WO2019135125A1

WO2019135125A1 - Semi-solid dosage form for topical application

Info

Publication number: WO2019135125A1
Application number: PCT/IB2018/059726
Authority: WO
Inventors: Y. Joseph Mo; Chun Kwong Chu
Original assignee: Nal Pharmaceutical Group Limited
Priority date: 2018-01-02
Filing date: 2018-12-06
Publication date: 2019-07-11
Also published as: CA3085974A1; AU2018399939A1; SG11202005758UA

Abstract

It relates to topical dosage forms for topical application on skin for selective absorption by the skin tissue, particularly for administration of medicinal agents where a localized systemic application is desirable for medicines such as but not limited to glucosamine. In particular, it relates to pharmaceutical formulation of osteoarthritis drugs in the class of hexosamines or in combination of one or more nonnarcotic analgesics.

Description

SEMI-SOLID DOSAGE FORM FOR TOPIC AL APPLICATION

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. Provisional Application Serial No. 62/612,846, filed January 2, 2018 and U.S. Provisional Application Serial No. 62/621,242, filed January 24, 2018, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to topical dosage forms for topical application on skin for selective absorption by the skin tissue.

BACKGROUND OF THE INVENTION

Osteoarthritis (OA) is one of the most common type of arthritis. An estimated of 21 million adults in the United Stated live with OA. OA is also known as degenerative joint disease, it is caused by break down of cartilage, the connective tissue that cushion the ends of bones within the joint. OA is characterized by pain, joint damage and limited joint motion. This disease generally occurs late in patient life, and hands and larger weight-bearing joints are mainly affected. Further, age, gender, obesity are risk factors for this disease.

Articular cartilage is composed of chondrocytes, which produce and maintain the cartilaginous matrix constituted by proteoglycans and collagen. Proteoglycans (PGs), a main lubricating substance in our cartilage, are formed by the linkage of glycosaminoglycans (GAGs) to the protein core. Cartilage is in an equilibrium of formation and degradation of the extracellular matrix. In OA cartilage, elevated level of interleukin- 1 (IL-l) and tumor necrosis factor-alpha (TNF-a) exacerbates cartilage matrix degradation and depresses PG synthesis. One of the commonly used treatments for OA management is glucosamine administrated orally.

Glucosamine not only is a basic component of glycosaminoglycans, but also stimulates the chondrocytes to produce proteoglycans and inhibit the catabolic cascade induced by IL-l . In vitro, glucosamine has been shown to rescue the imbalanced equilibrium with degrading exceeding synthesis. Over the years, clinical studies have demonstrated the long-term effectiveness of glucosamine in alleviating the pain and stiffness for OA patients.

Histamine is another pharmaceutical agent used in OA treatment, studies indicates that it has a significant impact on pain reduction which acts as a vasodilator to improve the blood flow. Histamine induces vasodilation through activation of vascular Hl and H2 receptors and evokes presynaptic inhibition of sympathetic vasoconstriction through activation of H3 in the central nervous system. As blood vessels open up more, there is greater flow of blood to the area to which it is applied. The increased blood flow produces warm sensation, which temporarily masks pain sensations in the joint or muscle. Some studies also indicated that histamine induces antinociception at the primary somatosensory cortex (PSC).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medicine for relieving pain, reducing inflammation, they are also a common treatment for OA by inhibiting cyclooxygenases (COX) involved in the formation of prostanoids. COX is an enzyme, also known as prostaglandin-endoperoxide synthase (PTGS) and it exits in two different isoforms, COX-l and COX-2. COX-2 was found to be predominantly expressed in injured tissue, it leads to the production of prostaglandins which acts as a messenger molecule in the process of inflammation. NSAIDs have long been used in clinical practice for the inhibition of prostaglandin synthesis by block the COX enzyme at the site of inflammation.

As a drug delivery system, ointment is also proven effective in delivering active ingredient therein in to skin. Thus, it is believed that cream formulations can work similarly to form an active film on skin and facilitate active ingredients therein to be absorbed and used by skin.

SUMMARY OF THE INVENTION

The present invention relates to topical dosage forms for topical application on skin for selective absorption by the skin tissue, particularly for administration of medicinal agents where a localized systemic application is desirable for medicines such as but not limited to glucosamine. In particular, the present invention relates to pharmaceutical formulation of osteoarthritis drugs in the class of hexosamines or in combination of one or more nonnarcotic analgesics.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows effect of penetration enhancers on the Glucosamine cream formulation

1A for penetrating snake skin; Figure 2 shows effect of penetration enhancers on the Glucosamine cream formulation 1A for penetrating rabbit skin;

Figure 3 shows effect of penetration enhancers on the Glucosamine cream formulation 1A for penetrating mouse skin;

Figure 4 shows effect of penetration enhancers on the Alprostadil cream formulation 2B-2E for penetrating mouse skin.

