A method for improving the stability of a pharmaceutical composition containing a highly permeable drug, and a pharmaceutical composition obtained thereby.

Abstract

To provide a method for improving stability of a pharmaceutical composition which comprises a high penetration drug substance and a pharmaceutically acceptable carrier.SOLUTION: The present invention provides a method for improving stability of a pharmaceutical composition which comprises a high penetration drug substance and a pharmaceutically acceptable carrier, the method comprising: packaging the high penetration drug substance and the pharmaceutically acceptable carrier in separate containers; and reconstituting a solution of the pharmaceutical composition by mixing the high penetration drug substance with the pharmaceutically acceptable carrier prior to administration to a patient in need thereof, characterized in that the pH of the reconstitution solution of the pharmaceutical composition is kept within a range of 2 to 6.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising at least one highly permeable drug (HPD) having at least one protonated amino group in its molecule and capable of rapidly passing through one or more biological barriers; a method for improving the stability of the pharmaceutical composition; and a method for using the pharmaceutical composition to prevent, diagnose and / or treat diseases or disorders in humans, animals, and plants. [Background technology]

[0002] Active substances or drugs that are effective in vitro may be difficult to deliver in vivo, and may not be as effective in vivo, in particular, because their ability to overcome one or more biological barriers before reaching the disease site of action is limited, causing the substance or drug to remain in the systemic circulation for a long period and be metabolized by the liver, kidneys, and other organs before reaching the disease site of action.

[0003] Currently, many drugs are administered via systemic routes, such as oral or parenteral administration, to reach the site of action of the disease or disorder. In systemic administration, higher doses of the drug are required to reach distal locations, and drugs delivered via such routes may cause adverse reactions.

[0004] For example, non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat acute or chronic illnesses characterized by pain and inflammation. While NSAIDs are absorbed through the mucous membranes of the stomach and intestines, oral administration is usually associated with adverse drug reactions, such as effects on the gastrointestinal tract (GI) and kidneys. For instance, aspirin is known to cause damage to gastric mucosal cells. Side effects of NSAIDs appear to be dose-dependent and can be severe, often leading to dyspepsia, gastroduodenal bleeding, gastric ulcers, gastritis, ulcer perforation, and even death.

[0005] The digestive tract, skin, and other biological membranes have lipophilic barriers. Most drugs that can penetrate biological membranes are lipophilic to a considerable extent, but digestive fluids, the blood system, and the water on the skin are mostly water, making it very difficult for lipophilic substances or drugs to dissolve in these systems.

[0006] In previous patent applications (Patent Documents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24), the applicant disclosed many novel compositions of HPD that are lipophilic and hydrophilic, soluble in both lipids and water, and permeable to lipid or aqueous barriers.

[0007] However, many of these novel HPDs are not very stable under aqueous conditions and cannot be stored for the long periods required for a reasonable shelf life of pharmaceutical products. Therefore, it is necessary to improve the stability of HPDs or compositions so that they can be efficiently and effectively delivered to the site of action of a disease (e.g., illness) to prevent, alleviate, or treat the disease in a biological subject. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International application PCT / IB2006 / 052732 [Patent Document 2] International application PCT / IB2006 / 052318 [Patent Document 3] International application PCT / IB2006 / 052732 [Patent Document 4] International application PCT / IB2006 / 052318 [Patent Document 5] International Application PCT / IB2006 / 052461

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[0009] In one embodiment, the present invention provides a method for improving the stability of a pharmaceutical composition comprising HPD and a pharmaceutically acceptable carrier, comprising packaging the HPD and the pharmaceutically acceptable carrier separately, and reconstituting a solution of the pharmaceutical composition by mixing the HPD and the pharmaceutically acceptable carrier when a patient intends to use it, characterized in that the pH of the reconstituted solution of the pharmaceutical composition is maintained within the range of about 2 to about 6.

[0010] In the context of the present invention, HPD refers to a prodrug having at least one protonated amine group in its molecule and capable of rapidly passing through one or more biological barriers, for example, 10, 50, 100, 200, 300, 500, or even 1000 times faster than the permeation rate of the corresponding parent drug.

[0011] Preferably, HPD contains one or two protonated amine groups in its molecule when administered to a patient.

[0012] In a preferred embodiment, the pharmaceutically acceptable carrier is a water-soluble carrier. The pharmaceutically acceptable carrier may be water, alcohol, acetone, dimethyl sulfoxide (DMSO), or a mixture thereof. Preferably, the pharmaceutically acceptable carrier is an aqueous solution containing 0% to 70% by volume of ethanol. More preferably, the pharmaceutically acceptable carrier is an aqueous solution containing 10% to 35% by volume of ethanol.

[0013] Preferably, the pharmaceutical composition is applied transdermally as a spray solution. In a preferred embodiment, the method according to the present invention further includes the step of storing the reconstituted solution in a refrigerator at a temperature of 2°C to 8°C.

[0014] In the method according to the present invention, the pharmaceutical composition may also contain a pH adjuster / buffer. In one embodiment, HPD is a highly permeable peptide, and the pH adjuster / buffer is a sodium, potassium, calcium, lithium, or magnesium salt of an organic acid. Preferably, the pH adjuster / buffer is a sodium, potassium, or lithium salt of acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, lactic acid, salicylic acid, citric acid, ascorbic acid, succinic acid, or maleic acid.

[0015] Preferably, the pH of the reconstituted pharmaceutical composition solution is 3 to 6, more preferably 3 to 5, and more preferably 3.5 to 4.5. Preferably, the concentration of HPD in the reconstituted solution is 1% to 30% by weight, preferably 1% to 20% by weight, and more preferably 3% to 10% by weight.

[0016] In preferred embodiments, HPD is 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate·HCl, 2-(diethylamino)ethyl(R,S)-2-(2-fluoro-4-biphenyl)propionate·HCl, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propionate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl, 2-(diethylamino) Ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate·HCl, 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate·HCl, 2-(diethyl Amino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazole acetate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate·HCl, 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl, 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate·HCl, 2-(diethylamino)ethyl The HPD is selected from the group consisting of (n)ethyl 4,5-diphenyl-2-oxazolepropionate·HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethylacetylsalicylate·HCl, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl. Preferably, the HPD concentration in the reconstituted solution is 3% to 8% by weight, the pH of the reconstituted solution is 3 to 5, and the pharmaceutically acceptable carrier is an aqueous solution containing 15% to 35% by volume of ethanol.

[0017] In another preferred embodiment, HPD is selected from the group consisting of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl, H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2·HCl, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl. Preferably, the concentration of HPD in the reconstituted solution is 3% to 8% by weight, the pH of the reconstituted solution is 3 to 5, the pH adjuster / buffer is sodium acetate, and the pharmaceutically acceptable carrier is an aqueous solution containing 15% to 35% by volume of ethanol.

[0018] The HPD according to the present invention is stable at room temperature and can be stored for more than two years under dry conditions. According to the method of the present invention, a pharmaceutical composition comprising HPD and a pharmaceutically acceptable carrier when reconstituted as a solution can be stored for a reasonable period, for example, more than one month. It can be stored for more than two months, or even longer.

[0019] In another embodiment, the present invention provides pharmaceutical compositions obtained from any embodiment of the above method. In another embodiment, the present invention provides methods for using the disclosed pharmaceutical compositions to prevent, diagnose, and / or treat diseases or disorders in humans, animals, and plants.

[0020] In another embodiment, the present invention provides an improved method and a therapeutic kit based on an HPD composition that ensures convenience of administration and stability of the resulting pharmaceutical composition. Other aspects and advantages of the present invention will be better understood in light of the following detailed description, examples, and claims. [Modes for carrying out the invention]

[0021] When a drug is administered in solid, semi-solid, or suspension form, the rate of absorption is often controlled by how the drug granules dissolve in the liquid or moisture present at the administration site (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, p. 21). HPDs disclosed in previous patent applications have two common structural features: a lipophilic moiety and a hydrophilic moiety containing a protonated primary, secondary, or tertiary amine group. These have very high solubility in gastric juice, blood, or moisture on the skin, and high solubility in oil, allowing them to easily permeate biological membranes. These features make the formulation of HPDs much simpler.

[0022] Transdermal delivery systems help avoid direct damage to the gastrointestinal tract and drug inactivation caused by "first-pass metabolism" in the gastrointestinal tract and liver. This allows for local delivery of the appropriate concentration of drug to the intended site of action without systemic exposure. Further problems associated with oral drugs, as reported by Fishman et al. (U.S. Patent No. 7,052,715), are: It has been shown that to effectively treat distal areas of pain or inflammation, the concentration levels achieved in the bloodstream must be high. These levels are often much higher than those required to precisely target specific sites of pain or injury. By controlling the release rate, transdermal delivery systems allow drugs to consistently reach optimal therapeutic blood levels, enhancing drug efficacy and reducing side effects.

