Method for improving the stability of a pharmaceutical composition comprising a high penetration drug, and the pharmaceutical composition obtained therefrom

Abstract

Provided are pharmaceutical compositions comprising at least one high penetration drug (HPD) that has at least one protonated amino group in its molecular and is capable of penetrating across one or more biological barriers in high rates, methods for improving the stability of the pharmaceutical compositions, and methods of using the pharmaceutical compositions for preventing, diagnosing and / or treating condition or disease in human, animals and plants.

Description

FIELD OF THE INVENTION This invention relates to pharmaceutical compositions comprising at least one high penetration drug (HPD) that has at least one protonated amino group in its molecule and is capable of penetrating across one or more biological barriers in high rates, methods for improving the stability of the pharmaceutical composition, and methods of using the pharmaceutical composition for preventing, diagnosing and / or treating condition or disease in human, animals and plants. BACKGROUND Active agents or drugs that are effective in vitro may not be as effective in vivo due to the delivery difficulties in vivo, in particular, their limited penetration ability across one or more biological barriers before reaching the site of action where diseases occur in vivo, then the agents or drugs will stay in general circulation for a long time, and liver, kidneys, and other organs will metabolize the agents or drugs before they reach the site of action where diseases occur. Currently many drugs are administered through systematic route, such as oral or parenteral administration, to reach an action site of a condition or disease. Since higher dosage of drugs is required to reach a distal location in the systematic administration, drugs delivered by such route may cause adverse reactions. For example, non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for treatment of acute or chronic conditions where pain and inflammation are present. Although NSAIDs are absorbed in the stomach and intestinal mucosa, oral administration usually accompanies adverse drug reactions such as gastrointestinal (GI) effects and renal effects. For instance, aspirin is known to cause gastric mucosal cell damage. The side effects of NSAIDs appear to be dosedependent, and in many cases severe enough to pose the risk of dyspepsia, gastroduodenal bleeding, gastric ulcerations, gastritis, ulcer perforation, and even death. The gastrointestinal, skin, and other biologic membranes have lipophilic barriers. Most of drugs that can penetrate biologic membranes in significant rates are lipophilic; however, the gastrointestinal juice, the blood system, and the moisture on the skin are mostly water and the lipophilic agents or drugs are very difficult to be dissolved in these systems. In the previous   patent applications   (PCT / IB2006 / 052732,   PCT / IB2006 / 052318, PCT / IB2006 / 052732,   PCT / IB2006 / 052318,   PCT / IB2006 / 052461,   PCT / IB2006 / 052815, PCT / IB2006 / 052563,   PCT / IB2006 / 052575,   PCT / IB2006 / 053091,   PCT / IB2006 / 053090, PCT / IB2006 / 053594,   PCT / IB2006 / 052549,   PCT / IB2006 / 053619   PCT / IB2006 / 054170, PCT / IB2006 / 054724,   PCT / IB2006 / 053741,   PCT / IB2007 / 050122,   PCT / IB2007 / 050322, PCT / IB2007 / 052090,  PCT / US2009 / 066884,  PCT / CN2010 / 072561,  PCT / CN2010 / 073743, PCT / CN2013 / 072693, PCT / CN2013 / 072728), the applicant disclosed many compositions of novel HPDs that are lipophilic and hydrophilic and can dissolve in both lipid and water and penetrate the lipid or aqueous barriers. However, many of these novel HPDs are not very stable in aqueous conditions and cannot be stored for a long time that is required for a reasonable shelf life of the pharmaceutical products. Therefore, there is a need to improve the stability of HPDs or compositions so that they are capable of being delivered efficiently and effectively to an action site of a condition (e.g., a disease) to prevent, reduce or treat the condition in a biological subject. CONTENTS OF THE INVENTION In one aspect, the present invention provides a method for improving the stability of a pharmaceutical composition which comprises an HPD and a pharmaceutically acceptable carrier, the method comprising: packaging the HPD and the pharmaceutically acceptable carrier separately; and reconstituting a solution of the pharmaceutical composition by mixing the HPD with the pharmaceutically acceptable carrier when a patient intends to use it; characterized in that the pH of the reconstitution solution of the pharmaceutical composition is maintained in the range of about 2 to about 6. In the context of the invention, HPD refers to a prodrug that has at least one protonated amine group in its molecule and is capable of penetrating across one or more biological barriers in high 2021236811   23 Jun 2026 rates, e.g. 10 times, 50 times, 100 times, 200 times, 300 times, 500 times, or even 1,000 times higher than the penetration rate of the corresponding parent drug. Advantageously, the HPD comprises one or two protonated amine groups in its molecule when being administered to the patient. 5 In an embodiment, the pharmaceutically acceptable carrier is an aqueous carrier. The pharmaceutically acceptable carrier may be water, alcohol, acetone, or dimethyl sulfoixide (DMSO), or a mixture thereof. Preferably, the pharmaceutically acceptable carrier is an aqueous solution containing 0-70% ethanol by volume. More preferably, the pharmaceutically acceptable carrier is an aqueous solution containing 10-35% ethanol by volume. 