Figure 5 shows effect of penetration enhancers on the Alprostadil cream formulation 2F-2K for penetrating mouse skin.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description is merely exemplary in nature and is not intended to limit application and uses. The following examples further illustrate the present invention without, however, limiting the scope of the invention thereto. Various changes and modifications can be made by those skilled in the art on the basis of the description of the invention, and such changes and modifications are also included in the present invention.

One embodiment of the present invention provides a semi-solid topical composition comprising a matrix comprising an effective amount of a pharmaceutically active agent and one or more penetration enhancers having a combined hydrophilic-lipophilic balance of about 1 to about 16, wherein the matrix is a semi-solid dosage form such as ointment and cream.

In other embodiment of the invention, the pharmaceutical active agent is such as osteoarthritis agents, wound healing agents, anesthetic agents, nonnarcotic analgesics such as the nonsteroidal anti-inflammatory agent (NSAIDS), erectile dysfunction agents, female sexual dysfunction agents, antihistamine, anti-colds and anti-allergy agents, cough suppressant agents, respiratory disorder agents, antiemetic agents, antagonists of CGRP receptors, drugs for hormone replacement, Alzheimer's disease agents, caffeine and caffeine salt compounds, antitumor agents, antiviral agents and antifungal agents. In particular embodiment of the invention, the pharmaceutically active agent is an osteoarthritis agent or in combination of one or more nonnarcotic analgesics. In other particular embodiment of the invention, the pharmaceutically active agent is an antiviral agent or in combination of one or more anesthetic agent. In another embodiment of the invention, the semi-solid topical composition comprises enhancers. Enhancers are such as PEG-8 beeswax, PEG-75 stearate, pegoxol-7 stearate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol dioleate, 2-hydroxypropyl stearate, 2-hydroxypropyl laurate, propylene glycol oleate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dilaurate, polypropylene glycol (17) dioleate, propyleneglycol monolaurate, propylene glycol monomyristate, dipropylene glycol dipelargonate, polypropylene glycol monobutyl ether oleate, propylene glycol dipelargonate, propylene glycol didecanoate, dipropylene glycol dipelargonate, propylene glycol bis(9,l O-epoxystearate), propylene glycol monoisostearate, propylene glycol diundecanoate, glycol monoethyl ether, diethylene glycol monobutyl ether, oleoyl macrogolglycerides, lauroyl macrogolycerides, stearoyl macrogolgylycerides, caprylocaproyl macrogolglycerides, triglycerides medium-chain, polyglyceryl-3 diisostearate, polyglyceryl oleate, ethylene glycol paimitostearate, dissopropyl adipate, di-n-butyl adipate, dimethyl adipate, dimethyl isosorbide and diethylene glycol monoethyl ether. In a particular embodiment of the invention, the semi-solid dosage form contains one or more penetration enhancers in an amount of from about 0.1% by weight to about 20%, about 0.1% by weight to about 15%, or about 1% by weight to about 10% by weight of the semi-solid dosage form.

Further, the semi-solid topical composition comprises a surfactant, a secondary absorption enhancer, a humectant, an emulsifier, a solubilizing agent, a solvent, a base polymer, a diluent, an antioxidant, a fragrance, and a preservative.

The invention also provides a method of drug delivery wherein applying the semi-solid topical composition of the invention topically on the skin of a subject in need thereof, wherein at least a fraction of 1% to 80% or greater of the drug is delivered to and absorbed by the skin and absorbed systemically.

Semi-solid dosage form

Semi-solid dosage forms are dermatological preparations to be applied topically on the skin to produce local or systemic effect. For example, semi-solid dosage forms includes but not limited to ointment, creams, pastes, and gels.