[0023] HPDs can also take the form of prodrugs. A good prodrug should be able to readily release the parent drug in plasma and / or other organs / tissues. A very good linker between the functional unit (parent drug) and the transport (or transport) unit (having at least one amino group) is an ester bond that can be cleaved quickly in most tissues. The drug should be dissolved in some solvent before it can penetrate the skin, digestive system, or other biological barriers, and this solvent should not harm the skin, digestive system, or other biological barriers.

[0024] For oral administration, solid dosage forms are suitable because the drug remains inside the digestive system and the abundant digestive fluids can dissolve it. However, oral administration has the drawback of "first-pass metabolism," where 100% of the drug / prodrug passes through the digestive system, potentially causing severe damage to it. For transdermal administration, the drug should be dissolved or suspended in some medium. Most organic solvents will damage the skin, and water is the best solvent for topical and transdermal administration. Hydrolysis of esters in water can be promoted by both acids and bases, but strongly acidic and basic conditions will damage the skin or other biological barriers. Since amino groups in transport units are bases and promote the hydrolysis of ester bonds, most amino groups should be retained in a protonated form.

[0025] In one embodiment, the present disclosure provides a method for improving the stability of a pharmaceutical composition comprising a highly permeable drug substance and a pharmaceutically acceptable carrier, The highly permeable drug substance and the pharmaceutically acceptable carrier are packaged in separate containers. This includes reconstituting a solution of a pharmaceutical composition by mixing a highly permeable drug substance with a pharmaceutically acceptable carrier before administering it to a patient requiring administration, The present invention provides a method characterized in that the pH of the reconstituted solution of a pharmaceutical composition is maintained within the range of 2 to 6.

[0026] In some embodiments, it may be preferable for the highly permeable drug substance to contain one or two protonated amine groups within its molecule when administered to a patient. In some embodiments, the pharmaceutically acceptable carrier may preferably be a water-soluble carrier. In some embodiments, the pharmaceutically acceptable carrier may preferably be water, alcohol, acetone, DMSO, or a mixture thereof.

[0027] In some embodiments, the pharmaceutically acceptable carrier may preferably be an aqueous solution containing 0% to 70% by volume of ethanol. In some embodiments, the pharmaceutically acceptable carrier may preferably be an aqueous solution containing 10% to 35% by volume of ethanol. In some embodiments, the reconstituted solution may be preferably applied transdermally as a spray solution.

[0028] In some embodiments, the method may preferably further include storing the reconstituted solution in a refrigerator at a temperature of 2°C to 8°C. In some embodiments, the pharmaceutical composition may preferably further contain a pH adjuster or buffer in a pharmaceutically acceptable carrier. In some embodiments, the highly permeable drug is preferably a highly permeable peptide, and the pH adjuster / buffer is preferably a sodium, potassium, calcium, lithium, or magnesium salt of an organic acid.

[0029] In some embodiments, the pH adjuster / buffer may preferably be a sodium salt, potassium salt, or lithium salt of an organic acid selected from the group consisting of acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, lactic acid, salicylic acid, citric acid, ascorbic acid, succinic acid, and maleic acid.

[0030] In some embodiments, the pH of the reconstituted pharmaceutical composition solution is in the range of 3 to 6. In some embodiments, the pH of the reconstituted pharmaceutical composition may preferably be in the range of 3 to 5. In some embodiments, the pH of the reconstituted pharmaceutical composition solution may be more preferably 3.5 to 4.5.

[0031] In some embodiments, the concentration of the highly permeable drug in the reconstituted solution is in the range of 1% to 30% by weight. In some embodiments, the concentration of the highly permeable drug in the reconstituted solution may preferably be in the range of 1% to 20% by weight. In some embodiments, it may be even more preferable that the concentration of the highly permeable drug in the reconstituted solution be in the range of 3% to 10% by weight.

[0032] In some embodiments, the highly permeable drug substance is 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate·HCl, 2-(diethylamino)ethyl R,S)-2-(2-fluoro-4-biphenyl)propionate·HCl, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propionate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl, 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate Tate·HCl, 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate·HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate Tate·HCl,2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate·HCl,2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl,2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate·HCl,2-(diethylamino)ethyl 4,5-diphenyl-2-o The following are selected from the group consisting of xazolepropionate·HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethylacetylsalicylate·HCl, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl.

[0033] In some embodiments, it is preferable that the concentration of the highly permeable drug in the reconstituted solution is 3% to 8% by weight, the pH of the reconstituted solution is 3 to 5, and the pharmaceutically acceptable carrier is a 15% to 35% by volume aqueous alcohol solution.

[0034] In some embodiments, the highly permeable drug is selected from the group consisting of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl, H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2·HCl, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl.

[0035] In some embodiments, the concentration of the highly permeable drug in the reconstituted solution is preferably 3% to 8% by weight, the pH of the reconstituted solution is preferably 3 to 5, the pH adjuster / buffer is preferably sodium acetate, and the pharmaceutically acceptable carrier may preferably be a 15% to 35% by volume aqueous solution of alcohol.

[0036] In another embodiment, the Disclosure provides pharmaceutical compositions obtained from any embodiment of the disclosed method. In another embodiment, the present disclosure is a method for treating a disorder in a subject requiring treatment, the treatment being prepared according to any embodiment of the disclosed method. The present invention provides a method comprising administering a therapeutically effective amount of a pharmaceutical composition to a subject.

[0037] In some embodiments, the pharmaceutical composition may preferably be a freshly reconstituted solution prepared by mixing a highly permeable drug substance from a separator container with a pharmaceutically acceptable carrier according to any embodiment of the disclosed method.

[0038] In another embodiment, the present disclosure relates to a highly permeable drug substance in a first container, a pharmaceutically acceptable carrier in a second container, and a pH adjuster in the first container, the second container, or another third container. The present invention provides a therapeutic kit comprising a buffer, wherein the highly permeable drug substance comprises one or two protonated amine groups, and the highly permeable drug substance, a pharmaceutically acceptable carrier, and a pH adjuster / buffer can be mixed to form a reconstituted solution that can be administered to a subject requiring administration.

[0039] In some embodiments, it may be preferable that the reconstituted solution has a pH in the range of 2 to 6 and is stable with respect to storage at a temperature in the range of 2°C to 20°C for a period prior to administration to a subject requiring administration.

[0040] In some embodiments, the highly permeable drug substance is 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate·HCl, 2-(diethylamino)ethyl(R,S)-2-(2-fluoro-4-biphenyl)propionate·HCl, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propionate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate· HCl, 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate·HCl, 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 3-(6-methoxy-2 -Naphthyl)propionate·HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazole acetate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate·HCl, 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl, 2-(diethylamino)ethyl 2-[(4-chlorophenyl )-5-benzoxazole]propionate·HCl, 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazolepropionate·HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethylacetylsalicylate·HCl, 2-(diethylamino)ethyl 5-(2,A pharmaceutically acceptable carrier selected from the group consisting of 4-difluorophenyl)-2-acetoxybenzoate·HCl, H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl, H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2·HCl, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl may preferably be a mixture of aliphatic C1-C6 alcohols and water.

[0041] In some embodiments, it is preferable that the concentration of the highly permeable drug in the reconstituted solution is 3% to 8%, the pH of the reconstituted solution is 3 to 5, the pH adjuster / buffer is sodium acetate, and the pharmaceutically acceptable carrier is a 15% to 35% by volume aqueous alcohol solution.

[0042] In another embodiment, the Disclosure provides treatment for a disease or condition in a subject using a therapeutic kit prepared according to any embodiment of the disclosed method. Such a therapeutic kit may, optionally, be used for administration of a pharmaceutical composition to a subject by a healthcare professional or for convenient self-administration by the subject.

[0043] The diseases or conditions that can be treated by the pharmaceutical compositions provided herein may be any disease or condition in which a highly permeable drug substance can produce a desired therapeutic effect with the advantage of a high penetration rate through certain biological barriers. Several non-limiting examples of diseases or conditions are given herein and are all encompassed by the present invention.

[0044] Another aspect of the present invention relates to a method of using the composition of the present invention or the pharmaceutical composition thereof in treating a disease in a living subject. This method includes administering the pharmaceutical composition to a living subject.

[0045] Some examples of diseases that can be treated by this method include those that can be treated with the parent drugs of HPD. These include, but are not limited to, stroke, arthritis, depression, Alzheimer's disease, Parkinson's disease, migraines, sexual dysfunction, sepsis, drug-resistant bacterial infections, epilepsy, diabetes, psoriasis, lupus erythematosus, ulcerative colitis, asthma, lower and upper respiratory tract infections, allergic rhinitis, allergic conjunctivitis, itching, and runny nose.

