some time and there were no side effects. The compositions were applied generously onto the sites of back pain.
Example 6
A male patient with basal cell carcinoma was first treated by an oncologist who attempted to surgically excise the lesion (without success) and then irradiated the lesion again without success. The patient then attended before Dr. Falk who applied Applicant’s formulation (diclofenac with sodium hyaluronate and excipients). Application was made three times daily for about a month and the lesion disappeared. Some excoriation anterior and slightly superior developed over the
AP/P/ 9 3 / 0 0 4 9 2
BAD ORIGINAL ft last two weeks but was cleared by the application of hyaluronic acid by itself.
This resolution clearly indicates that even with prior applications of unsuccessful therapies (surgery and irradiation), Applicant's formulations can be used successfully.
Example 7
In another patient, a drug (methotrexate) was carried in hyaluronic acid and applied topically to a patient with psoriasis. The formulation was absorbed and the psoriasis cleared.
Example 8
A patient with dermal (skin) metastases in a fibratic scar form and metastatic cancer in the form of musculoskeletal involvement in her thorax.
On topical application of our formulation comprising diclofenac (Voltaren) in hyaluronic acid (sodium hyaluronate), her pain decreased dramatically and her skin and boney involvements steadily improved.
TOPICAL DICLOFENAC ACID 3% IN HYALURONIC ACID GEL (2.5%) BASE
A practitioner reviewed the effectiveness of topical Diclofenac Acid 3% in hyaluronic acid gel (2..5%) base in acute traumatic injuries of no longer than 3 days duration. The cases were all in the spectrum of ages between 18 and 65. Normal exclusion criteria were followed regarding exclusion of
AP/P/ 9 3 / 0 0 4 9 2
BAD ORIGINAL ft pregnancy, aspirin or N.S.A.I.D., allergies or active peptic ulceration .
As an overall, the following impressions were gained from 30 cases:
1. The topical H.D.(composition comprising sodium hyaluronate and diclofenac) had an obvious analgesic action with onset occurring rapidly within one hour; this is a phenomenon not obviously seen with other non-steroidals that we have used.
2. There was a very definite patient acceptance of the gel as a form of treatment, being logical, easy to apply, without local or systemic side effects, rapid absorption with no staining of clothing.
3. The anti-inflammatory action was equivalent on a guestimate based cn experience of similar injuries to oral N.S.A.I.D.s, without the threat or risk of side effects.
In summary, compared with other topical N.S.A.I.D.s the analgesic effect is distinct, the anti-inflammatory is equal to oral N.S.A.I.D.s and the patients' acceptance is far superior to any other diclofenac or piroxicam topical that the practitioner evaluated.
Following the practitioner's basic preamble regarding the parallelism of topical N.S.A.I.D.s and topical steroids,the practitioner has used the former in contact dermatitis, insect bites and U.V. erothema, all with very positive effects, again pointing direction to trials of a double blind nature in these fields .
AP/P/ 93/00492
BAD ORIGINAL ft
5 | 2.5¾_HYALURONIC | ACID WITH | 3%DICLO F5NIC ACID ί HD ) | ||||
Patients Initials (Ml or (F) | □ ate Of Firth | Si | □: i o r a s i s | Positive Negat ive enable to Co.--e - n t | (?) (N) | ||
10 | LA (M) | 11.04.56 | Hyper- | Severe diseenfort following | ? | ||
aesthes ia | extensive s·;rjery to dorsal spine with insertion of | Example | c f | ||||
rods in 193 9. Even contact | peripheral | ||||||
with clothes produced sig- | action on | ||||||
15 | nificant discomfort. | super- | |||||
Initially treated with EMLA | se.nsitiza- | ||||||
with only transient anaes- | tion of | ||||||
thetic results, however | nerve | ||||||
even after 3 days treatment | ending | ||||||
20 | with Hyal diclofenac acid noticed marked decrease in supersen sitivity which has continued for at least 4 weeks while still using gel. | queried | |||||
25 | KB (F) | 09.06.58 | Chronic | Treated right knee which was | P | ||
chonoro- | worse initially and was | ||||||
malicia | amazed at the response, then | ||||||
perhaps | started to treat left knee | ||||||
30 | dating back | that was not so painful. | |||||
to 1376. | again with positive response. Here we nave a built-in co.nt rol . | ||||||
35 | DB (F) | Chronic | Initially felt so-e improve- | N | |||
neurogenic | ment which was not continued | ||||||
pain in | although initial y quite | ||||||
ankle with | positive - ouery placebo | ||||||
associated | react ion . | ||||||
40 | dysaestnesia. | ||||||
DC (F) | 07.11.51 | Chronic back pain - query due to facet | N | ||||
45 | syndrome or trigger points, really diagnosis | ||||||
50 | uncertain. |
AP/P/ 9 3 / 0 0 492
BAD ORIGINAL ft
-„a.WJ2ASLWJiJa .iL[I}LJl H£LQ£ίWL·2^
Patients Initials (M) nr (FI
CC
AG (F)
CH (F)
SH (F)
DM (M)
PJ
Date
Of
Birth
18.01.25
07.11.58
22.08.61
16.07.55
17.06.47
15.06.45
File — | Diagnosis | Cornetts on Cutcome |
Chronic cap- | Definite effect over knee | |
s u X i t i s | where application to tar- | |
right hip | get distance short. No | |
right knee | obvious effect over hip. | |
Myositis in | Initially given placebo in | |
rhomboids | error, only marginal or | |
muscles | minimal effect, if any. | |
following | Found active to be effect- | |
motor vehiclt | five while being used, did | |
accident | net cure condition which needed trigger point therapy . | |
Chronic | No significant effect, nor | |
relapsing | has aggressive therapy since | |
tendonitis | including injection with | |
right elbow | cortisone and numerous opinions . | |
Tendonitis | Control of tendonitis while | |
and myositis | using preparation. Is now back at work . | |
Neuronitis | This patient has a very unusual pain in n i s left groin following nerve injury, with the use of preparation noticed decrease in pain sensation while on medication. Hyperaoath.es i a altered although pain (which may be phantom) still present. | |
Capsulitis | Symptoms im,proved 5C% wnile | |
of right | using Hyal diclofenac acid. | |
wr isc | however, on discontinuation pain reappeared. Exact etiology uncertain. |
Positive (P) Negative (N) Unable to Comment ((J)
IBJU
AP/P/ 9 3 / 0 0 492
BAD ORIGINAL ft
CHRONIC CONDITIONS VAX VAT. I, QilS .
HXai52Bfiltt£L.
Patients Initials (M) or (F)
DJ (F)
DK (F)
Oate
Of .rillt.h
27.08.38
File
Ua.
DorsaL m.yosi t r
Severe capsulitis left shouldei
Te-ts Out ie.
__CBQ_L
Positive (?) Negative (N)
Control while using gel equal and with less side effects than tiger calm. Controlled symptoms while using medication. Exact diagnosis as to cause of myositis uncertain.
This patient has had capsulitis left shoulder for many years and treated with only transient relief with cortisone injections, poor relief with topical piroxicam. Was started on topical diclofenac acid and noticed relief of pain in 20 minutes continuing for 1-6 hours. See letter /.irch 11/92. At present is using H.O. regularly, has found it to be useful in other areas of chronic pain. Is President North American Chronic Pain Association, has good insight into mcoioaticn and piacecos etc. has two 3.C.S. implant s.
enable r*
O
J2U.
?
Extremely rewarding case
AP/P/ 9 3 / 0 0 492
BAD ORIGINAL ft nmx
Positive (P)
Negative (N)
Unable to
Comment (U)
CHRONIC CONDITIONS - EVAI-HAV TONS.