Pharmaceutical Active Agent The pharmaceutical active agent is such as osteoarthritis agents, wound healing agents, anesthetic agents, nonnarcotic analgesics such as the nonsteroidal anti-inflammatory agent (NSAIDS), erectile dysfunction agents, female sexual dysfunction agents, antihistamine and anti-cold and allergy agents, cough suppressant agents, respiratory disorder agents, respiratory disorder agents, antiemetic agents, antagonists of CGRP receptors, drugs for hormone replacement, Alzheimer's disease agent, caffeine and caffeine salt compounds, antitumor agents, antiviral agents and antifungal agents. The pharmaceutical active agent according to the embodiment of the invention, the osteoarthritis agent is glucosamine, N-acetylglucosamine, glucosamine sulfate, glucosamine hydrochloride or other pharmaceutically acceptable salts thereof; the wound healing agent is alprostadil, povidone-iodine (PVP-I) or its pharmaceutically acceptable salts thereof; the anesthetic agent is lidocaine (xylocaine), procaine, benzocaine or its pharmaceutically acceptable salts thereof; the nonnarcotic analgesics is histamine dihydrochloride, white willow bark, menthol, salicylamide, salicylic acid, glycol salicylate, methyl salicylate, nonsteroidal anti-inflammatory agents (NSAIDS) such as acetaminophen, Ibuprofen, ketoprofen, indomethacin, aspirin (low dose for cardiovascular), naproxen sodium, ketorolac, diclofenac, meloxicam, salsalate, piroxicam or other pharmaceutically acceptable salts thereof; the erectile dysfunction agent is sildenafil, tadalafil, alprostadil, vardenafil or its pharmaceutically acceptable salts thereof; the female sexual dysfunction agent is sildenafil, tadalafil, alprostadil, vardenafil or its pharmaceutically acceptable salts thereof; the antihistamine, anti-cold and anti-allergy agent is cetirizine hydrochloride, loratadine, chlorcyclizine hydrochloride, chlorpheniramine maleate, dextrochlorpheniramine maleate, dexbrompheniramine maleate, diphenhydramine citrate, diphenhydramine hydrochloride, doxylamine succinate, phenindamine tartrate, pheniramine, pyrilamine maleate, triprolidine hydrochloride, thonzylamine hydrochloride, clemastine fumarate or other pharmaceutically acceptable salts thereof; the cough suppressant agent is menthol, camphor, dextromethorphan hydrobromide, guaifenesin, codeine phosphate, codeine or other pharmaceutically acceptable salts thereof; the respiratory disorder agent is pseudoephedrine hydrochloride, phenylephrine hydrochloride, guaifenesin, dextromethorphan hydrobromide, ephedrine or other pharmaceutically acceptable salts thereof; the antiemetic agent is granisetron, ondansetron, AZ-001 (Staccato® prochlorperazine, proprietary product of Alexza), AZ-004 (Staccato® loxapine; proprietary product of Alexza), Levadex® (dihydroergotamine, proprietary product of Allergan, Inc.), Zelrix™ (sumatriptan; proprietary product of NuPathe Inc.), VR- 147(proprietary product of Vectura), ROX-828(ketorolac tromethamine containing 6% lidocaine, proprietary product of ROXRO PHARMA, Inc.), COL- 144 (lasmiditan, proprietary product of Colucid Pharmaceuticals), BF-l (proprietary product of Biofrontera), diphenhydramine, scopolamine or other pharmaceutically acceptable salts thereof; the drug for hormone replacement is estradiol, testosterone or its pharmaceutically acceptable salts thereof; the Alzheimer's agent is donepezil, galantamine, rivastigmine, tacrine, memantine or its pharmaceutically acceptable salts thereof; the antitumor agent is gefitinib or its pharmaceutically acceptable salts thereof; the antiviral agent is sorivudine and its pharmaceutically acceptable salts thereof; and the antifungal agent is terbinafine, terbinafine hydrochloride, butenafine, butenafine hydrochloride and other pharmaceutically acceptable salts thereof.

Enhancer

The present invention comprises one or more enhancers. The enhancer is selected from group consisting of PEG-8 beeswax, PEG-75 stearate, pegoxol-7 stearate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol dioleate, 2-hydroxypropyl stearate, 2-hydroxypropyl laurate, propylene glycol oleate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dilaurate, polypropylene glycol (17) dioleate, propyleneglycol monolaurate, propylene glycol monomyristate, dipropylene glycol dipelargonate, polypropylene glycol monobutyl ether oleate, propylene glycol dipelargonate, propylene glycol didecanoate, dipropylene glycol dipelargonate, propylene glycol bis(9,l O-epoxystearate), propylene glycol monoisostearate, propylene glycol diundecanoate, glycol monoethyl ether, diethylene glycol monobutyl ether, oleoyl macrogolglycerides, lauroyl macrogolycerides, stearoyl macrogolgylycerides, caprylocaproyl macrogolglycerides, triglycerides medium-chain, polyglyceryl-3 diisostearate, polyglyceryl oleate, ethylene glycol paimitostearate, dissopropyl adipate, di-n-butyl adipate, dimethyl adipate, dimethyl isosorbide and diethylene glycol monoethyl ether. The semi-solid topical composition further comprises a secondary absorption enhancer such as glycerol and terpenes. The semi-solid topical composition further contains one or more penetration enhancers in an amount of from about 0.1% by weight to about 20%, about 0.1% by weight to about 15%, or about 1% by weight to about 10% by weight of the semi-solid dosage form.

Surfactant

The semi-solid topical composition of the invention further comprises the surfactant.