[0046] One or more HPDs or their pharmaceutical compositions may be administered to a living subject by any route of administration known in the art, including, but not limited to, oral, intestinal, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, cutaneous, ophthalmic, pulmonary, subcutaneous, and / or parenteral administration. The pharmaceutical compositions may be administered in various unit dosage forms depending on the method of administration.

[0047] Parenteral administration typically refers to routes of administration involving injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and / or intrasternal injections and / or infusions.

[0048] One or more HPDs or their pharmaceutical compositions may be administered to a subject in the form of formulations or preparations suitable for each route of administration. Formulations useful in the method of the present invention may comprise one or more HPDs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic components. Formulations may, for convenience, be provided in unit dosage forms and may be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be produced in combination with a carrier material to make a single dosage form will vary depending on the subject being treated and the specific mode of administration. The amount of HPD that can produce a pharmaceutically effective dose in combination with a carrier material is generally the amount of HPD that produces a therapeutic effect.

[0049] Methods for preparing these formulations or compositions may include mixing HPD with one or more pharmaceutically acceptable carriers and optionally one or more auxiliary components. Generally, formulations are prepared by homogeneously and tightly mixing HPD with a liquid carrier.

[0050] Liquid dosage forms for oral, transdermal, or topical administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to HPDs, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and colorants. It may also include preservatives, fragrances, and other additives.

[0051] In addition to HPD, the suspension may also include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0052] Formulations for topical, transdermal, epidermal, or cutaneous administration of the HPD composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants. Ointments, pastes, creams, and gels may contain, in addition to the HPD composition, additives such as animal fats and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to the HPD composition, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane. The best formulations for topical or transdermal administration are pure water, solutions, aqueous solutions, aqueous alcohol solutions, and solutions of isopropanol and water.

[0053] The HPD composition may be delivered to the target site using a transdermal patch. Such a formulation may be prepared by dissolving or dispersing the active ingredient in a suitable medium. An absorption enhancer may be used to increase the flow of the HPD composition through the skin. The rate of such flow may be controlled by providing a rate control membrane or by dispersing the HPD composition in a polymer matrix or gel.

[0054] Preparations suitable for parenteral administration include HPD in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted immediately before use into sterile injectable solutions or dispersions, the preparations may also include antioxidants, buffers, bacteriostatic agents, solutes to make the preparation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0055] Suitable aqueous and non-aqueous carriers that can be used in formulations suitable for parenteral administration include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0056] Formulations suitable for parenteral administration may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. The inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid, can ensure prevention of microbial action. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. Furthermore, the inclusion of absorption-delaying agents such as aluminum monostearate and gelatin can provide long-term absorption of the injectable pharmaceutical form.

[0057] Injectable depot formulations can be prepared by forming a microcapsule matrix of HPD or in biodegradable polymers such as polylactide-polyglycolide. Depending on the HPD-to-polymer ratio and the properties of the specific polymer used, the drug The release rate can be controlled. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot-injectable formulations can also be prepared by encapsulating HPD in liposomes or microemulsions compatible with body tissues.

[0058] In some embodiments, one or more HPDs or their pharmaceutical compositions are delivered to the site of action in a therapeutically effective dose. As is known in the field of pharmacology, the precise amount of a pharmaceutically effective dose of an HPD that yields the most effective results in terms of therapeutic efficacy in a given patient will depend, for example, on the activity, specific properties, pharmacokinetics, pharmacodynamics, and bioavailability of a particular HPD, the physiological conditions of the subject (including race, age, sex, weight, diet, type and stage of disease, general physical condition, responsiveness to a given dose and type of drug), the properties of the pharmaceutically acceptable carrier in the formulation, the route and frequency of administration used, and the severity or tendency of the disease being treated. However, the above guidelines can be used as a basis for fine-tuning the treatment, for example, to determine the optimal dose of administration, which only requires routine experimentation consisting of monitoring the subject and adjusting the dose (Remington: The Science and Practice of Pharmacy (Gennaro ed. 20)). Edition, Williams & Wilkins PA, USA) (2000)).

[0059] In some embodiments, one or more HPDs and / or combinations of other drugs are applied to a subject for a desired use (e.g., treatment, screening, etc.).

[0060] When applying a combination of multiple drugs (e.g., one or more HPDs and / or other drugs) to a subject, each drug may be applied separately, or one or more drugs may be applied simultaneously as separate drugs (e.g., two or more drugs may be sprayed substantially simultaneously without mixing the drugs before spraying), or one or more drugs may be mixed together before application to the subject, or any combination of the above application methods. The drugs may be applied in any possible order.

[0061] In some embodiments, the HPD of the present invention can cross one or more biological barriers, so that the HPD can be administered locally (e.g., topically or percutaneously) to reach the site where the disease occurs without requiring systemic administration (e.g., oral or parenteral administration). Through local administration and permeation of the HPD, the HPD can reach the same level of local concentration of the active substance or drug with a much smaller amount or dose compared to systemic administration of the parent active substance or drug, or it can reach a higher level of local concentration that cannot be achieved with systemic administration, or that would require a significantly higher dose of the active substance in systemic administration if possible.

[0062] High local concentrations of HPDs, or their parent active ingredients when cleaved, can treat diseases more effectively or much more rapidly than parent active ingredients delivered systemically, and can treat new diseases that were previously impossible or unobservable. Local administration of HPDs allows the living subject to mitigate the potential discomfort associated with systemic administration, such as systemic exposure to the active ingredient and adverse reactions related to gastrointestinal / renal effects. Furthermore, local administration can avoid the need for systemic administration (e.g., injection) and eliminate the pain associated with parenteral injections, as HPDs can cross multiple biological barriers and reach the entire body, for example, through systemic circulation.

[0063] In some embodiments, the HPD or pharmaceutical composition according to the present invention may be administered systemically (e.g., orally, transdermally, or parenterally). The HPD or the active agent of the HPD (e.g., a drug or metabolite) can enter the systemic circulation at a faster rate than the parent agent and reach the site of action of the disease more rapidly. Furthermore, the HPD is effective when the parent agent is administered alone. Because it can cross biological barriers that were previously impedable (e.g., the blood-brain barrier and the blood-milk barrier), it provides novel treatments for diseases that were previously impossible or unobservable.

[0064] In another embodiment of this pattern, the resulting liquid formulation is a formulation according to any one of the embodiments described herein, or any combination thereof.

[0065] The term "approximately" when applied to parameters such as pH and concentration indicates that the parameter may vary by ±10%, preferably within ±5%, and more preferably within ±2%. As will be understood by those skilled in the art, when the parameter is not critical, the numerical value is often given only for illustrative purposes and not limiting purposes.

[0066] As used herein, the terms “a,” “an,” or “the” refer to both singular and plural forms of a noun. Generally, when either the singular or plural form of a noun is used, it refers to both the singular and plural forms of the noun.

[0067] As used herein, the term “treating” means to cure, alleviate, suppress, or prevent. Taste. As used herein, the term “treatment” means healing, relief. It means deterrence or prevention.

[0068] As used herein, the terms “living subject” or “subject” mean an organ, a group of organs working together to perform a particular task, a living organism, or a group of living organisms. As used herein, the term “living organism” means a collection of molecules that function more or less as a stable whole and possess the characteristics of life, such as animals, plants, fungi, or microorganisms.

[0069] As used herein, the term “animal” means a eukaryote characterized by voluntary movement. Examples of animals include, but are not limited to, vertebrates (e.g., humans, mammals, birds, reptiles, amphibians, fish, cystobranches, and lancelets), tunicates (e.g., Thalia, Ascidians, Solverae, and Ascidians), articulated groups (e.g., insects, myriapods, mollusks, spiders, sea spiders, femoropods, crustaceans, and annelids), and geckos (gehyrea). Examples include aarthropoda and helminths (e.g., rotifera). Preferably, the subject is a human or mammal, such as a cat, dog, horse, or monkey.

[0070] As used herein, the term "plant" refers to organisms belonging to the plant kingdom. Examples of plants include, but are not limited to, seed plants, bryophytes, ferns, and ferns other than those in the class Pteridium. Examples of seed plants include, but are not limited to, cycads, ginkgo, conifers, gnetophytes, and angiosperms. Examples of bryophytes include, but are not limited to While not definitive, examples include liverworts, hornworts, and mosses. Examples of ferns, though not limited to them, include plants of the Ophioliales order (e.g., Ophiolia, Dwarf Fern, and Vitis coignetiae), the family Triadaceae, and sacral ferns. Examples of ferns outside the class Pteridaceae, though not limited to them, include the class Hypogynostigma (e.g., Hypogynostigma, Selaginella, and Isoetes), the family Psidaceae (e.g., Hypogynostigma and Psidium), and the family Equisetaceae (e.g., Equisetum).