HYALURONIC ACID-JilIK
3% DICLOFENAC ACID
Patients
Initials (M) ar IF)
JL (M)
RMC(F)
RM <F>
GM (F)
PM (F)
Date
Of
Ri rth
13.12.45
13.06.51
20.08.52
20.09.46
File aiaa.icsis
Chronic myos ic i s secondary t cuery facet syndrome
Neuronitis following facet rhizotomy with result ing pain in her back
Chronic capsulitis
Sub-acute tendon i t i s right ankle
Pain has failed to respond to many aggressive treatment s .
It is a difficult case with considerable overlay, she obtained seme relief with H.D., would estimate 30-40% Interestingly hyperanaesthesia was decreased.
Using H.D. significant improvement in pain while used, on stepping treatment recurrence of pain, needed intra-articular cortisone.
Rapid resolution of pain within one day and positive return of function.
DN (F)
10.03.44
Acute on chronio osteoarthritis of first rotatarsal ph =.iy ngeai joints
Chronic fasciait is of feet
Rapid analgesic response with rapid settlement.
Excellent response to application of H.D. with occlusion. had failed to respond to oral N.S.A.I.D.s and physiotherapy. Query positive result due to short application target distance in a vascular tissue.
AP/P/ 9 3 / 0 0 4 9 2
Ίϊ
CHRONIC CONDITIONS | =_EVALUATIONS·.· | ||||
LLXA. | LURQNIC | flCIDWITHJ. DJ CLOFENT C AC ID_(HD) | |||
Pcs ' t ive (? ) | |||||
5 Patients | Date | Negative ([J) | |||
Initials | Of | Fi if | D n a 01 e to | ||
(Ml or (.=1) | Birth | No. | Diagnosis | Cs.-tcnts nt Cutct-e | Co—ent ID) |
BP (F) | 04.03.20 | Severe | Initially ore knee treated | ? | |
10 | chronic | with such good results that | |||
arthritis of | both knees treated, see | Sice | |||
the knee. | letter. Not only aid pain | e f feces- | |||
Unable to | decrease but marked swell- | non/Inci- | |||
take oral | ing around knees. Signifi- | cental | |||
15 | N.S.A.I.D.s | cant relief of pain and | resolution | ||
increase in movement as a | cf area cf | ||||
result of this and perhaps | thro,mbo- | ||||
reduction cf swelling. | phlebit is | ||||
TntrestiroJv has severe | below area | ||||
20 | superficial var’csje veins. | of treat | |||
develooed t h ro-.oooh 1 e'o i t 1 s | rent | ||||
around r<oht knee and the | |||||
showed far less red-ess an:1 | |||||
25 | tenderness then the t'-.rom- | ||||
tooh’.ebit-s be'ow this area. | |||||
S? (M) | 06.11.48 | Idio- | Has had similar episodes | u | |
pathic | with poor response t ο many | ||||
30 | diffuse | treatments i r.c ud ir g | |||
capsulitis | N.S.A.I.D.s per os | ||||
of hands | |||||
MS | C4.C6.45 | Chronic | Has cecn exposed to nurber- | J | |
35 | neuronitis | ous treatments including | |||
due to | tow attempts of surgery | ||||
injury co | without effect. There is | ||||
lateral | decrease ir. hyceraesth.es ia | ||||
cutaneous | but ro charge ir cain. | ||||
40 | nerve of | ||||
thigh | |||||
MS (F) | 04.06.28 | Chronic | Failed to respond to number | ? | |
capsulitis | of treatments, good back- | ||||
45 | ground resolution of pain, | ||||
however, still had acute | |||||
t | pain with certain movements. |
AiK'P/ 93/00492
BAD ORIGINAL Ά
HWd2£OHI.<L_
Patients
Initials (Mt .or—IU.
IS (F)
GS (F)
VK (F)
GH (M)
Date
Cf
BLr&h.
15.01.48
26.03.47
01.01.39
03.11.21
Filt No. | Diagnosis . | Comments on Outcome |
Chronic | Had failed to respond to | |
capsulit is | numerous treatments including oral and tcpical N.S.A.I.D.s Using H.D there was equivalent control of pain as with other therapies which lasted while medication was used. Referred for surgical cpi.n icn . | |
Chronic | Oral diclofenac acid dis- | |
tendo- | continued due to gastritis | |
sinovit is | and also history of ulcera- | |
ticn . | tion. Control using H.D. equal to or better than oral N.S.A.I.D.s. | |
Chronic | Good relief cf pain and | |
tendonitis | tenderness while using H.D. however on discontinuation of gel symptoms returned, treated with intramuscular steroids . | |
Acute on | In view of age and general | |
chronic | parous medical condition. | |
osteo- | ideal for tcpical. Had | |
arthritis | been previously on topical | |
left hand | piroxicam for left shoulder capsulitis . |
Positive (P) Negative (N) Unable to Xgrc.gnl.-iUi for pain N for resolution
Commented on better absorption compared to tcpical piroxicam
6 t» 0 u / £ 6 /a/dV
BAD ORIGINAL
GHBQN τΠ... CPHPJJJ0B5... ’
5 | HYALURONIC ACID WITH___3%_DICLOFENAC ACID_(HD) | ||||||
Patient s Initials | Date Of Birth | File No. | Diagnosis | Co--e-.ts on Dutco-e | Positive (?) Negative (N) Unable to Com-ent (U) | ||
/«) | or (F) | ||||||
JA | (M) | 06.02.58 | 5evera pest- | Produced gcoe superficial | p | ||
10 | tr a ύ τ a c i c | analgesia especially whore | |||||
and surgical | staples were irritating stc- | ||||||
CSC9O- | cutaneous tissue, little | ||||||
arthritis of | effect on deeper, severe | ||||||
left leg | csteoarthritic pain of knee. | ||||||
15 | with staples | This pain was cf consider- | |||||
Peer result | able severity, needing nar~ | ||||||
to oral N.S.A.I.D.s also gastric | cct ics. | ||||||
20 | irritation . | ||||||
IM | (M) | 30.11.51 | Chronic | Severe rhombo id inflammation | P | ||
superficial | right side, treated with | ||||||
myesitis | H.D., very definite improve- | ||||||
25 | rent in pain and tenderness. | ||||||
TK | (F) | 23.04.70 | Acute en | Excellent rapid analgesic | P | ||
chronic | followed by ant:-: ηf lanmatory | ||||||
capsulitis | response in yetng women who | ||||||
30 | due to | could not take oral N.S.A.D.s | |||||
sports | cue tc past gastritis. | ||||||
injury right hand | |||||||
35 | AD | (F) | 03.01.49 | Chronic | Poor response to H.D. After | N | |
diffuse pain | intensive investigation and | ||||||
thought to | numerous consultations and | ||||||
be .myesitis | treatment, pain still undiagnosed and unresponsive. | ||||||
40 | NH | (F) | 25.03.25 | Subacute | Excellent response analgesic | ? | |
capsulitis | ar.d anti-inflammatory-wise | ||||||
right ankle | within a few cays. Marked clinical improvement. in | ||||||
45 | view of this patient’s | ||||||
parous general red leal con· | |||||||
ditio.n and hy pcr t e -. s ion, net suitable for oral NSAIDs. |
APtPt 93/00492
BAD ORIGINAL ft
CHRONIC CONDITIONS - EVALUATIONS
Patients Init ials (M) or (F)
KO
MW (F)
LP (F)
HYALURONIC ACID. WITH 3% DICLOFENAC ACID (HD)
Positive (?)
Dt. t e Of airta
18.04.34
07.05.46
20.07.23
Fill ibu Piasr.gsia
Subacute laments oa, gatcsas rheumat old arthritis
Heberden's nodes, painful, swollen causing difficulty in movement
Acute on sub-acute osteoarthritis of the hands with
Heberden·s nodes
Negative (N)
Unable to .Consent LilL
Had failed to respond to oral N.S.A.I.D.s, which caused gastritis, tried cn topical piroxicam with negative effects. Negative response to H.D.