10 In an embodiment, the pharmaceutical composition is applied transdermally as a spray solution. In an embodiment, the method according to the present invention further comprises a step of storing the reconstitution solution in a refrigerator at a temperature of 2-8°C. In the method according to the present invention, the pharmaceutical composition may also comprise a pH adjusting and buffering agent. In an embodiment, the HPD is high penetration 15 peptide and the pH adjusting and buffering agent is sodium, potassium, calcium, lithium, or magnesium salt of an organic acid. Preferably, the pH adjusting and buffering agent is 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. In an embodiment, the pH of the reconstitution solution of the pharmaceutical composition is 320   6, preferably 3-5, more preferably 3.5-4.5. In an embodiment, the concentration of the HPD in the reconstitution solution is 1%-30% by weight, preferably 1%-20% by weight, more preferably 3%-10% by weight. In an embodiment, the HPD is selected from the group consisting of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate.HCl,       2-(diethylamino)ethyl       (R,S)-2-(2-fluoro-4- 25 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- 2021236811   23 Jun 2026 (diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate.HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.HCl, 2-(diethylamino)ethyl [(1-benzyl-1H-indazol-3-yl)oxy]acetate.HCl,          2-(diethylamino)ethyl          2-[(4-chlorophenyl)-5- 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)ethyl acetylsalicylate.HCl, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HCl. In an embodiment, the concentration of the HPD in the reconstitution solution is 3-8% by weight, 10 the pH of reconstitution solution is 3-5 and the pharmaceutically acceptable carrier is an aqueous solution containing 15-35% ethanol by volume. In another embodiment, the 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, 15 and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HCl. The concentration of the HPD in the reconstitution solution is 3-8% by weight, the pH of reconstitution solution is 3-5, the pH adjusting and buffering agent is sodium acetate and the pharmaceutically acceptable carrier is an aqueous solution containing 15-35% ethanol by volume. In an embodiment, the HPD according to the present invention is stable at room temperature and 20 can be stored for more than two years when kept in dry condition. By means of the method according to the present invention, the pharmaceutical composition comprising an HPD and a pharmaceutically acceptable carrier when reconstituted as a solution can be stored for a reasonable shelf life, e.g. more than one month, or even more than two months. In another aspect, the present invention provides the pharmaceutical compositions obtained from 25 any embodiments of the above method. In another aspect, the present invention provides methods of using the pharmaceutical compositions disclosed for preventing, diagnosing and / or treating condition or disease in human, animals and plants. In an embodiment, there is provided a method for improving the stability of a pharmaceutical 30 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; wherein 2021236811   23 Jun 2026 the reconstitution solution is applied transdermally, the high penetration drug substance comprises protonated amine group and ester bond in its molecule, the pharmaceutically acceptable carrier is an aqueous carrier, the concentration of the high penetration drug substance in the reconstitution solution is in the range of 3%-30% by weight, the pH of the reconstitution 5 solution of the pharmaceutical composition is modified within the range of 3 to 6, and the high penetration drug substance is selected from the group consisting of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)     propionate.HA,     2-(diethylamino)ethyl     (R,S)-2-(2-fluoro-4- biphenyl)propionate.HA, 2-(diethylamino)ethyl   2-(p-isobutylphenyl)propionate.HA,   2- (dimethylamino)ethyl   2-(p-isobutylphenyl)propionate.HA,   2-(dibutylamino)ethyl   2-(p- 10 isobutylphenyl)propionate.HA, 2-pyrrolidinemethyl (R,S)-2-(p-isobutylphenyl)propionate.HA, 4-piperidineethyl (R,S)-2-(p-isobutylphenyl)propionate.HA,  1-pyrrolidineethyl (R,S)-2-(p- isobutylphenyl)propionate.HA, 1-piperidineethyl (R,S)-2-(p-isobutylphenyl)propionate.HA, 2-(diethylamino)ethyl   1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate.HA,   2- (diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-15 acetate.HA, 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.HA, 2- (diethylamino)ethyl      5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate.HA,      2- (diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate.HA,  2-(diethylamino)ethyl 4-(4- chlorophenyl)-2-phenyl-5-thiazoleacetate.HA, 2-(diethylamino)ethyl  1-(4-chlorobenzoyl-5- methoxy-2-methyl-1H-indole-3-acetoxyacetate.HA,   2-(diethylamino)ethyl [(1-benzyl-1H- 20 indazol-3-yl)oxy]acetate.HA,          2-(diethylamino)ethyl          2-[(4-chlorophenyl)-5- benzoxazole]propionate.HA, 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazolepropionate.HA, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate.HA, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate.HA,                 2-(diethylamino)ethyl acetylsalicylate.HA, 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HA, H-25 Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HA, H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HA, H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2.HA,     