The surfactant is such as anionic, cataionic, nonionic, amphoteric, saturated and unsaturated higher aliphatic acid salts such as sodium laurate, sodium stearate, sodium oleate, sodium linolenate, and other pharmaceutically acceptable salts thereof, long-chain alkyl sulfate salts, alkylbenzenesulfonic acids such as hexylbenzenesulfonic acid, octylbenzenesulfonic acid, dodecylbenzenesulfonic acid, and its pharmaceutically acceptable salts thereof, polyoxyalkylene alkyl ether sulfate salts, polyoxyalkylene alkenyl ether sulfate salts, the salts of polyoxyethylene alkyl sulfate esters, the salts of the alkyl esters of sulfosuccinic acid, polyoxyalkylene sulfosuccinate salts, the salts of the alkyl esters of polyoxyalkylene sulfosuccinic acid, the alkali metal salts of the polyoxyalkylene-modified dimethylpolysiloxane esters of sulfosuccinic acid, polyoxyalkylene alkylphenyl ether sulfate salts, long-chain alkanesulfonic acid salts, long-chain alkylsulfonates, polyoxyethylene alkylphenyl ether sulfate salts, polyoxyalkylene alkyl ether acetate salts, long-chain alkyl phosphate salts, polyoxyalkylene alkyl ether phosphate salts, acylglutamate salts, alpha- acylsulfonate salts, long-chain alkylsulfonate salts, alkylarylsulfonate salts, long-chain alpha- olefinsulfonate salts, alkylnaphthalenesulfonate salts, long-chain alkanesulfonic acid salts, long-chain alkyl or alkenyl sulfate salts, long-chain alkylamide sulfate salts, long-chain alkyl or alkenyl phosphate salts, alkylamide phosphate salts, alkyloylalkyltaurate salts, N-acylamino acid salts, sulfosuccinate salts, alkyl alkyl ether carboxylate salts, amide ether carboxylate salts, the salts of esters of alpha- sulfofatty acids, alanine derivatives, glycine derivatives, and arginine derivatives; salts can be exemplified by alkali-metal salts such as the sodium salt and potassium salt, alkanolamine salts such as the triethanolamine salt, and the ammonium salt, the sodium salt; alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, lauryltrimethylammonium chloride, cetyltrimethylammonium chloride, beef tallow alkyltrimethylammonium chloride, behenyltrimethylammonium chloride, octyltrimethylammonium hydroxide, dodecyltrimethylammonium hydroxide, stearyltrimethylammonium bromide, behenyltrimethylammonium bromide, distearyldimethylammonium chloride, dicocoyldimethylammonium chloride, dioctyldimethylammonium chloride, di(POE)oleylmethylammonium (2EO) chloride, benzalkonium chloride, alkylbenzalkonium chloride, alkyldimethylbenzalkonium chloride, benzethonium chloride, stearyldimethylbenzylammonium chloride, lanolin-derived quaternary ammonium salts, diethylaminoethylamide of stearic acid, dimethylaminopropylamide of stearic acid, behenamidopropyldimethylhydroxypropylammonium chloride, stearoylcolaminoformylmethylpyridinium chloride, cetylpyridinium chloride, tall oil alkylbenzylhydroxyethylimidazolinium chloride, and benzylammonium salts; phospholipids, such as lecithin, phosphatidylethanolamine, phosphatidic acid, phosphatidylinositol, phosphatidylserine, phosphatidylcholine, phosphatidylglycerol, sphingomyelin, and cardiolipin, and the hydrogenates of the preceding. Particularly preferred are the hydrogenated natural lecithins as yielded by the hydrogenation of, for example, soy lecithin, egg yolk lecithin, corn lecithin, cottonseed oil lecithin, rapeseed lecithin; polyoxyalkylene ethers, polyoxyalkylene alkyl ethers, polyoxyalkylene fatty acid esters, polyoxyalkylene fatty acid diesters, polyoxyalkylene resin acid esters, polyoxyalkylene (hardened) castor oils, polyoxyalkylene alkylphenols, polyoxyalkylene alkylphenyl ethers, polyoxyalkylenephenyl phenyl ethers, polyoxyalkylene alkyl esters, polyoxyalkylene alkyl esters, sorbitan fatty acid esters, polyoxyalkylene sorbitan alkyl esters, polyoxyalkylene sorbitan fatty acid esters, polyoxyalkylene sorbitol fatty acid esters, polyoxyalkylene glycerol fatty acid esters, polyglycerol alkyl ethers, polyglycerol fatty acid esters, sucrose fatty acid esters, fatty acid alkanolamides, alkyl glucosides, polyoxyalkylene fatty acid bisphenyl ethers, polypropylene glycol, poly ether-modified silicones such as polyoxyalkylene-modified diorganopolysiloxanes, polyglycerol-modified silicones, glycerol-modified silicones, saccharide-modified silicones, perfluoropolyether-type surfactants, polyoxyethylene-polyoxypropylene block copolymers, alkyl polyoxyethylene-polyoxypropylene block copolymer ethers and a mixtures thereof.