Very slew positive outcome, initially improvement in pain followed by reduction in swelling. Etiology of this condition is unknown, partly genetic. Would have been interesting to treat alternate digits, plus cr minus thermographic confirmation .
Initially treated with Idarac, poor response overall, some improvement in generalised arthritis of hands but none on Heberden's nodes. Pain flared on stoopi.ny Idarac due to gastritis Started on H.D., especially favourable results with subsidence of tenderness of nodes and settling of arthritis. Interestingly enough, no flare up on discontinuation after one month
AP/P/ 93/00492 bad original £ ___τ—jaaidz&ziaiis
HI2L Patients Initials (Ml or (FI | LURONIC | ACID WITH 3%DICLOFENAC ACID (HD) | |||
□ate Of Bi rth | Fi le No . | □ i agnosis | Comments on Outcome | Positive (P) Negative IN) Unable to Comment (Ul | |
JG IF) | 24.11.50 | Post facet rhizotcmy hyperaesthesia, with marked pain a.-.d hyperaesthesia between scapulae | Had failed to respond to oral N.S.A.I.D.s a.-.d E.M.L.A. Application of H.D. improved the surface pain significar.tly but had no effect on the deeper pain. My impression was that the deeper pain was due to section of the facet nerve and beyond the reach of the topical medication. There is little doubt that the skin sensitivity was decreased. | □ | |
SW (F) | 10.09.39 | Knee pain due to chondro malacia | Upset in past due to oral N.S.A.I.D.s., also hypertension made one 'cathe to use this medication with serum levels. Good analgesic and ant i-i.nf lammatory action, however cn discontinuation pain flared. Seen for arthroscopic surgery with relief of pain. | P (Effective while being used) Condition only cured by surgery |
Two types of pain-response in only one
1. Interestingly in the whole series, there was not one case of local side effects and as expected from past studies, no general or systemic. Since this report was prepared we have had one case of mild folliculitis which responded to discontinuation of treatment, will rechallenge.
2. A number· of patients commented that they felt the gel improved the texture and softness of their skin, and commented that it was messy or stained their clothes.
3. In one case of topical thrombophlebitis where the
I inflamed vein crossed the area of treatment, the vein in the area of treatment improved while that outside at a distance did not. Again, similar to using oral N.S.A.I.D.s. ***.
CM σ>
*4-
ΙΌ | |
the | Q. |
the | Q. |
< | |
did |
bad original
Photographs were taken of patients with basal cell carcinoma Figures 1-6 photographs, and of mice with tumors induced in the skin of the hind legs (Figure 7 photographs) . The patients were treated by using combinations of NSAIDS, (nonsteroidal anti-inflammatory drugs) and hyaluronic acid (including sodium hyaluronate) according to the invention (3% diclofenac in 2.5% sodium hyaluronate gel base). Each of the six sets of Figures made up of photographs of the different persons include a legend describing or explaining each picture appropriately labelled. The mice had tumours induced in the skin of their hind legs and dosage amounts (2ml) of Novatrone (10 mg. per dosage amount) (MITOXANTRONE (t.m.) and 2.5% sodium hyaluronate were applied (rubbed onto) the skin at the site of the pathology. The tumours reduced in size clearly illustrating the percutaneous delivery of the medicine by the hyaluronic acid. (See Figure 7).
The following additional comments are made with respect to the patients.
With respect to R.W. and Figure 5, the reader will note in Figures 5a and 5c the patient suffered from basal cell carcinoma on his back (Figure 5c) and his temple (Figure 5a). Because of the age of the individual (86) the basal cell carcinoma on his back could not be reached by him for application of the medication. Thus the basal cell carcinoma in 5c remained untreated and grew (see Figure 5d) . However, the portion indicated in 5a on his temple could be reached and after application of the basal cell carcinoma formulation to the temple and forehead the results are as in 5b; the basal cell
AP/P/ 93/00492
BAD ORIGINAL ft carcinoma is disappearing. Thus, the gentlemen's own method of treatment acted as a control.
With respect to R.F. and Figures 4, two areas of basal cell carcinoma in need of treatment are shown by the arrows in
Figures 4a and 4c and the results are shown in Figures 4b and 4d as indicated by the arrows after treatment with Applicant's invention.
With respect to H.A., male, and Figures 3, Figure 3a
indicates | two | areas of | basal | cell carcinoma | by | the | arrows, |
10 close-ups | of | which are | shown | in Figures 3c | and | 3e. | After |
treatment | with | the NSAIDS | and | HA gel three times a | day | for the |
period between January 26, 1992 and March 16, 1992 the basal cell carcinoma is clearing as per Figures 3b, 3d and 3f.
The same is true with respect to male M.F. and Figures 15 2 which appears clear in the photographs (see Figure 2a and the response shown in Figure 2b) .
With respect to male, W.D. and Figures 1, the upper lesion in Figure la (indicated by the upper arrow) is gone after treatment with Applicant's invention (See Figure lb) and the two lower lesions in Figure la are well on their way to disappearing (See Figure lb).
With respect to female D and Figure 6, the lesion was left untreated for a long period and gradually encompassed her eye. Surgery could not be undertaken without jeopardizing the eye. By applying Applicant's invention (dosage amounts) over a prolonged period, the basal cell carcinoma has constantly decreased in size.
With respect to Figure 7, (7a) shows mice having tumors in the skin induced in their hind legs. After continuous
AP/P/ 93/00492
BAD ORIGINAL d applications to the shaved hind legs having the tumors in the skin by rubbing in dosage amounts by Applicant's invention, the tumors have decreased in size.
The effect of Hyaluronic acid as a drug carrier of anti-cancer agent (5-FU) 5-Fluoracil was also studied.
(Intratumour injection study)
B. EXPERIMENTAL MODEL. 12}
1. Method and Material
a. Animal : Fisher 344 rat, male
200-250g
b. Tumor model
Fisher Bladder Carcinoma Tumor (2mm viable tumor fragment) was transplanted subcutaneously on the right frank by trocar
c. Treatment was started when tumor size is about 1.5 cm.
(2 weeks after implantation.)
1. These drugs were administrated by intratumor injection.
(right frank)
At the same time, iiuec£-l.on.,into-normal. skin (left fran; was carried out similarly.
Group A : H-5-FU 5mg/kg + saline /0.3ml (i.t.)
B : H-5-FU 5mg/kg + HA 15 mg/kg /0.3ml (s.c.)
3H-FU without or with HA was injected as a single dose (0.3ml) into the center of the tumor (on the right frank) with a 30 gause needle. At the same time, injection into normal skin (on the left frank) was carried out similarly.
The tumor and skin was then removed at different times (lh,6hr) for counting radioactivity of the remaining content in the tissue.
2. Result
All the results were expressed as Mean + S.E.
AP/P/ 93/0049 2“
BAD ORIGINAL
TUMOR TISSUE
NORMAL SKIN cpm
10000 η m 5-FU +HA group E9 5-FU group <*»+) cpm
10000 η
800040002000gg 5-FU +HA group E3 5-FU group f<*
1hr 6hr
60000
3. Conclusion
1. In 5-FU_HA group radioactivity was accumulated and retained in the tumor tissue for a long period, whereas rapid clearance was demonstrated in normal tissue. (skin)
2. In 5-FU group, radioactivity immediately disappeared from the tumor or the normal tissue by diffusion, primarily into blood capillaries.
---- 5FU can traverse freely between the interstitial space and blood capillary.
AP/P/ 93/00492
BAD ORIGINAL
The Effect of Hyaluronic Acid as a Drug Carrier in Target Cancer
Chemotherapy
A. EXPERIMENTAL MODEL. _ilL Intravenous Injection)
1. Method and Material
a. Animal : Fisher 344 rat, male
200-250g
b. Tumor model
Fisher Bladder Carcinoma
Tumor (2mm viable tumor fragment) was transplanted subcutaneously on the right frank by trocar
c. Treatment was started when tumor size is about 1.5 cm.