[0071] As used herein, the term "fungus" refers to eukaryotes that belong to the Kingdom Fungi. Examples of fungi include, but are not limited to, chytrids, phyla of cyanes, phyla of neocallimatology, phyla of zygomycetes, phyla of glomum, phyla of ascomycetes, and phyla of basidiomycetes.

[0072] As used herein, the term “microorganism” means a tiny organism (e.g., having a length on the scale of micrometers). Examples of microorganisms include, but are not limited to, bacteria, fungi, archaea, protists, and microplants (e.g., green algae) and microanimals (e.g., plankton, planarians, and amoebas).

[0073] I. Example of HPD The following are some structural examples of drugs that have high permeability to biological barriers (skin, blood-brain barrier, blood-milk barrier, and other biological barriers): [ka]

[0074] [ka]

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[0251] [ka]

[0252] During the ceremony, X is selected from the group consisting of none, O, C=O, OC(=O), C(=O)O, OC(=O)OCHR1O, OC(=O)OCHR1S, S, SC(=O), C(=O)S, OC(=O)SCHR1O, SC(=O)OCHR1O, NH, NR6, and NR6-C(=O)O.

[0253] X1, X2, X3, X4, X5, X 6、 X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 These are independently, none, O, C=O, OC(=O), C(=O)O, OC(=O)OCHR1O, OC(=O)OCHR1S, S, SC(=O), C(=O)S, OC(=O)SCHR1O, SC(=O)OCHR1O, NH, NR6, NR6-C(=O)O, H, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, CH3CH2CH2CH 2、 Selected from the group consisting of CH3CH2CH(CH3), CH3CO, R5CO, CH3CS, R5CS, CH3OCO, R5OCO, CH3OCS, CH3O, CH3S, CH3NH, R5OCS, substituted and unsubstituted alkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkenyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkynyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkyloxyl residues having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyloxyl residues having 1 to 12 carbon atoms, substituted and unsubstituted aryl residues having 1 to 12 carbon atoms, and substituted and unsubstituted heteroaryl residues having 1 to 12 carbon atoms.

[0254] Y1 is selected from the group consisting of H, F, Br, Cl, I, CH3, CH3O, CF3, OR7, CF3O, and R5O. Y2 is selected from the group consisting of H, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, and 4-iodophenyl. Y3 is selected from the group consisting of H, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, and 4-iodophenyl.

[0255] Y4 is selected from the group consisting of H, F, Br, Cl, I, CH3, CF3, OR7, and CH3O. Y5 is selected from the group consisting of H, CH3CO, C2H5CO, and C3H7CO, and Y6 is selected from the group consisting of H, F, Br, Cl, I, CH3, CF3, OR7, and CH3O. Y7 is selected from the group consisting of H, F, Br, Cl, I, CH3, CF3, OR7, and CH3O.

[0256] HA is a pharmaceutically acceptable acid, including hydrofluoric acid, hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfuric acid, bisulfite, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, dodecanoic acid, palmitic acid, stearic acid, lactic acid, salicylic acid, citric acid, ascorbic acid, tartaric acid, uric acid, pantothenic acid, tartaric acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, and formic acid. , may be selected from the group consisting of benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid.

[0257] R is absent, or selected from the group consisting of substituted and unsubstituted alkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkenyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkynyl residues having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl residues having 1 to 12 carbon atoms, cycloalkenyl residues, or cycloalkynyl residues, substituted and unsubstituted heterocycloalkyl residues or heterocycloalkenyl residues having 1 to 1 2 carbon atoms, substituted and unsubstituted alkoxyl residues or alkenyloxyl residues having 1 to 12 carbon atoms, substituted and unsubstituted perfluoroalkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted haloalkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted aryl residues having 1 to 12 carbon atoms, and substituted and unsubstituted heteroaryl residues having 1 to 12 carbon atoms; wherein any CH2 in R may be further replaced with O, S, P, NR6, or any other pharmaceutically acceptable group, and any combination thereof; examples of R include CH2, CHR5, CHR5CH2, CH2CH2CH2, CH2CH2CH2CH2, and CH2CH2CH2CH2CH2,

[0258] R1, R2, R3, R4, R 6、 R 6’ , R7, R 7’ , R8, R 8’ , R 9、 R 9’ , R 10 , R 10’ , R 11 , R 12 , R 13 , R 14 , and R 15These are independently selected from the group consisting of H, CH3CO, R5CO, CH3CS, R5CS, CH3OCO, R5OCO, CH3OCS, CH3O, CH3S, CH3NH, R5OCS, substituted and unsubstituted alkyls having 1 to 12 carbon atoms, substituted and unsubstituted alkenyls having 1 to 12 carbon atoms, substituted and unsubstituted alkynyls having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyls, cycloalkenyls, or cycloalkynyls having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyls or heterocycloalkenyls having 1 to 12 carbon atoms, substituted and unsubstituted alkoxyls or alkeneoxyls having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyloxyls or cycloalkenyloxyls having 1 to 12 carbon atoms, substituted and unsubstituted aryls having 1 to 12 carbon atoms, substituted and unsubstituted heteroaryls having 1 to 12 carbon atoms, and any combination thereof.

[0259] R5 is selected from the group consisting of substituted and unsubstituted alkyls having 1 to 12 carbon atoms, substituted and unsubstituted alkenyls having 1 to 12 carbon atoms, substituted and unsubstituted alkynyls having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyls having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyls having 1 to 12 carbon atoms, substituted and unsubstituted alkoxyls having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyloxyls having 1 to 12 carbon atoms, substituted and unsubstituted aryls having 1 to 12 carbon atoms, substituted and unsubstituted heteroaryls having 1 to 12 carbon atoms, and residues thereof.

[0260] Z represents CH2=C, CH=CH, C≡C, CONH, CSNH, COO, OCO, COS, COCH2, or CH2CO. All hydrogen in the parent drug or transport unit can be replaced with deuterium without significantly altering its pharmaceutical, chemical, and physical properties. T is a transport unit selected from the group consisting of, for example, protonated amine groups, particularly pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amine groups in protonated form. Examples of T are structures T-1, T-2, T-3, T-4, T-5, T-6, T-7, T-8, T-9, T-10, T-11, and T-12:

[0261] [ka]

[0262] [ka]

[0263] In the formula, R1 and R2 are as defined above, and R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 This is selected from the group consisting of none, substituted and unsubstituted alkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkenyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkynyl residues having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl residues, cycloalkenyl residues, or cycloalkynyl residues having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyl residues or heterocycloalkenyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkoxyl residues or alkeneoxyl residues having 1 to 12 carbon atoms, substituted and unsubstituted perfluoroalkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted haloalkyl residues having 1 to 12 carbon atoms, substituted and unsubstituted aryl residues having 1 to 12 carbon atoms, and substituted and unsubstituted heteroaryl residues having 1 to 12 carbon atoms. Here, any CH2 in R can be further replaced with O, S, P, NR6, or any other pharmaceutically acceptable group, and any combination thereof, and all hydrogen in the parent drug or transport unit can be replaced with deuterium without significantly altering its pharmaceutically, chemical, and physical properties.

[0264] As used herein, the term “pharmaceutically acceptable salt” means a salt of the compound of the present invention that is safe for application to a subject. Examples of pharmaceutically acceptable salts include salts of acidic or basic groups present in the compound of the present invention. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, and benzoate. Examples include salts, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,11-methylene-bis-(2-hydroxy-3-naphthoates)). Certain compounds of the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, and diethanolamine salts. For an overview of pharmaceutically acceptable salts, see BERGE ET AL., 66 J. PHARM. SCI. 1 - 19. See (1977) (which, by reference, constitutes part of this specification).

[0265] As will be understood by those skilled in the art, the structures defined above include only stable compounds that do not violate the principles of covalent bond formation.

[0266] II. Method for improving the stability of reconstituted solutions of pharmaceutical compositions Unexpectedly, unlike typical ester or ammonium compounds, the stability of HPD in solution varied significantly with the pH, concentration, and temperature of the solution, while the acid forming the salt with the amine group, and the substituents on the amine group, had only a slight effect on stability. The results are shown below.

[0267] 1. Effect of concentration on stability Table 1: Effect of the concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl salt containing 1 equivalent of sodium acetate on stability in 50% ethanol at 25°C. [Table 1] The concentration of the H-Val-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl salt affected its stability, and it was unstable at concentrations of 0.1% or less.