H-Tyr-Gly-Gly-Phe-Leu- OCH(CH3)2.HA, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HA, wherein HA is a pharmaceutically acceptable acid. In another aspect, the present invention provides treatment kits based on the improved methods and HPD compositions to ensure convenience of administration and stability of the pharmaceutical compositions obtained. Other aspects and advantages of the invention will be better understood in view of the following detailed description, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION When a drug is administered in solid, semisolid, or suspension form, the rate of absorption is often controlled by how the drug particles dissolve in the fluid or moisture at the site of administration (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 21). HPDs that were disclosed in previous patent applications have two structural features in common: a lipophilic portion and a hydrophilic portion comprising a primary, secondary, or tertiary amine group in protonated form. They have a very high solubility in gastric juice, blood system, or moistures on the skin and have a high solubility in oil, which enables them to penetrate biological membranes easily. These features make the formulation of the HPDs much simpler. Transdermal delivery systems help to avoid directly hurting the gastro-intestinal tract and inactivation of the drugs caused by the “first pass metabolism” in the gastro-intestinal tract and liver. It can provide local delivery of appropriate concentrations of a drug to the intended site of action without systemic exposure. Fishman et al. (U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications is that the concentration levels achieved in the bloodstream must be significant in order to effectively treat distal areas of pain or inflammation. These levels are often much higher than would be necessary if it were possible to accurately target the particular site of pain or injury. By controlling the rate of release, transdermal delivery systems enable drugs to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of drugs. The HPDs may adopt the form of pro-drugs. A good pro-drug should be able to release the parent drug easily in plasma and / or in other organs / tissues. A very good linker between the functional unit (parent drug) and the transportational (or transporting) unit (with at least one amino group) is an ester bond which can be cleaved in most tissues in a short time. Before the drug can penetrate skin, GI system, or other biological barriers, it should be dissolved in some solvent, which should not hurt skin, GI system, or other biological barriers. For oral administration, a solid formulation is suitable because the GI system can keep the drug inside and the plenty of GI juices can dissolve the drug, but oral administration has the disadvantage of the '‘first pass metabolism”, and 100% of the drugs / pro-drugs will pass the GI system and may hurt the GI system severely. For transdermal administration, the drug should be dissolved or suspended on some medium. Most organic solvent will hurt skin, and water is the best solvent for topical and transdermal administration. The hydrolysis of ester in water can be accelerated by both acids and bases, and strong acidic and basic condition will hurt skin or other biological barriers. Because the amino group in the transporting unit is a base and would help hydrolyze the ester bond, most of the amino groups should be kept in the protonated form. In one aspect, the present disclosure provides a method for improving the 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 the range of 2 to 6. In some embodiments, sometimes preferred, the high penetration drug substance comprises one or two protonated amine groups in its molecule when being administered to the patient. In some embodiments, sometimes preferred, the pharmaceutically acceptable carrier is an aqueous carrier. In some embodiments, sometimes preferred, the pharmaceutically acceptable carrier is water, alcohol, acetone, DMSO, or a mixture thereof. In some embodiments, sometimes preferred, the pharmaceutically acceptable carrier is an aqueous solution containing 0-70% ethanol by volume. In some embodiments, sometimes preferred, the pharmaceutically acceptable carrier is an aqueous solution containing 10-35% ethanol by volume. In some embodiments, sometimes preferred, the reconstitution solution is applied transdermally as a spray solution. In some embodiments, sometimes preferred, the methods further includes storing the reconstitution solution in a refrigerator at a temperature of 2-8 °C. In some embodiments, sometimes preferred, the pharmaceutical composition further comprises a pH adjusting and buffering agent in the pharmaceutically acceptable carrier. In some embodiments, sometimes preferred, the high penetration drug is high penetration peptide; and the pH adjusting and buffering agent is a sodium, potassium, calcium, lithium, or magnesium salt of an organic acid. In some embodiments, sometimes preferred, the pH adjusting and buffering agent is sodium, potassium, 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. In some embodiments, the pH of the reconstitution solution of the pharmaceutical composition is in the range of 3 to 6. In some embodiments, sometimes preferred, the pH of the reconstitution solution of the pharmaceutical composition is in the range of 3 to 5. In some embodiments, sometimes more preferred, the pH of the reconstitution solution of the pharmaceutical composition is 3.5-4.5. In some embodiments, the concentration of the high penetration drug in the reconstitution solution is in the range of l%-30% by