(2 weeks after implantation .) .... tumor weight :1.0 + 0.3g The drug was administered Intravenously (through the penile vein)
Group A B C
5-FU 20mg/kg 5-FU 20mg/kg 5-FU 20mg/kg (3H-5-FU30pCi) (3H-5-FU30gCi) (3H-5-FU30gCi) + saline + HA 15mg/kg + HA 15mg/kg + (3H-HA30gCi)
2. Sample Collection accumulation of ADR, 5-FU in tumor tissue and liver (1) . Tumor was surgically removed (and blood was collected) at *predeterminated time after drug administration. Tumor weight was measured (and blood was centrifuged to obtain a plasma sample .) * 15min, 60 min, 3hr, 4hrs,.... after drug administration.....
Liver was removed for radioactivity counting at the same time.
(2) . Radioactivity level in tumor tissue was counted, using a liquid scintillation counter.
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BAD ORIGINAL
3 . | Conclusion Radioactivity in Tumor Tissue and | Liver | |||
Tumor | Liver | ||||
15min | 3H-5FU | (n=6) | 2310±165 | 18680+625 | |
5 | 3H-5FU+HA | (n=6) | 352+190 | 23593+1460 | |
3H-5FU+3H-HA | (n=4) | 4087+631 | 32060±2145 | ||
60min | 3H-5FU | (n=3) | 1751+149 | 5451±841 | |
3H-5FU+HA | (n=4) | 2599+489 | 8265+1849 | ||
10 | |||||
3hrs | 3H-5FU | (n=6) | 1493±227 | 2230+449 | |
3H-5FU+HA | (n=6) | 2512+449 | 2897+340 | ||
3H-5FU+3H-HA | (n=4) | 3606±929 | 6977+1633 | ||
15 | 5hrs | 3H-FU | (n=3) | 853+129 | 1129±70 |
3H-5FU+HA | (n=3) | 1981+479 | 1754+248 | ||
3H-5FU+3H-HA | (n=3) | 2168 + 163 | 3018+325 | ||
mean + | S.E. | ||||
20 | HA : | 15 mg/kg (30μΟί/’<ς) | |||
(CPM) | Radioactivity la Tumor Time | ||||
5000 η | 5-FU | : 20mg/kg (30gCi/kg) |
400025
3000
2000 1000
400 (arbutu)
1. Radioactivity in tumor tissue in 5-FU + KA group is higher than that in 5-FU group. There is significant difference (p>0.05, ANOVA) between with and without HA at 3hrs after injection. The high intratumor concentration was retained for a prolonged time in 5-FU+HA group. (This retention wa3 confirmed by the intratumor injection study.)
2. These results teach that HA can enhance 5-FU uptake in tumor tissue. Thi3 phenomenon results from HA distribution (in tumor tissue HA may be lost from the extracellular matrix) and the vascular uniqueness of tumor tissue (hyperpermiability of tumor vessels to macromolecular drug, HA).
As many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
Claims (2)
- THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:1. The use of:(I) a medicinal and/or therapeutic agent in a therapeutically effective amount for the treatment of a disease or condition of the skin and/or exposed tissue of a human, and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, for the manufacture of a pharmaceutical composition for the topical treatment of said disease or a condition of the skin and/orC exposed tissue characterized in that said composition is applied in a dosage amount in which component (2) exceeds 5 mg/cm- of the skin and/or exposed tissue to which the dosage amount is to be applied and is in such form that component (2) is immediately available to transport component (1) percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition to be treated in the skin or exposed tissue.2. The use of Claim 1 wherein the hyaluronic acid and/or sails thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.3. The use of Claim 2 wherein the hyaluronic acid and/or salt thereof is sodium hyaluronate.4. The use of Claim 1. 2 or 3 wherein the molecular weight of the form of hyaluronic acid is less than about 750.000 daltons.5. The use of Claim 1, 2. 3 or 4 wherein the disease and/or condition of the skin and/or exposed tissue at the site of the trauma and/or pathology is selected from at least one of basal cell carcinon .·., the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, liver spots, squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin.AP/P/ 93/00492BAD ORIGINAL-91malignancies and/or tumours in the skin, genital warts (condyloma acuminata), cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women.6. The use of Claim 1, 2, 3, 4 or 5 wherein the medicine and/or therapeutic agent comprises an effective non-toxic dosage amount which inhibits prostaglandin synthesis.7. The use of Claim 6 w'herein the medicine and/or therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID).(8. The use of Claim 1, 2, 3, 4 or 5 wherein the medicine and/or therapeutic agent is an anti-cancer drug.9. The use of Claim 8 wherein the anti-cancer drug is selected from novantrone.10. The use of Claim 7 wherein the NSAID is selected from diclofenac, diclofenac sodium indomethaci n. naproxen, and (+/-) tromethamine salt of ketorolac.11. The use of Claim 7 wherein the NSAID is selected from . Ibuprofen, Pirocicam, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.12. The use of any preceding claim wherein component (2) is sodium hyaluronate having a molecular weight of between 150.000 daltons and 225,000 daltons.13. The use of Claim 7 or 12 wherein the NSAID is diclofenac sodium.14. The use of Claim 3, 4 or 5 wherein component (1) is diclofenac sodium and the concentration of the diclofenac sodium is 3% by weight of the pharmaceutical composition, component (2) isAP/P/ 93/00492BAD ORIGINAL-92sodium hyaluronate in a concentration of 2*/2r/f by weight of the pharmaceutical composition having a molecular weight of 661.600 daltons and the pharmaceutical composition further comprises glycerine 5% by weight of the composition, benzyl alcohol 39i by weight of the composition and sterile water.15. The use of any preceding claim wherein the pharmaceutical composition comprises suitable topical excipients.16. The use of any preceding claim wherein component (2) in
each dosage amount is in an amount of at least 10 τ mg/cm of skin r'' and/or exposed tissue to which it is to be applied. 17. The use of Claim 1, 2. 3. or 5 for the treatment of pain wherein component (2) of each dosage amount is in an amount of at least 20 mg/em~ of the skin and/or exposed tissue to which it is to be applied and component (1) is an NSAID.18. The use of Claim 1, 2, 3 or 4 for the treatment of pain wherein component (2) of each dosage amount is an amount of at least lOnig/cm of skin and/or exposed tissue io which it is to be applied and component (1) is an NSAID.(.19. The use of Claim 5 wherein the disease and/or condition is basal cell carcinoma.20. The use of Claim 5 wherein the disease or condition is actinic keratoses.21. The use of Claim 5 wherein the disease or condition is liver spots.AP/P/ 9 3 / 0 0 4 9 222. The use of Claim 5 wherein the disease or condition squamous cell tumours. 23. The use of Claim 5 wherein the disease or condition metastatic cancer of the breast to the skin. BAD ORIGINAL ft24. The use of Claim 5 wherein the disease or condition is primary and metastatic melanoma of the 1 skin. 25. The use of Claim 5 wherein the disease or condition is malignancies and/or tumour of the skin. 26. Tnc use of Claim 5 wherein the disease or condition is genital warts (condyloma acuminata). 27. The use of Claim 5 wherein the disease or condition is cervical cancer. 28. The use of Claim 5 wherein the disease or condition is Human Papilloma Virus (HPV). 29. The use of Claim 5 wherein the disease or condition is psoriasis.30. The use of Claim 5 wherein the disease or condition is corns on the feet or the hair loss on the head of pregnant women. 3 1. The use of Claim 1. 2. 