[0268] Table 2: Effect of the concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt containing 1 equivalent of sodium acetate on stability in 50% ethanol at 25°C. [Table 2] The concentration of the H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt affected its stability, and it was unstable when the concentration was 0.1% or less.

[0269] Table 3: Effect of the concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HBr salt containing 1 equivalent of sodium acetate on stability in 50% ethanol at 25°C. [Table 3] The concentration of the H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HBr salt affected its stability, and it was unstable at concentrations of 0.1% or less.

[0270] Table 4: Effect of the concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·citrate containing 1 equivalent of sodium acetate on stability in 50% ethanol at 25°C. [Table 4] The concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·citrate affected stability, and it was unstable at concentrations of 0.1% or less.

[0271] Table 5: Stability of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl salt containing 1 equivalent of sodium acetate in 50% ethanol at 25°C. The impact on [Table 5] The concentration of the H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl salt affected its stability; it was unstable at concentrations below 0.1%.

[0272] Table 6: Effect of the concentration of 2-(diethylamino)ethyl(R,S)-2-(6-methoxy-2-naphthyl)propionate·HCl on stability in water at 25°C. [Table 6] Note: In many cases, (R,S)- is omitted before the chemical name of a racemic mixture; 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate is the same as 2-(diethylamino)ethyl(R,S)-2-(6-methoxy-2-naphthyl)propionate. The concentration of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0273] Table 7: Effect of the concentration of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl on stability in water at 25°C. [Table 7] The concentration of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0274] Table 8: Effect of the concentration of 2-(diethylamino)ethylacetylsalicylate·HCl on the stability of the salt in 15% ethanol at 5°C. [Table 8] The concentration of 2-(diethylamino)ethylacetylsalicylate·HCl salt affected stability, and the solution was unstable at concentrations of 0.1% or less.

[0275] Table 9: Effect of concentration of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl on its stability in 15% acetone at 5°C. [Table 9] The concentration of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0276] Table 10: Effect of the concentration of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl on stability in water at 25°C. [Table 10] The concentration of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0277] Table 11: Effect of the concentration of 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate·HCl on stability in water at 25°C. [Table 11]

[0278] The concentration of 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0279] Table 12: Effect of the concentration of 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl on stability in water at 25°C. [Table 12] The concentration of 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0280] Table 13: Effect of the concentration of 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate·HCl on stability in water at 25°C. [Table 13] The concentration of 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0281] Table 14: Effect of the concentration of 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate HCl on stability in water at 25°C. [Table 14] The concentration of 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0282] Table 15: Effect of the concentration of 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazole acetate HCl on stability in water at 25°C. [Table 15] The concentration of 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazole acetate·HCl salt affects stability, and when the concentration is 0.1% or less... It was unstable.

[0283] Table 16: Effect of the concentration of 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl on stability in water at 25°C. [Table 16] The concentration of 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0284] Table 17: Effect of the concentration of 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate HCl on stability in water at 25°C. [Table 17] The concentration of 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0285] Table 18: Effect of the concentration of 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazolepropionate·HCl on stability in water at 25°C. [Table 18] The concentration of 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazole propionate·HCl salt affected stability, and the solution was unstable at concentrations of 0.1% or less.

[0286] Table 19: Effect of 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate·HCl concentration on stability in water at 25°C. [Table 19] The concentration of 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate·HCl salt affected stability, and it was unstable at concentrations of 0.1% or less.

[0287] Table 20: Effect of the concentration of 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate·HCl salt on stability in water at 25°C. [Table 20] The concentration of 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate·HCl salt affects stability, and when the concentration is 0.1% or less... It was unstable.

[0288] It was found that the HPD concentration significantly affects the stability of the pharmaceutical composition. HPD concentrations of less than 1% by weight in aqueous solution were unstable, but concentrations of 1% by weight or more are desirable. Advantageously, the HPD concentration in the composition may be 1% to 30% by weight, preferably 1% to 20% by weight, more preferably 3% to 15% by weight, and more preferably 5% to 10% by weight. The type of substituent and salt had little effect on stability.

[0289] In contrast, the concentration of common esters does not significantly affect stability.

[0290] Table 21: Effect of ethyl benzoate concentration on stability in 50% ethanol at 25°C. [Table 21] Ethyl benzoate was very stable at concentrations of 0.01% to 10% or higher. Concentration had only a slight effect on stability.

[0291] Table 22: Effect of isopropyl benzoate concentration on stability in 50% ethanol at 25°C. [Table 22] Isopropyl benzoate was very stable at concentrations of 0.01% to 10% or higher, and was more stable than ethyl benzoate. Concentration did not affect stability.

[0292] Table 23: Effect of t-butyl benzoate (common ester) concentration on stability in 50% ethanol at 25°C. [Table 23] t-butyl benzoate is very unstable at all concentrations, and ethyl benzoate and benzoate are also unstable. It was far less stable than isopropyl fragrans.

[0293] Table 24: Effect of isopropyl 2-amino-3-phenylpropanoate concentration on stability in 50% ethanol at 25°C. [Table 24] Isopropyl 2-amino-3-phenylpropanoate was very stable at concentrations of 0.01% to 10%, and far more stable than ethyl 2-amino-3-phenylpropanoate. This is likely because the isopropyl group is more sterically hindered than the ethyl group.

[0294] Table 25: Effect of t-butyl 2-amino-3-phenylpropanoate concentration on stability in 50% ethanol at 25°C. [Table 25] t-butyl 2-amino-3-phenylpropanoate was unstable at concentrations of 0.01% to 10%.

[0295] 2. Effect of pH value on stability

[0296] Table 26: Stability of a 5% solution of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt in 25% ethanol at various pH levels over 30 days at 25°C. [Table 26] The solution of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt was stable only at pH 3-6 and could be stored at room temperature for about one year.

[0297] Table 27: Stability of a 5% solution of H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl salt in 25% ethanol at various pH levels over 30 days at 25°C. [Table 27] The solution of H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl salt was stable at pH 3-6 and could be stored at room temperature for approximately one year.

[0298] Table 28: Stability of a 5% solution of H-Tyr-Gly-Gly-Phe-Leu-OCH2CH3·HCl salt in 25% ethanol at various pH levels over 30 days at 25°C. [Table 28] The solution of H-Tyr-Gly-Gly-Phe-Leu-OCH2CH3·HCl salt was stable only at pH 3-6 and could only be stored at room temperature for about 3 months.

[0299] Table 29: Stability of a 5% solution of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl salt in 25% ethanol at various pH levels over 30 days at 25°C. [Table 29] The solution of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl salt was stable only at pH 3-6 and could only be stored at room temperature for about 3 months.

[0300] Table 30: Stability of a 5% solution of H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl salt in 25% ethanol at various pH levels over 30 days at 25°C. [Table 30] The solution of H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl salt was stable only at pH 3-6 and could be stored at room temperature for about one year.

[0301] These results indicate that the reconstituted solution is stable only at pH 3 to 6, preferably pH 3 to 5, and more preferably pH 3.5 to 4.5. The pH of the solution can be adjusted with any acid or base, preferably a weak base, such as HCl or NaOH. The pH adjuster / buffer may be a sodium, potassium, calcium, lithium, or magnesium salt of an organic acid, such as a sodium, potassium, or lithium salt of acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, lactic acid, salicylic acid, citric acid, ascorbic acid, succinic acid, or maleic acid.

[0302] Table 31: Stability of 7% solutions of 2-(diethylamino)ethyl(R,S)-2-(6-methoxy-2-naphthyl)propionate·HCl (C-1), 2-(diethylamino)ethyl(R,S)-2-(6-methoxy-2-naphthyl)propionate·HBr (C-2), and 2-(diethylamino)ethyl(R,S)-2-(6-methoxy-2-naphthyl)propionate·citrate (C-3) in water at various pH values ​​(pH adjusted with 3N HCl or 3N NaOH) for 28 days at 25°C. [Table 31]

[0303] These results indicate that only the pH value, and not the HCl, HBr, or citric acid or other acids that formed a salt with 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate, significantly influenced the stability of the 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate salt.

[0304] Table 32: Stability of 7% 2-(diethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl (C-4), 2-(dimethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl (C-5), and 2-(dibutylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl (C-6) in 25% ethanol at various pH values ​​(pH adjusted with 3N HCl or 3N NaOH) for 28 days at 25°C. [Table 32]

[0305] These results indicate that the sizes of R1, R2, and R on the amino group are aminoalkyl (R,S This indicates that it did not significantly affect the stability of )-2-(p-isobutylphenyl)propionate.