weight. In some embodiments, sometimes preferred, the concentration of the high penetration drug in the reconstitution solution is in the range of l%-20% by weight. In some embodiments, sometimes more preferred, the concentration of the high penetration drug in the reconstitution solution is in the range of 3%-10% by weight. In some embodiments, the high penetration drug substance is selected from the group consisting of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HC1, 2-(diethylamino)ethyl (R,S)-2-(2-fluoro-4-biphenyl)propionate.HCl,              2-(diethylamino)ethyl              2-(p- isobutylphenyl)propionate.HCl, 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2-methyl-l / / -indole-3-acetate.HCl,            2-(diethylamino)ethyl             5-fluoro-2-methyl-l-[[4- (methylsulfinyl)phenyl]methylene]-l / / -indene-3-acetate.HCl, 2-(diethylamino)ethyl l-methyl-5-(4-methylbenzoyl)-l / Z-pyrrole-2-acetate.HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-l,4-dimethyl-l / f-pyrrole-2-acetate.HCl,           2-(diethylamino)ethyl           3-(6-methoxy-2- naphthyl)propionate.HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl, 2-(diethylamino)ethyl l-(4-chlorobenzoyl-5-methoxy-2-methyl-lH-indole-3-acetoxyacetate.HCl, 2-(diethylamino)ethyl [(l-benzyl-l / 7-indazol-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)ethyl acetylsalicylate.HC1, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HCl. In some embodiments, sometimes preferred, the concentration of the high penetration drug in the reconstitution solution is 3-8% by weight, the pH of reconstitution solution is 3-5, and the pharmaceutically acceptable carrier is 15-35% ethanol in water by volume. In some embodiments, the high penetration 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.HC1, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HC1. In some embodiments, sometimes preferred, the concentration of the high penetration drug in the reconstitution solution is 3-8%, the pH of reconstitution solution is 3-5, the pH adjusting and buffering agent is sodium acetate, and the pharmaceutically acceptable carrier is 15-35% ethanol in water by volume. In another aspect, the present disclosure provides a pharmaceutical composition obtained from any embodiment of the methods disclosed. In another aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition prepared according to any embodiment of the methods disclosed. In some embodiments, sometimes preferred, the pharmaceutical composition is a freshly prepared reconstitution solution by mixing the high penetration drug substance with the pharmaceutically acceptable carrier from separate containers, according to any embodiment of the methods disclosed. In another aspect, the present disclosure provides a treatment kit comprising: a high penetration drug substance in a first container, a pharmaceutically acceptable carrier in a second container, and a pH adjusting and buffering agent in the first container, the second container, or a separate third container, wherein the high penetration drug substance comprises one or two protonated amine groups, and wherein the high penetration drug substance, the pharmaceutically acceptable carrier, and the pH adjusting and buffering agent can be mixed together to form a reconstitution solution ready for administration to a subject in need thereof. In some embodiments, sometimes preferred, the reconstitution solution has a pH in the range of 2 to 6 and is stable for storage at a temperature in the range of 2-20 °C for a period of time prior to administration to the subject in need thereof. In some embodiments, sometimes preferred, the high penetration drug substance is selected from the group consisting of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HCl, 2-(diethylaminojethyl (7?,5)-2-(2-fluoro-4-biphenyljpropionate.HCl, 2-(diethylaminojethyl 2-(p-isobutylphenyljpropionate.HCl, 2-(diethylaminojethyl l-(4-chlorobenzoyl)-5-methoxy-2-methyl-l / / -indole-3-acetate.HCl,            2-(diethylamino)ethyl             5-fluoro-2-methyl-l-[[4- (methylsulfinyl)phenyl]methylene]-l / / -indene-3-acetate.HCl, 2-(di ethyl ami nojethyl l-methyl-5-(4-methylbenzoyl)-l / Z-pyrrole-2-acetate.HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-l,4-dimethyl-U7-pyrrole-2-acetate.HCl,           2-(di ethylaminojethyl           3-(6-methoxy-2- naphthyljpropionate.HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl, 2-(diethylaminojethyl l-(4-chlorobenzoyl-5-methoxy-2-methyl-lH-indole- 3-acetoxyacetate.HCl, 2-(diethylamino)ethyl [(l-benzyl-U / -indazol-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)ethyl acetylsalicylate.HC1, 2-(diethylamino)ethyl 5-(2,4-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.HC1, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HC1; and the pharmaceutically acceptable carrier is a mixture of an aliphatic Ci-Ce alcohol and water. In some embodiments, sometimes preferred, the concentration of the high penetration drug in the reconstitution solution is 3-8%, the pH of reconstitution solution is 3-5, the pH adjusting and buffering agent is sodium acetate, and the pharmaceutically acceptable carrier is 15-35% ethanol in water by volume. In another aspect, the present disclosure provides treatment of a disease or disorder in a subject using the treatment kits prepared according to the any embodiment of the methods disclosed. Such treatment kits can be used for administration of the pharmaceutical composition to the subject by a healthcare professional or for convenient self-administration by the subject, as the case may be. The disease or disorder that can be treated by the