3 or 4 for the treatment of pain wherein component (1) is a non-steroidal anti-inflammatory drug (NSAID) and wherein component (2) present in each dosage amount exceeds 10 mg/cm* of the skin and/or exposed tissue to which it is to be applied.32. A method of treating a disease and/or condition selected from basal cell carcinoma, actinic keratoses, liver spots, squamous cell tumours, metastatic cancer of the breast to the skin. primary and metastatic melanoma of the skin, malignancies and/or tumour of the skin, genital warts (condyloma acuminata), cervical cancer, Human Papilloma Virus (HPV), Psoriasis, corns on the feet, hair loss on me head of pregnant women, said method comprising administering topically to the skin and/or exposed tissue of a human, a dosage amount of a pharmaceutical composition, said dosage amount ’/P/ 9 3 / 0 0 4 9 2BAD ORIGINAL ft-94comprising:(1) a medicinal and/or therapeutic agent in a therapeutically effective amount to treat a disease or condition of the skin and/or exposed tissue and: - (2) hyaluronic acid homologues. analogues, derivatives, subunits of hyaluronic acid.characterized in that and/or salts thereof and/or complexes, esters, fragments and said dosaee amount of said composition is in a dosage form suitable for topical application to the skin and/or exposed tissue and in a dosage amount in which '•y component (2) exceeds 5 mg/em- of the skin or exposed tissue to which the dosage amount is to be applied, and is in such form that component (2) is immediately available to transport component (I) percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition to be treated.33. A method of treating pain topically, said method comprising administering topically to the skin and/or exposed tissue of a human, a dosage amount of a pharmaceutical composition, said dosage amount comprising:(1) a medicinal and/or therapeutic agent in a therapeutically effective amount to treat pain of the skin and/or exposed tissue and:(2) hyaluronic acid and/or salts thereof and/or homologues. analogues, derivatives, complexes, esters, fragments and subunits of hvaluronic acid, characterized in that said dosase amount of >aid composition is in a dosage form suitable for topical application to the skin and/or exposed tissue and in a dosage amount in which component (2) exceeds 10 mg/cm* of the skin or exposed tissue to which the dosage amount is to be applied, and is in such form that component (2) is immediately available to transport component (1) percutaneously into the epidermis of the skin or exposed tissue to he site of trauma and/or pathology of pain to be treated, in the skin or exposed tissue.4 6 frO 0 / £ 6 IdliSVBAD ORIGINAL-9534. The method of Claim 32 wherein component (2) is sodium hyaluronate having a molecular weight less than 750.000 daltons.35. The method of Claim 33 wherein component (2) is sodium hyaluronate having a molecular weight less than 750.000 daltons.36. The method of Claim 32. 33. 34 or 35 wherein component (1) is a non-steroidal anti-inflammatory drug (NSAID).37. The method of Claim 36 wherein the NSAID is diclofenac sodium.38. The method of Claim 32. 33, 34. 35, 36 or 37 wherein component (2) is sodium hyaluronate whose molecular weight is between 150,000 daltons and 225.000 daltons.39. The method of Claim 36 wherein the NSAID is selected from diclofenac, diclofenac sodium, ibuprofen, piroxicam, flunixen and flunixen meglumine.40. The method of Claim 32 or 34 wherein component (!) is an anti-cancer agent.41. The method of Claim 32. 33. 34. 35. 36, 37, 38, 39 or 40 wherein the pharmaceutical composition further comprises suitable topical excipients.42. The method of Claim 32 or 34 wherein the disease and/or condition is basal cell carcinoma.AP/P/ 93/00492
43. The method of Claim 32 or 34 w herein the disease condition is actinic keratoses. 44. The method of Claim 32 or 34 wherein the disease condition is liver spots. 45. The method of Claim 32 or 34 wherein the disease BAD ORIGINAL ft —96— condition is squamous cell tumours.46. The method of Claim 32 'r 34 wherein the disease or condition is metastatic cancer of the : breast to the skin. 47. The method of Claim 32 or 34 wherein the disease or condition is primary and metastatic melanoma of the skin. 48. The method of Claim 32 or 34 wherein the disease or condition is malignancies and/or tumour of the skin. 49. The method of Claim 32 or 34 wherein the disease or condition is genital warts (condyloma acuminata). 50. The method of Claim 32 or 34 wherein the disease or condition is cervical cancer. 5 1. The method of Claim 32 or 34 wherein the disease or condition is Human Papilloma Virus (HPV). 52. The method of Claim 32 or 34 wherein the disease or condition is psoriasis. 53. The method of Claim 32 or 34 wherein the disease or condition is corns on the feet. 54. The method of Claim 32 or 34 wherein the disease or condition is the hair loss on the head of pregnant women.55. The method of Claim 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43, 44. 45. 46. 47. 48, 49. 50. 51, 52. 53 or 54 wherein the administering takes place a number of times a day over a number of weeks.56. The use of a dosage amount of a pharmaceutical composition comprising:AP/P/ 93/00492BAD ORIGINAL-97(1) a medicinal and/or therapeutic agent for the treatment of a disease or condition of the skin and/or exposed tissue of a human; and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and sub-units of hyaluronic acid for the treatment topically of basal cell carcinoma, actinic keratoses, liver spots, squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma of the skin, malignancies and/or tumour of the skin, genital warts (condyloma acuminata), cervical cancer. Human Papilloma Virus (HPV). psoriasis, corns on the feet, and hair loss on the head of pregnant women wherein the dosage amount is in a dosage form suitable for topical application to the skin and/or exposed tissue of a human and wherein component (2) exceed 5 mg/cm- of the skin or exposed tissue to which the dosage amount is applied.57. The use of a dosage amount of a pharmaceutical composition comprising:(1) a medicine and/or therapeutic agent for the treatment of pain of the skin and/or exposed tissue of a human; and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters. c\j fragments and sub-units of hyaluronic acid O>for the topical treatment of pain in the skin and/or exposed tissue of a human wherein the dosage amount is in a dosage form suitable for ° topical application and wherein component (2) exceeds 10 mg/cm- of the skin or exposed tissue to which the dosage amount is applied.σ>58. The use of Claim 56 wherein component (2) is sodium hyaluronate having a molecular weight less than 750.000 daltons.59. The use of Claim 57 wherein component (2) is sodium hyaluronate having a molecular weight less than 750.000 daltons.BAB ΘΒΙβΙΝΑΙ $-98—60. The use of Claim 58 or 59 wherein the sodium hyaluronate has a molecular weight between 150.000 daltons and 225.000 daltons.61. The use of Claim 56. 57. 58, 59 or 60 wherein the pharmaceutical composition further comprises suitable topical excipients.62. The use of Claim 56, 57. 58, 59. 60 or 61 wherein component (1) is a non-steroidal anti-inflammatory drug (NSAID).63. The use of Claim 62 wherein the NSAID is diclofenac sodium.(64. The use of Claim 56 or 58 wherein component (1) is an anti-cancer agent.65. The use of Claim 64 wherein the anti-cancer agent is novantrone.66. The use of Claim 56 or 58 w'herein the disease and/or condition is basal cell carcinoma.67 The use of Claim 56 or 58 w herein the disease ο ί- condition is actinic keratoses. ( 68 The use of Claim 56 or 58 w herein the disease ο ί- condition is liver spots. 69 The use of Claim 56 or 58 wherein the disease ο r condition is squamous cell tumours. 