Humectant

The semi-solid topical composition of the invention further comprises the humectant. The humectant is such as sorbitol, mineral oil, vegetable oil, glycerol; betaine, guanidine, urea, glycolic acid, glycolate salts, ammonium glycolate, quaternary alkyl ammonium glycolate, lactic acid, lactate salts, ammonium lactate, quaternary alkyl ammonium lactate, aloe vera, aloe vera gel, allantoin, urazole, alkoxylated glucose, hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine and derivatives, esters, salts and mixtures thereof; collagen, gelatin, aloe vera, hyaluronic acid or volatile water-soluble solvents, such as ethanol or propylene glycol.

Emulsifier

The semi-solid topical composition of the invention may further comprise the emulsifier. The emulsifier is such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils such as, cottonseed, groundnut, corn, germ, olive, castor and sesame oils, glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof; carbomer, hydroxypropyl cellulose, sodium lauryl sulfate; glycerin fatty acid esters (monoglycerides, MG); mono- and di-glycerides (MG & DG) such as Grindsted HV 40™, Poem J-2021™; distilled monoglycerides; citric acid esters of MG (CMG); diacetyl tartaric acid esters of mono- and di-glycerides (DATEMs) such as Panodan AL 10™; polyglycerol esters of fatty acids (PGE); polyglycerol polyricinoleate (PGPR); sorbitan esters of fatty acids such as Palsgaard 7463™; sucrose esters of fatty acids; calcium stearoyl lactylates; sodium stearoyl lactylates; lecithin including enzyme digested lecithin; and caseinates such as sodium caseinates including Alanate 191™; diacetyl tartaric acid esters of mono- and di-glycerides (DATEMs).

Solubilizing Agent

The semi-solid topical composition of the invention further comprises the solubilizing agent. The solubilizing agent is such as citric acid, ethylenediamine-tetraacetate, sodium meta phosphate, succinic acid, urea, cyclodextrin, polyvinylpyrrolidone, diethylammonium- ortho benzoate, and micelle-forming solubilizers such as TWEEN® and spans, such as TWEEN 80®; polyoxyethylene sorbitan fatty acid ester, polyoxyethylene n-alkyl ethers, n-alkyl amine n- oxides, polyoxamers, organic solvents, such as acetone, phospholipids, cyclodextrin, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200 to 600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide, miglyol, glycerin and glycerol.

Solvent

The semi-solid topical composition of the invention further comprises the solvent. The solvent is such as methylene chloride; beta-cyclodextrin; dichloromethane; oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil; for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof; physiological saline solution such as glycerol; alcohols such as methanol, ethanol, propanol, isopropyl alcohol; sugar solutions such as glucose or mannitol solutions, or mixtures thereof; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene; ether solvents such as diethyl ether, tert-butylmethyl ether, dimethoxyethane, tetrahydrofuran, dioxane and THF; aliphatic hydrocarbon solvents; ester solvents such as ethyl acetate; ketone solvents; chlorinated hydrocarbon solvents such as dichloromethane, chloroform and 1 ,2-dichloroethane; an organic solvent such as acetonitrile, l,3-dimethyl-2-imidazolidinone, dimethylformamide, N-dimethylacetamide, N-methylpyrrolidine, dimethylsulfoxide, pyridine, nitromethane, and mixtures thereof.

Base polymer

The semi-solid topical composition of the invention further comprises the base polymer. The base polymer is such as polysaccharide-based polymers, such as guar, xanthan and/or their derivatives; hydrophobic base polymers such as SIS (styrene/isoprene/styrene)- triblock copolymers, SBS (styrene/butadiene/styrene)-triblock copolymers, SBR (copolymers of styrene and butadiene), synthetic and/or natural polyisoprenes, polyamide, polyester, co- polyester, polyurethane and/or mixtures thereof are also possible as further matrices; water- soluble polymers, plant base polymers such as gum arabic, tragacanth gum, galacian, guar gum, carob gum, karaya gum, carragbeein, pectin, agar, quince seed (Marumero) algae colloid (seaweed extract), starch from such as rice, corn, potato, wheat, glycyrrhinic acid; microorganism base polymers such as xanthane gum, dextran, succinoglutan, pullulan; animal base polymers such as collagen, caseine, albumin, gelatin; starch base polymers such as carboxymethyl starch, methythydroxypropyl starch; cellulose base polymers such as methyl cellulose nitro cellulose, ethyl cellulose, methythydroxypropyl cellulose, hydroxyethyl cellulose, sodium cellulose sulfate, hydroxypropyl cellulose, sodium carboxymethyl cellulose (CMC), crystalline cellulose, cellulose powder; alginate base polymers such as sodium alginate, alginate propylene glycol esters; vinyl base polymers such as a polyvinyl alcohol, polyvinylmethyl ether, polyvinylpyrrolidone carboxyvinyl polymer (Carbopol), alkyl modified carboxyvinyl polymer, polyoxyethylene base polymers such as polyethylene glycol 2000, 4000, 6000; acryl base polymers such as polyacrylates or its salt thereof, polyoxyethylene polyoxypropylene copolymer brae polymer, sodium polyacrylate, polyethylene acrylate, polyacryl amide, polyethylene imine,and cationic polymer may be mentioned.