pharmaceutical compositions provided by the present disclosure can be any disease or disorder to which the high penetration drug substance can provide desired therapeutic effects with advantages of high penetration rate through certain biological barriers. Some nonlimiting nexamples of the diseases or disorders have been mentioned in the present disclosure, which are all encompassed by the present invention. Another aspect of the invention relates to a method of using a composition of the invention, or a pharmaceutical composition thereof in treating a condition in a biological subject. The method comprises administrating the pharmaceutical composition to the biological subject. Some examples of the conditions the method can treat include conditions that can be treated by the parent drug of the HPD. For example, without limitation, stroke, arthritis, depression, Alzheimer’s disease, Parkinson’s disease, migraine, sexual dysfunction, sepsis, drug-resistant bacterial infections, epilepsy, diabetes, psoriasis, lupus erythematosus, ulcerative enteritis, asthma, lower and upper respiratory tract infections, allergic rhinitis, allergic conjunctivitis, itchiness, and runny nose. The one or more HPDs or a pharmaceutical composition thereof can be administered to a biological subject by any administration route known in the art, including without limitation, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and / or parenteral administration. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. A parenteral administration refers to an administration route that typically relates to injection which includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intra cardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and / or intrastemal injection and / or infusion. The one or more HPDs or a pharmaceutical composition thereof can be given to a subject in the form of formulations or preparations suitable for each administration route. The formulations useful in the methods of the invention include one or more HPDs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The amount of an HPD which can be combined with a carrier material to produce a pharmaceutically effective dose will generally be that amount of an HPD which produces a therapeutic effect. Methods of preparing these formulations or compositions include the step of bringing into association an HPD with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association an HPD with liquid carriers. Liquid dosage forms for oral, transdermal or topical administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the HPD, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the HPD, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations for the topical or transdermal or epidermal or dermal administration of an HPD composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to the HPD composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the HPD composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. The best formulations for the topical or transdermal administration are pure water, solution, aqueous solution, ethanol and water solution, and isopropanol and water solution. Transdermal patches can also be used to deliver HPD compositions to a target site. Such formulations can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the HPD compositions across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the HPD compositionsin a polymer matrix or gel. Formulations suitable for parenteral administration comprise an HPD in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacterostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers which may be employed in the formulations suitable for parenteral administration include water, ethanol, polyols (e. g., such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for parenteral administration may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. Injectable depot forms are made by forming microencapsule matrices of an HPD or in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the HPD to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the HPD in liposomes or microemulsions which are compatible with body tissue. In certain embodiments, one or more HPDs or a pharmaceutical composition thereof is delivered to an action site in a therapeutically effective dose. As is known in the art of pharmacology, the precise amount of the pharmaceutically effective dose of an HPD that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon, for example, the activity, the particular nature, pharmacokinetics, pharmacodynamics, and bioavailability of a particular HPD, physiological condition of the subject (including race, age, sex, weight, diet, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), the nature of pharmaceutically acceptable carriers in a formulation, the route and frequency of administration being used, and the severity or propensity of the condition that is to be treated. However, the above guidelines can be used as the basis for fine-tuning the treatment, e. g., determining the optimum dose of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage. Remington: The Science and Practice of Pharmacy (Gennaro ed. 20.sup.th edition, Williams & Wilkins PA, USA) (2000). In certain embodiments, a combination of one or more HPDs and / or other drug(s) is applied to the subject for the desired use (e.g. treatment, screening, etc.). When applying a combination of a plurality of drugs (e.g. one or more HPDs and / or other drug(s)) to a subject, each drug may be applied separately, or one or more of the drugs may be applied at the same time as separate drugs (e.g. spraying two or