7 0 The use of Claim 56 or 58 w herein the disease or condition is metastatic cancer of the breast to the skin. 7 1 The use of Claim 56 or 58 w herein the disease or condition is primary and metastatic melanoma of the skin.AP/P/ 93/00492BAD ORIGINAL $72. The use of Claim 56 or 58 wherein the disease or condition is malignancies and/or tumour of the skin. 73. The use of Claim 56 or 58 wherein the disease or condition is genital warts (condyloma acuminata) 74. The use of Claim 56 or 58 wherein the disease or condition is cervical cancer. 75. The use of Claim 56 or 58 wherein the disease ο ι- condition is Human Papilloma Virus (HPV). 76. The use of Claim 56 or 58 wherein the disease ογ condition is psoriasi s. 77. The use of Claim 56 or 58 wherein the disease or condition is corns on the feet or the hair loss on the head of pregnant women. 78. Percutaneous delivery of a therapeutically effective dosage amount of a drug which inhibits prostaglandin synthesis said dosage amount taken from a pharmaceutical composition and applied to the skin and/or exposed tissue of a human, the drug being transported to the site of trauma and/or pathology, on or in the skin and/or exposed tissue of the human, to treat a disease or condition of f the skin and/or exposed tissue, the delivery comprising topically administering to the skin and/or exposed tissue site of the trauma and/or pathology, the therapeutically effective, non-toxic (to the patient) dosage amount of the drug which inhibits prostaglandin synthesis, in a composition which also comprises an effective nontoxic amount of hyaluronic acid and/or salts thereof sufficient to transport, (facilitate or cause the transport of), the drug to the epidermis to the site of the trauma and/or pathology to block the synthesis of prostaglandin, wherein the amount of hyaluronic ucid and/or salts thereof exceeds at least about 5mg/cm- of the -kin and/or exposed tissue to which the composition is to be applied.79. The percutaneous delivery of Claim 78 wherein theP/ 9 3 / 0 0 4 9 2BAD ORIGINAL s-100hyaluronic acid and/or salts thereof is sodium hyaluronate.80. The percutaneous delivery of Claim 78 or 79 wherein the molecular weight of the hyaluronic acid and/or salts is less than about 750,00'· daltons.81. The percutaneous delivery of Claim 78. 79 or 80 wherein the drug comprises an anti-cancer drug for administration to a tumour or malignancy in the skin and/or exposed tissue.82. The percutaneous delivery of Claim 81 wherein the drug is < 10 mg of novantrone in the dosage amount of the composition and the hyaluronic acid and/or salts thereof in the dosage amount is in excess of about 5 mg of sodium hyaluronate per cm3 of the skin or exposed tissue (about 2.5% of the composition), to which the dosage amount is applied for the percutaneous transport of the novantrone.83. A composition suitable for topical application comprising glycerine (5% by weight), benzyl alcohol (3% by weight), diclofenac sodium (3% by weight), sodium hyaluronate (2.5% by weight) and sterile water (the balance) in a container.(.V ‘ 84. A composition suitable for topical application comprising methoxypolyethylene glycol (20%- by weight), benzyl alcohol (1% by weight), diclofenac sodium (3% by weight), sodium hyaluronate <2.5% by weight). and sterile water (the balance) in a container.85. The composition of Claim 83 or 84 wherein the sodium hyaluronate has a molecular weight less than 750,000 daltons.86. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nonAK'P/ 93/00492 bad original rf-101toxic dosage amounts can be taken for topical application comprising: 3% by weight of the composition of Glycerine 1.5% by weight of the composition of Benzyl Alcohol 1% by weight of the composition of Diclofenac Sodium 'c7c by weight of the composition of Sodium Hyaluronate having a molecular weight of 661.600 daltons 3% by weight of the composition of Liquid Wax and Sterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin f or exposed tissue on application to the skin and/or exposed tissue for ζ accumulation in the epidermis before passage therefrom.87. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:5% by weight of the composition of Glycerine3% by weight of the composition of Benzyl Alcohol3% by weight of the composition of Diclofenac Sodium2.5% bv weight of the composition of Sodium Hyaluronate having a molecular weight of 661.600 daltons andAP/P/ 9 3 / 0 0 4 9 2BAD ORIGINAL A-102Sterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue for accumulation therein in the epidermis before passage therefrom.88. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:20% by weight of the composition of Methoxypolvethy lent Glycol1% by weight of the composition of Benzyl Alcohol 3% by weight of the composition of D.clofenac Sodium 2.5% by weight of the composition of Sodium Hyaluronate having a molecular weight of 679.000 daltons and Sterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- ofCJ σ>ro o>gl a<BAD ORIGINAL $-103the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue for accumulation therein in the epidermis before passage therefrom.89. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:20% by weight of the composition of a solubilizer, Methoxypolyethylene Glycol1% by weight of the composition of a preservative.Benzvl AlcoholJ3% by weight of the composition of Diclofenac Sodium 2.5% by weight of the composition of Sodium Hyaluronate having a molecular weight of 679,000 daltons, and Sterile Water ( i· characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue forAP/P/ 9 3 / 0 0 492BAD ORIGINAL &-104accumulation therein in the epidermis before passage therefrom.90. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:5.5# by weight of the composition of Meglumine57c by weight of the composition of Ibuprofen \7c by weight of the composition of Benzyl Alcohol1% by weight of the composition of Glycerin57c by weight of the composition of Sodium Hyaluronate having a molecular weight of 661,600 daltons. andSterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form o>immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathologv of the disease or condition in the skin *** or exposed tissue on application to the skin and/or exposed tissue for accumulation therein in the epidermis before passage therefrom.Dl <91. A multidose multigram pharmaceutical composition tor topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:47c by weight of the composition of Meglumine bad ORIGINAL-105 2% by weight of the composition of Piroxicam 2.5% by weight of the composition of Sodium Hyaluronate having a molecular weight of 661.600 daltons. and Sterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue for accumulation therein in the epidermis before passage therefrom.92. A multidose multigram pharmaceutical composition fo topical application from which a substantial number of effective non toxic dosage amounts can be taken for topical application comprising: an oily phase comprising15% by weight of the composition of a liquid wax 16% by weight of the composition of a wax and 5% by weight of the composition of Glycerin and an aqueous phase comprising:5% by weight of the composition of Meglumine5% by weight of the composition of Ibuprofen1.5% by weight of the composition of Sodium Hyaluronate having a molecular weight of 200.000 daltons andAP/P/ 93/00492BAD ORIGINAL ft-1060.3% by weight of the composition of a preservative, Suttocide A and Sterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue lor accumulation therein in the epidermis before passage therefrom.93. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising: 3% by weight of the composition of Glycerin1.5% by weight of the composition of Benzyl Alcohol 3% by weight of the composition of Liquid Wax 1% by weight of the composition of Diclofenac Sodium 3% by weight of the composition of Sodium Hyaluronate having a molecular weight of 679,000 daltons. and Sterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosageAP/P/ 93/00492BAD ORIGINAL $-107amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/em- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/o· exposed tissue for accumulation therein in the epidermis before passage therefrom.<94. A multidose multigram pharmaceutical composition for topical application from u'hich a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:1.5% by weight of the composition of a preservative,Benzyl Alcohol3% by weight of the composition of Glycerin about 1% by weight of the composition of DiclofenacSodium ( 3% by weight of the composition of Liquid Wax ζ 3% by weight of the composition of Sodium Hyaluronate having a molecular weight is 661.600 daltons, and Sterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodiumAP/P/ 93/00492BAD ORIGINAL ft-108percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue for accumulation therein in the epidermis before passage therefrom.95. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising: an oily phase comprising 15% by weight of the .«imposition of a liquid wax 10% by weight of the composition of a wax and 5% by weight of the composition of Glycerine and an Aqueous Phase comprising5% by weight of the composition of Meglumine1.5% by weight of the composition of Sodium Hyaluronate having a molecular weight 207,000 daltons5% by weight of the composition of Ibuprofen and a 0.3% by weight of the composition of a preservative. Suttocide. andSterile Water characterized in that the said pharmaceutical composition is a multiple gm composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to theAP/P/ 93/00492 bad ORIGINAL A site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue for accumulation therein in the epidermis before passage therefrom.96. A multidose multigram pharmaceutical composition for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:2.5% by weight of the composition of Sodium Hyaluronate having a molecular weight is 661.600 daltons 1% by weight of the composition of Flunixin Meglumine andSterile Water characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the diclofenac sodium percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue for accumulation therein in the epidermis before passage therefrom.97. A method of percutaneous delivery of a therapeutically effective dosage amount of a drug which inhibits prostaglandin synthesis said dosage amount taken from a pharmaceutical composition and applied to the skin and/or exposed tissue of aAP/P/ 93/00492BAD ORIGINAL &-nohuman. the drug being transported to the site of trauma and/or pathology, on or in the skin and/or exposed tissue of the human, io treat a disease or condition of the skin and/or exposed tissue, the method of percutaneous delivery comprising topically administering to the skin and/or exposed tissue site of the trauma and/or pathology, the therapeutically effective, non-toxic (to the patient) dosage amount of the drug which inhibits prostaglandin synthesis, in a composition which also comprises an effective non-toxic amount of hyaluronic acid and/or salts thereof sufficient to transport (facilitate or cause the transport of), the drug to the epidermis to the site of th< trauma and/or pathology to block the synthesis of prostaglandin, wherein the amount of hyaluronic acid and/or salts thereof exceedsΛ at least about 5mg/cm*- of the skin and/or exposed tissue to which the composition is to be applied.98. The method of percutaneous delivery of Claim 97 wherein the hyaluronic acid and/or salts thereof is sodium hyaluronate.99. The method of percutaneous delivery of Claim 97 or 98 wherein the molecular weight of the hyaluronic acid and/or salts is less than about 750,000 daltons.100. The method of percutaneous delivery of Claim 97. 98. or 99 wherein the drug comprises an anti-cancer drug for administration to a tumour or malignancy in the skin and/or exposed tissue.AP/P/ 93/00492BAD ORIGINAL $-111101. The method of percutaneous delivery of Claim 99 wherein the drug is 10 mg of novantrone in the dosage amount of the composition and the hyaluronic acid and/or salts thereof in the dosage amount is in excess of about 5 mg of sodium hyaluronate per cm- of the skin or exposed tissue (about 2.59( of the composition), to which the dosage amount is applied for the percutaneous transport of the novantrone.102. A multidose, multigram pharmaceutical compositon for topical application from which a substantial number of effective nontoxic dosage amounts can be taken for topical application comprising:1-3% by weight of the composition of hyaluronic acid or pharmaceutically acceptable salt thereof having a molecular weight less than 750,000 daltons;1-5% by weight of the composition of a non-steroidal anti-inflammatory drug (NSAID);excipients for topical application; sterile water, characterized in that the said pharmaceutical composition is a multiple gm. composition, is in a dosage form suitable for topical application and said pharmaceutical composition comprises a plurality of dosage amounts each of which is in a dosage amount in which the sodium hyaluronate is in an effective dosage amount exceeding 5-10 mg/cm- of the skin or exposed tissue to which it is to be applied and in a form immediately available to transport the NSAID percutaneously into the epidermis of the skin or exposed tissue to the site of trauma and/or pathology of the disease or condition in the skin or exposed tissue on application to the skin and/or exposed tissue forAP/P/ 93/00492BAD ORIGINAL S.-112aceuinulation therein in the epidermis before passage therefrom.103. The pharmaceutical composition of Claim 102 wherein the NSAID is diclofenac sodium.104. The pharmaceutical composition of Claim 102 or 103 wherein the hyaluronic acid or pharmaceutically acceptable salt thereof is sodium hyaluronate.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002061566A CA2061566C (en) | 1992-02-20 | 1992-02-20 | Treatment of disease employing hyaluronic acid and nsaids |
IL224111 | 2013-01-02 |
Publications (2)
Publication Number | Publication Date |
---|---|
AP9300492A0 AP9300492A0 (en) | 1993-04-30 |
AP476A true AP476A (en) | 1996-03-18 |
Family
ID=4149300
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1993/000492A AP476A (en) | 1992-02-20 | 1993-02-19 | Eliminating maximum adjacent cut specification restrictions for telescoping pins |
Country Status (22)
Country | Link |
---|---|
EP (1) | EP0626864B1 (en) |
JP (1) | JP4005628B2 (en) |
KR (1) | KR100334973B1 (en) |
CN (1) | CN1078388A (en) |
AP (1) | AP476A (en) |
AT (1) | ATE244020T1 (en) |
AU (2) | AU3488993A (en) |
CA (1) | CA2061566C (en) |
CZ (1) | CZ290534B6 (en) |
DE (1) | DE69333072T2 (en) |
DK (1) | DK0626864T3 (en) |
ES (1) | ES2202311T3 (en) |
HK (1) | HK1005982A1 (en) |
HU (2) | HU225963B1 (en) |
IL (1) | IL104797A0 (en) |
MX (1) | MX9300905A (en) |
NZ (2) | NZ249072A (en) |
PT (1) | PT626864E (en) |
SG (1) | SG49874A1 (en) |
SK (1) | SK11093A3 (en) |
WO (1) | WO1993016733A1 (en) |
ZA (1) | ZA931174B (en) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2268476A1 (en) | 1991-07-03 | 1998-04-30 | Hyal Pharmaceutical Corporation | Use of hyaluronan in gene therapy |
CA2122519C (en) * | 1994-04-29 | 2001-02-20 | Rudolf Edgar Dr. Falk | Cancer treatment and metastasis prevention |
CA2094203A1 (en) * | 1993-04-16 | 1994-10-17 | Derek A. Willoughby | Inhibition of angiogenesis |
CA2196408A1 (en) * | 1994-08-10 | 1996-02-22 | Roderick T. Coward | Method of using hyaluronic acid for the detection, location and diagnosis of tumors |