[0306] Table 33: Stability of 7% 2-pyrrolidinemethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl (C-7), 4-piperidineethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl (C-8), 1-pyrrolidineethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl (C-9), and 1-piperidineethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl (C-10) in 25% ethanol at various pH values ​​and temperatures (pH adjusted with 3N HCl or 3N NaOH) for 28 days at 25°C. [Table 33]

[0307] These results indicate that the sizes of R1, R2, and R on the amino group did not significantly affect the stability of aminoalkyl(R,S)-2-(p-isobutylphenyl)propionate.

[0308] Table 34: Stability of 7% 2-(diethylamino)ethylacetylsalicylate maleate (A-1), 2-(diethylamino)ethylacetylsalicylate benzoate (A-2), 2-(diethylamino)ethylacetylsalicylate lactate (A-3), and 2-(diethylamino)ethylacetylsalicylate valerate (A-4) in water at various pH values ​​(pH adjusted with 3N HCl or 3N NaOH) for 14 days at 25°C. [Table 34]

[0309] These results indicate that only the pH value, and not the acids such as maleic acid, benzoic acid, lactic acid, or valeric acid that formed salts with 2-(diethylamino)ethylacetylsalicylate, significantly influenced the stability of the 2-(diethylamino)ethylacetylsalicylate salt.

[0310] These results further indicate that only the pH value, and not the acids such as HCl, HBr, citric acid, maleic acid, benzoic acid, or lactic acid that form the protonated amine group, significantly affected the stability of the solution. Furthermore, the size of the groups on the amino group, such as R1, R2, and R, did not significantly affect stability.

[0311] 3. Temperature effect on stability

[0312] Table 35: Stability of 5% solutions of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-1) containing 1 equivalent of sodium acetate, H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-2) containing 1 equivalent of sodium acetate, and H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-3) containing 1 equivalent of sodium acetate at various temperatures in 25% ethanol. [Table 35]

[0313] Solutions of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-1), H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-2), and H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-3) were more stable at lower temperatures and could be stored for more than one year at 25°C and 5°C.

[0314] Table 36: Stability of a 7% solution of (R,S)-2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 36]

[0315] These results indicate that solutions of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate·HCl salt in water were unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0316] Table 37: Stability of a 7% solution of 2-(diethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 37]

[0317] These results indicate that solutions of 2-(diethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt in water were unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0318] Table 38: Stability of a 7% solution of 2-(diethylamino)ethyl(R)-2-(p-isobutylphenyl)propionate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 38]

[0319] These results show that 2-(diethylamino)ethyl(R)-2-(p-isobutyl in water This indicates that solutions of phenyl)propionate·HCl salt are unstable at temperatures above 40°C and at pH levels below 3 or above 6, and that there was no significant difference between the (R,S) isomer and the (R) isomer.

[0320] Table 39: Stability of a 7% solution of 2-(diethylamino)ethyl 2-(2,4-dichlorophenoxy)benzeneacetate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 39]

[0321] These results indicate that 2-(diethylamino)ethyl 2-(2,4-dichlorophenoxy)benzene acetate HCl salt was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0322] Table 40: Stability of a 7% solution of 2-(diethylamino)ethyl(R,S)-2-(2-fluoro-4-biphenyl)propionate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 40]

[0323] These results indicate that a solution of 2-(diethylamino)ethyl(R,S)-2-(2-fluoro-4-biphenyl)propionate·HCl in water is conditioned at temperatures above 40°C and 3°C. This indicates that the substance was unstable at very low pH levels or above pH 6.

[0324] Table 41: Stability of a 7% solution of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 41]

[0325] These results indicate that a solution of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0326] Table 42: Stability of a 7% solution of 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 42]

[0327] These results indicate that 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate in water This indicates that the solution of the HCl salt was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0328] Table 43: Stability of a 7% solution of 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 43]

[0329] These results indicate that a solution of 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0330] Table 44: Stability of a 7% solution of 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 44]

[0331] These results indicate that a solution of 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0332] Table 45: Stability of a 7% solution of 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-triazole acetate HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 45]

[0333] These results indicate that a solution of 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-triazole acetate·HCl in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0334] Table 46: Stability of a 7% solution of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 46]

[0335] These results indicate that a solution of 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0336] Table 47: Stability of a 7% solution of 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 47]

[0337] These results indicate that a solution of 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0338] Table 48: Stability of a 7% solution of 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 48]

[0339] These results indicate that a solution of 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0340] Table 49: Various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH) Stability of a 7% solution of 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazole propionate HCl salt in (the above) [Table 49]

[0341] These results indicate that a solution of 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazole propionate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0342] Table 50: Stability of a 7% solution of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH). [Table 50]

[0343] These results indicate that a solution of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl salt in water was unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0344] These results indicate that the solution is more stable at lower temperatures and should be stored at temperatures below 25°C, preferably between 2°C and 8°C.

[0345] 4. Effect of solvent on stability

[0346] Table 51: 7% of 2-(diethylamino)ethylacetylsalicylate·HCl salt at various pH values ​​and temperatures in water (pH adjusted with 3N HCl or 3N NaOH) Solution stability [Table 51]

[0347] These results indicate that solutions of 2-(diethylamino)ethylacetylsalicylate·HCl salt in water were unstable at temperatures above 40°C and at pH levels below 3 or above 6.

[0348] Table 52: Stability of a 7% solution of 2-(diethylamino)ethylacetylsalicylate·HCl salt at various pH values ​​and temperatures in 15% ethanol (pH adjusted with 3N HCl or 3N NaOH). [Table 52]

[0349] These results indicate that the solvent (15% ethanol) did not significantly affect the stability of the 2-(diethylamino)ethylacetylsalicylate·HCl solution, but did improve its stability somewhat. Since 15% ethanol can inhibit bacterial growth, it is a good choice for the medical applications of 2-(diethylamino)ethylacetylsalicylate·HCl.

[0350] Table 53: Various pH values ​​and temperatures in 25% ethanol (pH set to 3N HCl or 3N Stability of a 7% solution of 2-(diethylamino)ethylacetylsalicylate·HCl salt in (prepared with NaOH) [Table 53]

[0351] These results indicate that the solvent (25% ethanol) did not significantly affect the stability of the 2-(diethylamino)ethylacetylsalicylate·HCl salt solution.

[0352] Table 54: Stability of a 7% solution of 2-(diethylamino)ethylacetylsalicylate·HCl salt at various pH values ​​and temperatures in 50% ethanol (pH adjusted with 3N HCl or 3N NaOH). [Table 54]

[0353] These results indicate that the solvent (50% ethanol) did not significantly affect the stability of 2-(diethylamino)ethylacetylsalicylate·HCl salt.

[0354] Tables 51 to 54 show that the amount of ethanol did not significantly affect the stability of the 7% solution of 2-(diethylamino)ethylacetylsalicylate·HCl salt. Compared to pure water as a solvent, solvents containing ethanol of various concentrations make the solution somewhat more stable. The concentration of ethanol may be 0% (volt / volt) to 70% (volt / volt), preferably 10% (volt / volt) to 35% (volt / volt), and more preferably 15% (volt / volt) to 25% (volt / volt). For example, an aqueous solution containing 15% ethanol, which can inhibit bacterial growth, is a good choice for medical applications.

[0355] Similar results were obtained in experiments using other solvents, such as aqueous solutions containing acetone or DMSO at various concentrations. In other words, the solvent did not significantly affect the stability of the solution.

[0356] Other HPDs exhibit very similar behavior. Other HPDs include, for example, HPD of peptides, e.g. H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3·HCl, H-Val-Pro-Asp[OC H(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl, H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2·HCl, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl,

[0357] As well as other HPDs, for example, 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate·HCl, 2-(diethylamino)ethyl(R,S)-2-(2-fluoro-4-biphenyl)propionate·HCl, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propionate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl, 2-(diethylamino)ethyl (Diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate·HCl, 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl) Ropionate·HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazole acetate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate·HCl, 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl, 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5- [Diethylamino]oxazole propionate·HCl, 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazole propionate·HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate·HCl, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl, That is the case.

[0358] It should be understood that the above-mentioned general, preferred, or more preferred features (which may be more) in one aspect of the present invention can be combined with other general, preferred, or more preferred features (which may be more) in another aspect of the present invention. For example, the HPD concentration in the reconstituted solution is 3% to 10%, the pH is 3 to 5, and the pharmaceutically acceptable carrier is 15% to 35% ethanol in pure water.

[0359] 5. Stability of pure HPD

[0360] Table 55: Stability of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-1), H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-2), and H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-3) at 25℃ / RH60% [Table 55]

[0361] These results indicate that the pure powders of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-1), H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-2), and H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2·HCl salt (T-3) are very stable and can be stored at room temperature for several years.