more drugs at substantially the same time without mixing the drugs before spraying), or one or more drugs can be mixed together before applying to the subject, or any combination of the above application methods. The drugs may be applied in any order possible. In certain embodiments, since an HPD of the invention is capable of crossing one or more biological barriers, the HPD can be administered locally (e.g., topically or transdermally) to reach a location where a condition occurs without the necessity of a systematic administration (e.g., oral or parenteral administration). A local administration and penetration of an HPD allows the HPD to reach the same level of local concentration of an agent or drug with much less amount or dosage of HPD in comparison to a systematic administration of a parent agent or drug; alternatively, a higher level of local concentration which may not be afforded in the systematic administration, or if possible, requires significantly higher dosage of an agent in the systematic administration. The high local concentration of the HPD or its parent agent if being cleaved enables the treatment of a condition more effectively or much faster than a systematically delivered parent agent and the treatment of new conditions that may not be previously possible or observed. The local administration of the HPD may allow a biological subject to reduce potential suffering from a systemic administration, e.g., adverse reactions associated with the systematic exposure to the agent, gastrointestinal / renal effects. Additionally, the local administration may allow the HPD to cross a plurality of biological barriers and reach systematically through, for example, general circulation and thus avoid the needs for systematic administration (e.g., injection) and obviate the pain associated with the parenteral injection. In certain embodiments, an HPD or a pharmaceutical composition according to the invention can be administered systematically (e.g., orally, transdermally, or parenterally). The HPD or the active agent (e.g., drug or metabolite) of the HPD may enter the general circulation with a faster rate than the parent agent and gain faster access to the action site of a condition. Additionally, the HPD can cross a biological barrier (e.g., blood brain barrier and blood milk barrier) which has not been penetrated if a parent agent is administered alone and thus offer novel treatment of conditions that were previously not possible or observed. In another embodiment of this aspect, the liquid formulation obtained is a formulation according to any one of the embodiments described herein, or any combination thereof. When the term “about” is applied to a parameter, such as pH, concentration, or the like, it indicates that the parameter can vary by ±10%, sometimes preferably within ±5%, and sometimes more preferably within ±2%. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting. The term “a”, “an”, or “the” as used herein, represents both singular and plural forms. In general, when either a singular or a plural form of a noun is used, it denotes both singular and plural forms of the noun. The term "treating" as used herein means curing, alleviating, inhibiting, or preventing. The term "treat" as used herein means cure, alleviate, inhibit, or prevent. The term "treatment" as used herein means cure, alleviation, inhibition or prevention. The term "biological subject," or "subject" as used herein means an organ, a group of organs that work together to perform a certain task, an organism, or a group of organisms. The term "organism" as used herein means an assembly of molecules that function as a more or less stable whole and has the properties of life, such as animal, plant, fungus, or micro-organism. The term "animal" as used herein means a eukaryotic organism characterized by voluntary movement. Examples of animals include, without limitation, vertebrata (e.g. human, mammals, birds, reptiles, amphibians, fishes, marsipobranchiata and leptocardia), tunicata (e.g. thaliacea, appendicularia, sorberacea and ascidioidea), articulata (e.g. insecta, myriapoda, malacapoda, arachnida, pycnogonida, merostomata, Crustacea and annelida), gehyrea (anarthropoda), and helminthes (e.g. rotifera). Preferably, the subject is human or a mammalian animal, such as cats, dogs, horses, monkey, or the like. The term "plant" as used herein means organisms belonging to the kindom Plantae. Examples of plant include, without limitation, seed plants, bryophytes, ferns and fern allies. Examples of seed plants include, without limitation, cycads, ginkgo, conifers, gnetophytes, angiosperms. Examples of bryophytes include, without limitation, liverworts, hornworts and mosses. Examples of fems include, without limitation, ophioglossales (e.g. adders-tongues, moonworts, and grape-ferns), marattiaceae and leptosporangiate ferns. Examples of fem allies include, without limitation, lycopsida (e.g. clubmosses, spikemosses and quillworts), psilotaceae (e.g. lycopodiophyta and whisk fems) and equisetaceae (e.g. horsetails). The term "fungus" as used herein means a eukaryotic organism that is a member of the kingdom Fungi. Examples of fungus include, without limitation, chytrids, blastocladiomycota, neocallimastigomycota, zygomycota, glomeromycota, ascomycota and basidiomycota. The term "microorganism" as used herein means an organism that is microscopic (e.g. with length scale of micrometer). Examples of microorganism include, without limitation, bacteria, fungi, archaea, protists and microscopic plants (e.g. green algae) and microscopic animals (e.g. plankton, planarian and amoeba). I. Examples ofHPDs Some