CA2154103C (en) * | 1995-07-18 | 1998-02-24 | Samuel Simon Asculai | Treatment of mucous membrane disease, trauma or condition and for the relief of pain |
JP3419785B2 (en) * | 1995-09-28 | 2003-06-23 | サングスタット メディカル コーポレイション | Use of hyaluronic acid as an immunosuppressant |
US6875753B1 (en) | 1996-03-14 | 2005-04-05 | The Governors Of The University Of Alberta | Methods for cell mobilization using in vivo treatment with hyaluronan (HA) |
US5939047A (en) * | 1996-04-16 | 1999-08-17 | Jernberg; Gary R. | Local delivery of chemotherapeutic agents for treatment of periodontal disease |
US6630168B1 (en) * | 1997-02-20 | 2003-10-07 | Biomedicines, Inc. | Gel delivery vehicles for anticellular proliferative agents |
DK1140198T3 (en) | 1999-01-13 | 2008-03-10 | Alchemia Oncology Pty Ltd | Use of hyaluronan in the manufacture of a drug for enhancing the efficacy of cytotoxic drugs |
US9066919B2 (en) | 2000-07-14 | 2015-06-30 | Alchemia Oncology Pty Limited | Hyaluronan as a chemo-sensitizer in the treatment of cancer |
AUPQ879500A0 (en) | 2000-07-14 | 2000-08-10 | Meditech Research Limited | Hyaluronan as cytotoxic agent, drug presensitizer and chemo-sensitizer in the treatment of disease |
US6576226B1 (en) | 2000-11-17 | 2003-06-10 | Gary R. Jernberg | Local delivery of agents for disruption and inhibition of bacterial biofilm for treatment of periodontal disease |
US6726898B2 (en) | 2000-11-17 | 2004-04-27 | Gary R. Jernberg | Local delivery of agents for disruption and inhibition of bacterial biofilm for treatment of periodontal disease |
EP2664334B1 (en) * | 2004-12-30 | 2015-03-04 | Genzyme Corporation | Regimens for intra-articular viscosupplementation |
EP1912658B1 (en) | 2005-07-27 | 2017-01-25 | Alchemia Oncology Pty Limited | Therapeutic protocols using hyaluronan |
JP5627181B2 (en) | 2005-09-07 | 2014-11-19 | アルケミア オンコロジー ピーティーワイ リミテッド | Therapeutic compositions comprising hyaluronan and therapeutic antibodies and methods of treatment |
EA015702B1 (en) * | 2007-05-28 | 2011-10-31 | Винченцо Массимо Ломбардо | Antiphlogistic and analgesic composition for topical use in a region of an animal locomotive system |
WO2010069519A1 (en) | 2008-12-18 | 2010-06-24 | Merz Pharma Gmbh & Co. Kgaa | Topical compositions comprising at least one active ingredient poorly soluble in water and biopolymers such as hyaluronic acid with a pka-value between 5-7 |
WO2012119261A1 (en) * | 2011-03-10 | 2012-09-13 | Biocia Inc. | Enhanced artificial mucus composition comprising hyaluronan for the treatment of rhinitis |
FR2994846B1 (en) | 2012-08-29 | 2014-12-26 | Vivacy Lab | COMPOSITION, STERILIZED, COMPRISING AT LEAST ONE HYALURONIC ACID AND MAGNESIUM ASCORBYL PHOSPHATE |
CN102961396A (en) * | 2012-12-17 | 2013-03-13 | 程玉李 | Application of hyaluronic acid metal salt to preparation of skin disease treatment drugs, as well as drug composition and preparation method of hyaluronic acid metal salt |
KR101439032B1 (en) * | 2013-06-13 | 2014-09-05 | 동아에스티 주식회사 | Pharmaceutical composition containing piroxicam and hyaluronic acid for the treatment of osteoarthritis |
TWI758928B (en) | 2014-11-21 | 2022-03-21 | 美商必治妥美雅史谷比公司 | Antibodies against cd73 and uses thereof |
IT201600079633A1 (en) * | 2016-07-28 | 2018-01-28 | Fidia Farm Spa | Preparation and purification process of the sodium salt of hyaluronic acid |
CN106729644A (en) * | 2016-11-22 | 2017-05-31 | 郑州兰茜生物工程有限公司 | A kind of gentle multiple-effect ectylotic and preparation method thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0197718A2 (en) * | 1985-04-05 | 1986-10-15 | FIDIA S.p.A. | New medicaments for topical use |
EP0368253A2 (en) * | 1988-11-08 | 1990-05-16 | UNION CARBIDE CHEMICALS AND PLASTICS COMPANY INC. (a New York corporation) | Delivery system for pharmaceutical or therapeutic actives |
US4937254A (en) * | 1985-11-27 | 1990-06-26 | Ethicon, Inc. | Method for inhibiting post-surgical adhesion formation by the topical administration of non-steroidal anti-inflammatory drug |
WO1991004058A2 (en) * | 1989-09-21 | 1991-04-04 | Norpharmco Inc. | Treatment of conditions and disease |
-
1992
- 1992-02-20 CA CA002061566A patent/CA2061566C/en not_active Expired - Lifetime
-
1993
- 1993-02-16 PT PT93903755T patent/PT626864E/en unknown
- 1993-02-16 AT AT93903755T patent/ATE244020T1/en active
- 1993-02-16 NZ NZ249072A patent/NZ249072A/en not_active IP Right Cessation
- 1993-02-16 EP EP93903755A patent/EP0626864B1/en not_active Expired - Lifetime
- 1993-02-16 DE DE69333072T patent/DE69333072T2/en not_active Expired - Lifetime
- 1993-02-16 SG SG1996007976A patent/SG49874A1/en unknown
- 1993-02-16 JP JP51440893A patent/JP4005628B2/en not_active Expired - Lifetime
- 1993-02-16 ES ES93903755T patent/ES2202311T3/en not_active Expired - Lifetime
- 1993-02-16 HU HU9303283A patent/HU225963B1/en unknown
- 1993-02-16 SK SK11093A patent/SK11093A3/en unknown
- 1993-02-16 AU AU34889/93A patent/AU3488993A/en not_active Abandoned
- 1993-02-16 DK DK93903755T patent/DK0626864T3/en active
- 1993-02-16 WO PCT/CA1993/000062 patent/WO1993016733A1/en active IP Right Grant
- 1993-02-16 NZ NZ299281A patent/NZ299281A/en not_active IP Right Cessation
- 1993-02-18 CZ CZ1993229A patent/CZ290534B6/en not_active IP Right Cessation
- 1993-02-19 MX MX9300905A patent/MX9300905A/en unknown
- 1993-02-19 AP APAP/P/1993/000492A patent/AP476A/en active
- 1993-02-19 ZA ZA931174A patent/ZA931174B/en unknown
- 1993-02-19 IL IL104797A patent/IL104797A0/en unknown
- 1993-02-20 CN CN 93101898 patent/CN1078388A/en active Pending
-
1994
- 1994-08-19 KR KR1019940702858A patent/KR100334973B1/en not_active IP Right Cessation
-
1995
- 1995-06-30 HU HU95P/P00650P patent/HU211689A9/en unknown
-
1998
- 1998-06-10 HK HK98105084A patent/HK1005982A1/en not_active IP Right Cessation
-
2000
- 2000-06-28 AU AU42729/00A patent/AU768058B2/en not_active Expired
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0197718A2 (en) * | 1985-04-05 | 1986-10-15 | FIDIA S.p.A. | New medicaments for topical use |
US4937254A (en) * | 1985-11-27 | 1990-06-26 | Ethicon, Inc. | Method for inhibiting post-surgical adhesion formation by the topical administration of non-steroidal anti-inflammatory drug |
US4937254B1 (en) * | 1985-11-27 | 1992-08-11 | Ethicon Inc | |
EP0368253A2 (en) * | 1988-11-08 | 1990-05-16 | UNION CARBIDE CHEMICALS AND PLASTICS COMPANY INC. (a New York corporation) | Delivery system for pharmaceutical or therapeutic actives |
WO1991004058A2 (en) * | 1989-09-21 | 1991-04-04 | Norpharmco Inc. | Treatment of conditions and disease |
Also Published As
Publication number | Publication date |
---|---|
ATE244020T1 (en) | 2003-07-15 |
CZ290534B6 (en) | 2002-08-14 |
KR100334973B1 (en) | 2002-10-12 |
WO1993016733A1 (en) | 1993-09-02 |
DE69333072T2 (en) | 2004-04-22 |
HUT70440A (en) | 1995-10-30 |
AU4272900A (en) | 2000-09-28 |
DK0626864T3 (en) | 2003-10-20 |
EP0626864A1 (en) | 1994-12-07 |
ES2202311T3 (en) | 2004-04-01 |
CA2061566C (en) | 2002-07-09 |
AP9300492A0 (en) | 1993-04-30 |
EP0626864B1 (en) | 2003-07-02 |
AU768058B2 (en) | 2003-11-27 |
HK1005982A1 (en) | 1999-02-05 |
HU225963B1 (en) | 2008-01-28 |
KR950700085A (en) | 1995-01-16 |
SK11093A3 (en) | 1993-09-09 |
JPH07507054A (en) | 1995-08-03 |
CZ9300229A3 (en) | 2002-06-12 |
SG49874A1 (en) | 1998-06-15 |
CN1078388A (en) | 1993-11-17 |
NZ299281A (en) | 2000-12-22 |
HU211689A9 (en) | 1995-12-28 |
JP4005628B2 (en) | 2007-11-07 |
IL104797A0 (en) | 1993-06-10 |
NZ249072A (en) | 1996-10-28 |
PT626864E (en) | 2003-11-28 |
MX9300905A (en) | 1993-10-01 |
ZA931174B (en) | 1993-09-16 |
CA2061566A1 (en) | 1993-08-21 |
AU3488993A (en) | 1993-09-13 |
DE69333072D1 (en) | 2003-08-07 |
HU9303283D0 (en) | 1994-03-28 |
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