Diluent

The semi-solid topical composition of the invention further comprises the diluent. The diluent is such as water, saline, finger's solutions, dextrose solution; calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.

Antioxidant

The semi-solid topical composition of the invention further comprises the antioxidant. The antioxidant is such as sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Fragrance

The semi-solid topical composition of the invention further comprises the fragrance. The natural fragrance is such as buttery, banana, almond, bitter almond, cherry, cinnamon, fruity, grape, orange, pear, pineapple, sugar, cotton candy, vanilla, wintergreen, minty, apple, rosemary, lavender, ginseng, musk, green tea, violet, lily, lemon, rose, jasmine, blueberry, peach, coconut, orange, mandarin, jam, apricot, fennel, honey, plum, raspberry, alcohol, etc. The artificial fragrance is such as but not limited to benzaldehyde, p-tolyl aldehyde, decyl aldehyde, cinnamic aldehyde, ionone, gamma undecalactone, anethole, malonates, phenylacetate acid ester, ethyl acid ester, cyclohexyl cinnamate, ethyl acetosuccinate, citronella, geraniol, and linalool.

Preservative

The semi-solid topical composition of the invention further comprises the preservative. The preservative is such as methyl hydroxy benzoate, propyl hydroxy benzoate, chorocresol, benzoic acid and phenyl mercuric nitrate.

Method of Preparation

The semi-solid topical composition of the present invention is prepared using the known methods or by adopting specific conditions suitable for the ingredients employed.

Examples of the semi-solid topical compositions and the amount of the ingredients are listed below, but not limited:

Glucosamine cream formulation

Alprostadil cream formulation

Gefitinib Cream Formulations

Sorivudine & Lidocaine Cream Formulation

QS: Quantum Satis (Add as much of purified water and sodium hydroxide as is needed ve the optimal percentage by weight ratio).

Method of Drug Delivery To deliver the pharmaceutically active agent the semi-solid topical composition of the invention is applied topically on the skin of a subject in need thereof. The pharmaceutically active agent is delivered to and absorbed by the skin and absorbed systemically. The total amount of the pharmaceutically active agent delivered is at least a fraction of 1% to 80% or greater of the drug.

EXAMPLES

Selected embodiments of the invention will be described in further detail with reference to the following experimental and comparative examples. These examples are for illustrative purposes only and are not intended to limit the scope of the invention.

EXAMPLE 1: GLUCOSAMINE CREAM FORMULATION

Glucosamine cream were prepared according to the components and amounts shown in Table 1.

Table 1.

EXAMPLE 2: ALPRO ST DIL CREAM FORMULATION

Alprostadil cream formulation were prepared according to the components and amounts shown in Table 2.

Table 2

Table 2 (Continued)

EXAMPLE 3: GEFITINIB CREAM FORMULATIONS

Gefitinib cream were prepared according to the components and amounts shown in

Table 3.

Table 3

EXAMPLE 4: SORIVUDINE & LIDOCAINE CREAM FORMULATION

Sorivudine/Lidocaine cream were prepared according to the components and amounts shown in Table 4. Table 4

QS: Quantum Satis (Add as much of purified water anc sodium hydroxide as is needed to achieve the optimal percentage by weight ratio).

EXAMPLE 5: EFFECT OF PENETRATION ENHANCERS IN TRANSDERMAL PENETRATION OF GLUCOSAMINE THROUGH SNAKE SKIN,

RABBIT SKIN, AND MOUSE SKIN

A Franz diffusion cell system was used to assess the influence of penetration enhancers on the formulation of glucosamine cream for penetrating snake skin, rabbit skin, and mouse skin. The test drug Example 1 A were applied on snake skin and allowed to diffuse for 8 hours, rabbit skin for 24 hours, and mouse skin for 84 hours. The cumulative amount of glucosamine penetrated at the end of each period was shown in Figures 1 to 3. The data in Figures 1 to 3 showed that enhancers promoted penetration of glucosamine the three different skins.

EXAMPLE 6: EFFECT OF PENETRATION ENHANCERS IN TRANSDERMAL PENETRATION OF ALPRO ST ADIL THROUGH MOUSE SKIN

A Franz diffusion cell system was used to assess the influence of penetration enhancers on the formulation of alprostadil cream for penetrating mouse skin. The test drugs listed in Table 5 were applied on mouse skin and allowed to diffuse for 18 hours. The cumulative amount of alprostadil penetrated at the end of 18th hour with regard to various enhancers in the formulations was shown in Figure 4. The data in Figure 4 showed that 1% of Caprylocaproyl Polyoxylglycerides and 1% of Medium-Chain Triglycerides promoted the penetration of alprostadil across mouse skin.