structure examples of the high biological barrier (skin, blood-brain barrier, blood-milk barrier, and other biological barriers) penetration drugs are listed as follows: Structure 3 5           Structure 4 Structure 6 Structure 8                     Structure 9 Structure 19 Structure 20                          Structure 21 o 5 Structure 22 o Structure 25 Structure 23                          Structure 24 Structure 26                          Structure 27 Structure 31 Structure 32 Structure 33 Structure 35 Structure 36 Structure 40 Structure 41 Structure 42 Structure 52 Structure 53 Structure 54 Structure 56 5 Structure 55 Structure 58 Structure 59 Structure 60 Structure 61 Structure 62 ci Structure 63 Structure 66 5 Structure 64 Structure 70 Structure 65 Structure 68 Structure 71 Structure 69 Structure 72 Structure 79 Structure 80 Structure 81 Structure 83 Structure 86 Structure 88 Structure 89 Structure 90 Structure 92 Structure 93 Structure 94                            Structure 95 Structure 96 Structure 98 Structure 99 5 Structure 97 Structure 100 Structure 103 Structure 104 Structure 102 Structure 105 10 Structure 107 Structure 108 Structure 106 Structure 109                  Structure 110 Structure 111 Structure 116 Structure 117 10 Structure 115 Structure 122 Structure 123 5 Structure 121 Y, Structure 127 Structure 128 Structure 129 10 10 Structure 133 Structure 134 Structure 135 Structure 136 Structure 137 Structure 138 Structure 139 Structure 140 Structure 141 Structure 166                         Structure 167 Structure 168 Structure 170 5 Structure 169 Structure 171 Structure 175 Structure 176 Structure 177 Structure 193 Structure 194 Structure 195 Structure 196 Structure 197 0 Structure 198 0 Structure 199 0 Structure 200 Structure 201 Structure 203 Structure 204 Structure 217 Structure 218 Structure 220 Structure 219 Structure 222 Structure 223 Structure 221 Structure 225 10 Structure 229 Structure 231 Structure 232 Structure 233 Structure 234 Structure 235 Structure 236 Structure 237                                     Structure 238 Structure 245 Structure 246 Structure 247 Structure 248 Structure 256 Rw               Rs                R4       O u         1 / -¼¾.                                         OR1d = y a Rj Structure 257 ch3              ch3              ch3     0 k. / A\                          OCH3 |        ch3 5                CH’ Structure 259 R10       Y5        Rs        Y2        R4 :WyWV 7\ / A. y4    y3    y,    or„ R? Structure 261 10 ch3 1                  ch3               ch3      0 OCH3 I \h3 ch3 Structure 263 h3cA ^ch3 J1                                      ch3 f 15 Structure 265 Rio       y5       r5       y2       r4        0 <?r) R, / Y< Ya Y' OR" r7 Structure 258 ch3              ch3              ch3     0 R      R,               / -¼.                                        R\ HCI \ R.                                                             och3 [      CH3                                            HCI ch3 Structure 260 0                      ch3 ch3              ch3     0 vL ch3 Structure 262 R10 II         Ys        r5        y2        r4        o <r> -VyrWW’ Rs—Y4 Ys Y’ ORl1 4 | Rs r7 Structure 264 Ri                                                                                           °           I--\ j-           r a A3 HA                         H3C-^ ^CH3                       HA | JJ                                         ch3                      r, f Structure 266 10 Structure 267 Structure 268 Structure 271 Structure 272 Structure 273 Structure 274 Structure 275 r4       ch3 H3C CH3 1           1 C JL H3CT ^CH3        \ Rs     / / L / Y1 \    L ch3      Z^-x-t oz Structure 276 R,^ H O'^rr..... Structure 278 CH3              CH, H3C CH3              I                      I 5 Structure 280 H,C CH3          jH’ pV*^^ ^CH, 10 Structure 282 CH,              CH, H3C ,CH3              1                      1 fl           " L       iL                                                __^,n R’ HA^ Structure 284 15 Ri CY~^^T "r / “ ’ It                                 ch3      0 Structure 277 ?'°             / 4 I’ I' 'Yyyyy x^t Y3       CH3     O Ry                         Rfi R7 Structure 279 7'         h3c     ch3          ?h=                                          / ----A 1        \ /                                   / ) N--R2 / ^¾¾. / -G\ / HA     < >|                               R ha N \ Rl ^ch3 Structure 281 ?WyW^ Xs x‘ x^ x’ ch3                                 t---xz Structure 283 ch3              ch3 H3C< ^,CH3           1                  1                 / u\       HA ^CH3                       t -- Structure 285 10 o                                  Rv 5 Structure 304 Structure 305 Structure 306 Structure 307 Structure 308 Structure 309 5 Structure 313 Structure 314 Structure 315 Structure 316 Structure 317 Structure 318 Structure 319 Structure 320 Structure 321 Structure 322 Structure 323 Structure 324 Structure 332 Structure 333 10         Structure 331 R10 I RlO                                                  CH                R5 1                                         X2 RoYY|Y  i^'r^ RS----X4        Xa                        «7 /            Rs       R«°----T ^R<                     ,R' RS' |                                      R’^ / r7                 t                                     HA I Structure 334                  Structure 335 / s\                                           ,s r jO _ y ex J _ >C^ “II            — Il h3c        ch3                                             H3C        CH3                      N 0 Structure 337                 Structure 338 o                                o A                                    / /             o /    T                        x x )—                     ^ch3      \__ X       । 