[0362] Table 56: Stability of H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2·HCl(U-1) and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl salt (U-2) at 25℃ / RH60% [Table 56]

[0363] These results indicate that the pure powders of H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2·HCl(U-1) and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2·HCl salts (U-2) are very stable and can be stored at room temperature for several years.

[0364] Table 57: 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl salt (A-1-1), 2-(diethylamino)ethyl(S)-2-(6-methoxy-2-naphthyl)propionate HCl salt (A-1-2), 2-(diethylamino)ethyl(R)-2-(6-methoxy-2-naphthyl)propionate HCl salt (A-1-3), 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HBr salt (A-1-4), 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate citrate (A-1-5), 2-(dimethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate citrate (A-1-5), at 25℃ / RH60% Stability of 2-2-naphthyl)propionate HCl salt (A-2), 2-(dibutylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl salt (A-3), 2-(dihexylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl salt (A-4), 2-(di-3-hexenylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl salt (A-5), 2-(di-3-hexynylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl salt (A-6), and 2-(di-2-(2-methoxyethoxy)ethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl salt (A-7).

[0365] [Table 57]

[0366] The solid form of 2-(6-methoxy-2-naphthyl)propionate·HA salt is very stable and could be stored at room temperature for more than two years. The size and shape of the alkyl group on the amino group and A - This did not significantly affect stability. The dried drug substance could be stored at 25°C for more than two years without significant changes.

[0367] Table 58: 2-(diethylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate·HCl salt (B-1-1), 2-(diethylamino)ethyl(S)-2-(2-fluoro-4-biphenyl)propionate·HCl salt (B-1-2), 2-(diethylamino)ethyl(R)-2-(2-fluoro-4-biphenyl)propionate·HCl salt (B-1-3), 2-(diethylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate·HBr salt (B-1-4), 2-(diethylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate·citrate (B-1-5), 2-(dimethylamino)ethyl 2-(2-fluoro Stability of 2-(2-fluoro-4-biphenyl)propionate HCl salt (B-2), 2-(dibutylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate HCl salt (B-3), 2-(dihexylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate HCl salt (B-4), 2-(di-3-hexenylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate HCl salt (B-5), 2-(di-3-hexynylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate HCl salt (B-6), and 2-(di-2-(2-methoxyethoxy)ethylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate HCl salt (B-7).

[0368] [Table 58]

[0369] The solid form of 2-(2-fluoro-4-biphenyl)propionate·HCl salt is very stable and could be stored at room temperature for more than two years. The size of the alkyl group on the amino group and A - This did not significantly affect stability. The dried drug substance could be stored at 25°C for more than two years without significant changes.

[0370] Table 59: 2-(diethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt (C-1-1), 2-(diethylamino)ethyl(S)-2-(p-isobutylphenyl)propionate·HCl salt (C-1-2), 2-(diethylamino)ethyl(R)-2-(p-isobutylphenyl)propionate·HCl salt (C-1-3), 2-(diethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HBr salt (C-1-4), 2-(diethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·citrate (C-1-5), 2-(dimethylamino)ethyl(R,S)-2-(p-isobutylphenyl) 2-(dibutylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt (C-2), 2-(dihexylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt (C-3), 2-(dihexylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt (C-4), 2-(di-3-hexenylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt (C-5), 2-(di-3-hexynylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt (C-6), and 2-(di-2-(2-methoxyethoxy)ethylamino)ethyl(R,S)-2-(p-isobutylphenyl)propionate·HCl salt (C-7)

[0371] [Table 59]

[0372] The solid form of 2-(p-isobutylphenyl)propionate·HA salt is very stable and could be stored at room temperature for more than two years. The size and shape of the alkyl group on the amino group and A - This did not significantly affect stability.

[0373] Other HPDs exhibit very similar behavior. Other HPDs include, for example, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate·HCl, 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate·HCl, 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate·HCl, 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate·HCl, and 2-(diethylamino)ethyl (Diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazole acetate·HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate·HCl, 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate·HCl, 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate·HCl, 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazolepropionate·HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate·HCl These are 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate·HCl, 2-(diethylamino)ethylacetylsalicylate·HCl, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate·HCl.

[0374] III. Administration of HPD via the permeation of biological barriers Another aspect of the present invention relates to a method for using a pharmaceutical composition to penetrate one or more biological barriers in a living subject. This method includes the step of administering the pharmaceutical composition to a living subject.

[0375] As used herein, the term “biological barrier” refers to a biological layer that divides the environment into various spatial regions or compartments, the division of which can regulate (e.g., restrict, limit, enhance, or do nothing) the passage, permeation, or movement of matter or objects from one compartment / region to the other. The various spatial regions or compartments referred to herein may have the same or different chemical or biological environments. Biological layers referred to herein include, but are not limited to, biological membranes, cell layers, biological structures, the inner surface of a subject, the inner surface of an organism, the inner surface of an organ, or the inner surface of a body cavity, the outer surface of a subject, the outer surface of an organism, the outer surface of an organ, or the outer surface of a body cavity, or any combination or combination thereof.

[0376] Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (e.g., nuclear membranes or organelle membranes, such as the Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosomes, cell nuclei, chloroplasts, plastids, peroxisomes, or the membranes or outer layers of microstructures).

[0377] The lipid bilayers referred to herein are, but are not limited to, bilayers of lipid class molecules including phospholipids and cholesterol. In specific embodiments, the lipids for the bilayer are amphiphilic molecules consisting of polar head groups and nonpolar fatty acid tails. The bilayer consists of two layers of lipids, one in which the hydrocarbon tails face each other and are linked by a hydrophobic effect to form an oily core, and the other in which the charged heads are arranged to face aqueous solutions on both sides of the membrane. In another specific embodiment, the lipid bilayer may also contain one or more embedded protein and / or sugar molecules.

[0378] Examples of cell layers include the inner layers of eukaryotic cells (e.g., epithelium, lamina propria, and smooth muscle or muscularis mucosa (in the digestive tract)), the inner layers of prokaryotic cells (e.g., the surface layer, i.e., the S layer, which refers to a monolayer of a two-dimensional structure composed of identical proteins or glycoproteins; specifically, the S layer refers to a part of the extracellular covering commonly found in bacteria and archaea), biofilms (structured communities of microorganisms surrounded by a self-developing macromolecular matrix and attached to living or inactive surfaces), and plant cell layers (e.g., the epidermis). The cells may be normal cells or pathological cells (e.g., disease cells, cancer cells).

[0379] Examples of biological structures include structures sealed by tight or closed junctions that provide barriers against the invasion of toxins, bacteria, and viruses, such as the blood-milk barrier, the blood-cerebrospinal fluid (CSF) barrier, the blood-synovial fluid (SF) barrier, and the blood-brain barrier (BBB). In particular, the BBB is composed of an impermeable type of endothelium and represents both a physical barrier via tight junctions that connect adjacent endothelial cells and a transport barrier composed of efflux transporters. Other examples of biological structures include mixtures of cells, proteins, and sugars (e.g., blood clots), such as the myelin sheath, which is the layer around the axon of a neuron formed by myelin, a dielectric material.

[0380] Examples of internal surfaces of subjects, organisms, organs, or body cavities include the buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa, and endometrium (uterine mucosa, inner wall layer of pollen grains, or inner wall layer of spores), or combinations or multiples thereof.

[0381] Examples of the outer surface of subjects, organisms, organs, or body cavities include capillaries (e.g., capillaries in cardiac tissue), mucous membranes continuous with the skin (e.g., nostrils, lips, ears, genital areas, and anus), the outer surface of organs (e.g., liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum and stomach, colorectum, intestines, veins, respiratory system, blood vessels, anorectum, and anus), skin, cuticle (e.g., dead layer of epidermal or keratinocytes, or the surface layer of overlapping cells covering the hair shaft of an animal, the multilayer structure on the outside of the epidermis of many invertebrates, plant cuticle, or high molecular weight cutin and / or culan), the outer layer of the wall of a pollen grain or the outer wall layer of a spore, and combinations or combinations thereof.

[0382] Furthermore, biological barriers may include sugar layers, protein layers, or any other biological layers, or combinations thereof. For example, skin is a biological barrier with multiple biological layers. Skin consists of the epidermis (outer surface), dermis, and subcutaneous layer. The epidermis consists of several layers, including the basal cell layer, spinous cell layer, granular cell layer, and stratum corneum. The cells in the epidermis are called keratinocytes. The stratum corneum ("cornea") is the outermost layer of the epidermis, and the cells in it are flat and scaly ("flat"). These cells contain a lot of keratin and are arranged in overlapping layers, which gives the skin surface toughness, oil resistance, and water resistance.