Table 5

Another Franz diffusion cell system was used to assess the influence of penetration enhancers (5%w/w) on the formulation of alprostadil cream for penetrating mouse skin (N=6). The test drugs listed in Table 6 were applied on mouse skin and allowed to diffuse for 20 hours. The cumulative amount of alprostadil penetrated at the end of 20^th hour with regard to various enhancers in the formulations was shown in Figure 5. The data in Figure 5 manifested that all the listed enhancers promoted the penetration of alprostadil across mouse skin upon a cream base containing Polysorbate 80 and Sorbitan Oleate. Table 6

EXAMPLE 7: WOUND HEALING STUDY OF ALPRO STADIL CREAM IN RABBITS

A wound healing study was used to assess the influence of penetration enhancers on the efficacy of alprostadil cream. The wounds on rabbits were made by scalding (deep-second degree). The test drugs were applied on wound once daily. The score represents the efficacy of wound healing progress, the higher the score, the faster the wound healing rate. The commercial product contains alprostadil without any claimed enhancer. The data in Table 7 showed that alprostadil does expedite wound healing as all the alprostadil containing groups scored higher than the control group. Furthermore, all enhancers containing group scored higher than the commercial product, which suggested that the enhancers could increase the amount of penetrated alprostadil and thus improve the efficacy. Table 7

EXAMPLE 8: EFFECT OF PENETRATION ENHANCERS IN TRANSDERMAL PENETRATION OF GEFITINIB

A Franz diffusion cell system was used to assess the influence of penetration enhancers on the formulation of gefitinib cream for penetrating mouse skin. The test drugs were applied on mouse skin and allowed to diffuse for 6 hours. The cumulative amount of gefitinib in the skin at the end of 6^th hour was shown in Table 8. The data in Table 8 showed that enhancers increased the absorption of gefitinib across into the mouse skin by 54%.

Table 8

EXAMPLE 9: STABILITY TEST OF SORIVUDINE & LIDOCAINE CREAM

Stability test were performed to determine the stability profiles of Sorivudine & Lidocaine cream formulations. Accelerate conditions for the stability test were 40 ± 2 C° and 75 ± 5% RH. Lidocaine and Sorivudine contents of formulation and their amount throughout the test are listed in Table 9 and Table 10.

Formulations 4A and 4B were stable for 2 months at accelerate conditions of 40 C° and 75% RH. Both formulations were stable with or without the addition of BHT as an antioxidant when the lidocaine content is kept at 2%. However, the initial contents of sorivudine of Formulations 4C, 4D and 4E are significantly reduced due to elevated apparent pH values observed for these formulations when adjusted with 1% NaOH solution, and when lidocaine is kept at a 4% level. The elevated pH conditions result in further reductions of the sorivudine contents observed for the 2-month stability results at accelerate storage conditions of 40 C° / 75% RH. On the other hand, lidocaine contents of Formulations 4 A through 4E were all stable for 2 months at accelerate conditions of 40 C° / 75% RH. In other words, the lidocaine contents are not affected by the pH adjustments with 1% NaOH solution. Table 9

Table 10

Claims

CLAIMS We claim:

1. A semi-solid topical composition comprising:

a matrix comprising an effective amount of a pharmaceutically active agent and one or more penetration enhancers having a combined HLB of about 1 to about 16,

wherein the matrix is a semi-solid dosage form such as ointment and cream.

2. The semi-solid topical composition of claim 1 wherein the pharmaceutical active agent is selected from the group consisting of osteoarthritis agents, wound healing agents, anesthetic agents, nonnarcotic analgesics such as the nonsteroidal anti-inflammatory agent (NSAIDS), erectile dysfunction agents, female sexual dysfunction agents, antihistamine, anti-colds and anti-allergy agents, cough suppressant agents, respiratory disorder agents, antiemetic agents, antagonists of CGRP receptors, drugs for hormone replacement,

Alzheimer's disease agents, caffeine and caffeine salt compounds, antitumor agents , antiviral agents and antifungal agents.

3. The semi-solid topical composition of claim 2 wherein

a) the osteoarthritis agent is glucosamine, N-acetylglucosamine, glucosamine sulfate, glucosamine hydrochloride or other pharmaceutically acceptable salts thereof;

b)the wound healing agent is alprostadil, povidone-iodine (PVP-I) or its

pharmaceutically acceptable salts thereof;

c) the anesthetic agent is lidocaine, procaine, benzocaine or its pharmaceutically acceptable salts thereof;

d)the nonnarcotic analgesics is histamine dihydrochloride, white willow bark, menthol, salicylamide, salicylic acid, glycol salicylate, methyl salicylate, NSAIDS such as acetaminophen, Ibuprofen, ketoprofen, indomethacin, aspirin (low dose for cardiovascular), naproxen sodium, ketorolac, diclofenac, meloxicam, salsalate, or piroxicam or other pharmaceutically acceptable salts thereof;