[0383] In some embodiments, the HPDs of this disclosure have an enhanced ability to cross one or more biological barriers, so that the HPDs can be administered locally (e.g., topically or transdermally) to reach the disease site without requiring systemic administration (e.g., oral or parenteral administration).

[0384] Local administration and permeation of HPDs allow HPDs to reach the same level of local concentration of the active substance or drug with a much smaller amount or dose compared to systemic administration of the parent drug, or to reach higher levels of local concentration that cannot be achieved with systemic administration or that, if possible, require significantly higher doses of the active substance in systemic administration.

[0385] Local administration of HPD allows the living subject to mitigate potential discomfort associated with systemic administration, such as systemic exposure to the active ingredient and adverse reactions related to gastrointestinal / renal effects. Furthermore, local administration avoids the need for systemic administration (e.g., injection) and eliminates the pain associated with parenteral injection, as HPD crosses numerous biological barriers and reaches the entire body, for example, through systemic circulation.

[0386] The HPDs of this disclosure exhibited high permeability through biological barriers (for example, approximately 10 times, 50 times, 100 times, 200 times, 300 times, 500 times, 1000 times, 10000 times, or more than the permeability when prostaglandins or prostaglandin analogs were administered alone). No adverse effects were observed in subjects administered with HPDs, whereas adverse effects were observed in subjects administered with the parent drug or its analogues at similar doses.

[0387] Those skilled in the art should understand that many different modifications can be made to the compounds, compositions, and / or methods of the present invention without departing from the spirit of the invention. Accordingly, the various embodiments of the invention described herein are illustrative only and are not intended to limit the scope of the invention. All patent and non-patent documents, by reference, constitute part of this specification in their entirety.

Claims

1. A method for improving the stability of a pharmaceutical composition comprising a highly permeable drug substance and a pharmaceutically acceptable carrier, The method includes the steps of packaging the highly permeable drug substance and the pharmaceutically acceptable carrier in separate containers and mixing them before use to reconstitute a solution of the pharmaceutical composition, The molecule of the highly permeable drug substance contains one or two protonated amine groups, the linker between the functional unit and the transport unit of the highly permeable drug substance is an ester bond, the pharmaceutically acceptable carrier is water, or a mixture of water and alcohol, acetone, or DMSO, the concentration of the highly permeable drug in the reconstituted solution is 3% to 30% by weight, the pH of the reconstituted solution is 3.5 to 4.5, and the reconstituted solution is applied transdermally.

2. The method according to claim 1, wherein the pharmaceutically acceptable carrier is an aqueous solution containing 0% to 70% by volume of ethanol.

3. The method according to claim 1, further comprising storing the reconstituted solution at room temperature or in a refrigerator at a temperature of 2°C to 8°C.

4. The method according to claim 1, wherein the pharmaceutical composition further comprises a pH adjuster / buffer in the pharmaceutically acceptable carrier.

5. The method according to claim 4, wherein the pH adjusting / buffering agent is a sodium salt, potassium salt, calcium salt, lithium salt, or magnesium salt of an organic acid.

6. The method according to claim 5, wherein the organic acid is selected from the group consisting of acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, lactic acid, salicylic acid, citric acid, ascorbic acid, succinic acid, and maleic acid.

7. The method according to claim 1, wherein the concentration of the highly permeable drug in the reconstituted solution is 3% by weight to 10% by weight.

8. The substances of the aforementioned highly permeable drug are 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl, 2-(diethylamino)ethyl (R,S)-2-(2-fluoro-4-biphenyl)propionate HCl, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propionate HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate HCl, and 2-(diethylamino)ethyl 5-flu Oro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate・HCl,2-(diethylamino)ethyl-1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate・HCl,2-(diethylamino)ethyl-5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate・HCl,2-(diethylamino)ethyl-3-(6-methoxy-2-naphthyl)propionate・HCl,2-(diethylamino)ethyl-4- (4-chlorophenyl)-2-phenyl-5-thiazole acetate / HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate / HCl, 2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate / HCl, 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate / HCl, 2-(diethylamino)ethyl 4,5-di Phenyl-2-oxazole propionate HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate HCl, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate HCl, 2-(diethylamino)ethylacetylsalicylate HCl, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate HCl, H-Val-Pro-Gly-Pro-Arg(NO ２ )-OCH(CH ３ ) ２ ・HCl, H-Ala-Pro-Gly-Pro-Arg (NO ２ )-OCH ２ CH ３ ·HCl, H-Val-Pro-Asp[OCH(CH ３ ) ２ -Pro-Arg(NO ２ )-OCH(CH ３ ) ２ ·HCl, H-Tyr-Gly-Gly-Phe-Leu-OCH(CH ３ ) ２ ·HCl, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH ３ ) ２ The method according to any one of claims 1 to 7, which is selected from the group consisting of ·HCl.

9. The method according to claim 8, wherein the concentration of the highly permeable drug in the reconstituted solution is 3% to 8% by weight, and the pharmaceutically acceptable carrier comprises an aqueous alcohol solution of 15% to 35% by volume.

10. A reconstituted solution for a pharmaceutical composition for transdermal application, The reconstituted solution comprises a highly permeable drug substance and a pharmaceutically acceptable carrier. The reconstituted solution is prepared by mixing the substance of the highly permeable drug with a pharmaceutically acceptable carrier just before use. A reconstituted solution for a pharmaceutical composition for transdermal application, wherein the molecule of the highly permeable drug substance contains one or two protonated amine groups, the linker between the functional unit and the transport unit of the highly permeable drug substance is an ester bond, the pharmaceutically acceptable carrier is water, or a mixture of water and alcohol, acetone, or DMSO, the concentration of the highly permeable drug in the reconstituted solution is 3% to 30% by weight, and the pH of the reconstituted solution is 3.5 to 4.

5.

11. A reconstituted solution of a pharmaceutical composition for transdermal application according to claim 10, used for the treatment of one or more diseases or conditions selected from the group consisting of stroke, arthritis, depression, Alzheimer's disease, Parkinson's disease, migraine, sexual dysfunction, sepsis, drug-resistant bacterial infection, epilepsy, diabetes, psoriasis, lupus erythematosus, ulcerative colitis, asthma, lower respiratory tract infections and upper respiratory tract infections, allergic rhinitis, allergic conjunctivitis, itching, and runny nose.

12. A therapeutic kit comprising spaces for independently storing a highly permeable drug substance and a pharmaceutically acceptable carrier, wherein a reconstituted solution can be formed by mixing the highly permeable drug substance and the pharmaceutically acceptable carrier before use, the molecule of the highly permeable drug substance contains one or two protonated amine groups, the linker between the functional unit and the transport unit of the highly permeable drug substance is an ester bond, the pharmaceutically acceptable carrier is water, or a mixture of water and alcohol, acetone, or DMSO, the concentration of the highly permeable drug in the reconstituted solution is 3% to 30% by weight, the pH of the reconstituted solution is 3.5 to 4.5, and the reconstituted solution is a therapeutic kit for transdermal application.

13. The substances of the aforementioned highly permeable drug are 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate HCl, 2-(diethylamino)ethyl (R,S)-2-(2-fluoro-4-biphenyl)propionate HCl, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propionate HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate HCl, and 2-(diethylamino)ethyl 5-flu Oro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate・HCl,2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate・HCl,2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate・HCl,2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate・HCl,2-(diethylamino)ethyl 4 -(4-chlorophenyl)-2-phenyl-5-thiazole acetate / HCl,2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate / HCl,2-(diethylamino)ethyl[(1-benzyl-1H-indazole-3-yl)oxy]acetate / HCl,2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate / HCl,2-(diethylamino)ethyl 4,5- Diphenyl-2-oxazolepropionate HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate HCl, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate HCl, 2-(diethylamino)ethylacetylsalicylate HCl, 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate HCl, H-Val-Pro-Gly-Pro-Arg(NO ２ )-OCH(CH ３ ) ２ ・HCl, H-Ala-Pro-Gly-Pro-Arg (NO ２ ) - OCH ２ CH ３ ・HCl, H-Val-Pro-Asp[OCH(CH ３ ) ２ ]-Pro-Arg(NO ２ )-OCH(CH ３ ) ２ ・HCl, H-Tyr-Gly-Gly-Phe-Leu-OCH (CH ３ ) ２ ・HCl, and H-Tyr-Gly-Gly-Phe-Met-OCH (CH ３ ) ２ A therapeutic kit according to claim 12, selected from the group consisting of HCl.

14. The therapeutic kit according to claim 12 or 13, further comprising a pH adjuster / buffer in the pharmaceutically acceptable carrier.

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