e) the erectile dysfunction agent is sildenafil, tadalafil, alprostadil, vardenafil or its pharmaceutically acceptable salts thereof; f) the female sexual dysfunction agent is sildenafil, tadalafil, alprostadil, vardenafil or its pharmaceutically acceptable salts thereof;

g)the antihistamine, anti-cold and anti-allergy agent is cetirizine hydrochloride, loratadine, chlorcyclizine hydrochloride, chlorpheniramine maleate, dextrochlorpheniramine maleate, dexbrompheniramine maleate, diphenhydramine citrate, diphenhydramine hydrochloride, doxylamine succinate, phenindamine tartrate, pheniramine, pyrilamine maleate, triprolidine hydrochloride, thonzylamine hydrochloride, clemastine fumarate or other pharmaceutically acceptable salts thereof;

h)the cough suppressant agent is menthol, camphor, dextromethorphan

hydrobromide, guaifenesin, codeine phosphate, codeine or other pharmaceutically acceptable salts;

i) the respiratory disorder agent is pseudoephedrine hydrochloride, phenylephrine hydrochloride, guaifenesin, dextromethorphan hydrobromide, ephedrine or other

pharmaceutically acceptable salts;

j) the anti emetic agent is granisetron, ondansetron, prochloperazine, loxamine, dihydroergotamine, sumatriptan, VR- 147, ketorolac tromethamine with lidocaine, lasmiditan, BF-l, diphenhydramine, scopolamine or other pharmaceutically acceptable salts thereof; k)the drug for hormone replacement is estradiol, testosterone or its pharmaceutically acceptable salts thereof;

l) the Alzheimer's disease agent is donepezil, galantamine, rivastigmine, tacrine, memantine or its pharmaceutically acceptable salts thereof;

m) the antitumor agent is gefitinib or its pharmaceutically acceptable salts thereof;

n)the antiviral agent is sorivudine or its pharmaceutically acceptable salts thereof; or o)the antifungal agent is terbinafine, terbinafine hydrochloride, butenafine, butenafine hydrochloride or other pharmaceutically acceptable salts thereof.

4. The semi-solid topical composition of claim 1, wherein the pharmaceutically active agent is selected from the group consisting of glucosamine, N-acetylglucosamine, glucosamine hydrochloride, glucosamine sulfate, alprostadil, sildenafil, tadalafil, vardenafil, cetirizine, donepezil, galantamine, rivastigmine, tacrine, memantine, terbinafine, terbinafine hydrochloride, butenafine, or butenafine hydrochloride.

5. The semi-solid topical composition of claim 1, wherein the pharmaceutically active agent is an osteoarthritis agent or in combination of one or more nonnarcotic analgesics.

6. The semi-solid topical composition of claim 1, wherein the pharmaceutically active agent is an antiviral agent or in combination of one or more anesthetic agent.

7. The semi-solid topical composition of claim 1, wherein said enhancers are selected from group consisting of PEG-8 beeswax, PEG-75 stearate, pegoxol-7 stearate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol dioleate, 2-hydroxypropyl stearate, 2-hydroxypropyl laurate, propylene glycol oleate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dilaurate, polypropylene glycol (17) dioleate, propyleneglycol monolaurate, propylene glycol monomyristate, dipropylene glycol dipelargonate, polypropylene glycol monobutyl ether oleate, propylene glycol dipelargonate, propylene glycol didecanoate, dipropylene glycol dipelargonate, propylene glycol bis(9,l0-epoxystearate), propylene glycol monoisostearate, propylene glycol diundecanoate, glycol monoethyl ether, diethylene glycol monobutyl ether, oleoyl macrogolglycerides, lauroyl macrogolycerides, stearoyl macrogolgylycerides, caprylocaproyl macrogolglycerides, triglycerides medium-chain, polyglyceryl-3

diisostearate, polyglyceryl oleate, ethylene glycol paimitostearate, dissopropyl adipate, di-n- butyl adipate, dimethyl adipate, dimethyl isosorbide and diethylene glycol monoethyl ether.

8. The semi-solid topical composition of claim 1, further comprising a surfactant, a humectant, an emulsifier, a solubilizing agent, a solvent, a base polymer, a diluent, an antioxidant, a fragrance, a secondary absorption enhancer or a preservative.

9. The semi-solid topical composition of claim 6, further comprising a secondary absorption enhancer selected from the group consisting of glycerol and terpenes.

10. The semi-solid topical composition of claim 1, wherein said semi-solid dosage form contains one or more penetration enhancers in an amount of from about 0.1% by weight to about 20%, about 0.1% by weight to about 15%, or about 1% by weight to about 10% by weight of the semi-solid dosage form.

11. A method of delivering the pharmaceutically active agent comprising:

applying the semi-solid topical composition of claim 1, topically on the skin of a subject in need thereof,

wherein at least a fraction of 1% to 80% or greater of the drug is delivered to and absorbed by the skin and absorbed systemically.