5        R12           6—R1d Structure 340 Ri3O °                                      o              R, \                                / /         HA 1 r zN\     \ \   1                         'y \   \ / ----X^5^\ Z^\ Z\ / CH3     ’--' ho                 :                                           °A 6h                                           r Structure 342 HA R   X Ris°x                                    o               R«q zX-'-x     ^-X ।    X / y' \__ / ^x. xX \__r       / \_- \ / ------ x \ / )—^Xx^x z^x x^x xCH3 R12O                       ;                                            R12O 10                           °R11 Structure 344 Rio 1 CH               R6 X x^X / \„         Rs      RnO^^Z r4 "°—I            1                      1 R?       Ri / X-          \       X^X) HA^X^ / x Structure 336 r-\ X1                         ri—nv 3 HA T                      ha V R             1 JI ,J                                              □ 1 !  X^ — II] । X_      H3c   CH3          N\XX O                                                  O Structure 339 HA R      z”2 O Rl\ / / /          N / Z. / -X  1 / x "X.iXX            / CH3 6r„ Structure 341 0 XX\ x^—x. xT T X X X_X \ x x \XX xX / X xh3 2             6---Rn Structure 343 HA o^p X._ ,x^x x^ \__.R N---- /    --- XX-"^ \x^X zX XX / / CH3 ORn Structure 345 Structure 365 Structure 364 Structure 367 Structure 366 Structure 369 Structure 368 Structure 370 Structure 373 10 Structure 372 Structure 374 Structure 375 Structure 379 5 Structure 378 Structure 380 Structure 381 10 Structure 382 Structure 384 Structure 383 Structure 385 10 Structure 387 Structure 386 Structure 389 Structure 388 R..0 R-i 10 Structure 391 Structure 390 Structure 392 Structure 393 Structure 394 Structure 395 10 Structure 398 Structure 402 Structure 403 Structure 404 Structure 405 Structure 407 Structure 406 Structure 411 Structure 410 Structure 415 10 Structure 414 0                              0 Xx    X"\ X"\ X^X xRx (                  x \ J x^nxxxxxxH HA / X :                                                         Ri OR 11 Structure 416 0                             0 ^xk                 JL / r\ zR X             HA \ ORi 1 5 Structure 418 o JI               / x Xx xJX OR,,              CH3 Structure 420 0                                  / A / ^a^sA VJ              - —AAzAAXx    R OR,,              ch3 Structure 422 0                                             / R1 A          / \ / \      .n / Xx^ / X^x X. \ \____ / /                              0 XX XX\^= / X3 10           X Structure 424 o                           o xX xX xX xT 0""          x 6r„ Structure 417 O                          0 1 AL                 / -.,, JL           / x Q""         x  LA —X^ xx XX x^X / ch3   n / X X /           RZ HA ORn Structure 419 j                                                            I’ A             Z\   XX          .N. ?        X^\ XX^-- / X"VZ          ^R, \ / / ' HA \__7                  o OR,,              CH3 Structure 421 0 )           A             Z\ J   ZxXX_t \ / 7                                                   II OR-j -| Structure 423 0 / ~~~~~~\ JI             zx XX         X    \ .z \ A \ /                         0             / HA —X          ZX     Rl \^= / ch3 ORn Structure 425 Structure 426 Structure 428 Structure 430 Structure 431 Structure 432 Structure 434 Structure 435 Structure 436 Structure 437 5 Structure 441 Structure 440 Structure 442 Structure 443 Structure 444 Structure 445 Structure 446 Structure 450 CO2R5 Structure 451 Structure 452 Structure 453 Structure 454 Structure 455 10 Structure 469 Structure 470 Structure 472 Structure 476 Structure 478 Structure 471 Structure 473 Structure 477 Structure 479 Structure 480 Structure 481 Structure 483 Structure 482 Structure 486 Structure 485 Structure 487 Structure 488 Structure 490 Structure 489 Structure 492 Structure 493 NOCH3 Structure 494 N0CH3 | HA r2 Structure 495 Structure 496 Structure 497 Structure 498 Structure 502 Structure 499 Structure 501 Structure 503 Structure 504 Structure 505 Structure 506 Structure 507 Structure 508 Structure 509 10 Structure 511 Structure 513 Structure 518 Structure 515 Structure 517 Structure 519 Structure 520 Structure 524 Structure 525 5          HA 2 HA Structure 526 Structure 528 Structure 527 Structure 529 Structure 534 Structure 535 Structure 537 Structure 536 Structure 539 10          Structure 538 Structure 542 Structure 546 Structure 541 Structure 547 Structure 581 Structure 583 Structure 585 Structure 586 Structure 587               Structure 588 Structure 589 Structure 590 Structure 591 Structure 592 Structure 599 Structure 601 Structure 600 Structure 602 Structure 603 Structure 604 Structure 605 Structure 606 Structure 607 Structure 612 Structure 611 Structure 613 Structure 619 10          Structure 617               Structure 618 Structure 650                Structure 651 Structure 652 Structure 654 Structure 655 Structure 662 Structure 665 Structure 667 Structure 666 Structure 675 Structure 674 Structure 678 Structure 676 Structure 679 10          Structure 677 Structure 680                Structure 681                      Structure 682 Structure 683                Structure 684                Structure 685 Structure 686                Structure 687                Structure 688 Structure 689                Structure 690                      Structure 691 Structure 709 Structure 711 Structure 713 Structure 714 Structure 717 Structure 718 Structure 719 Structure 720 Structure 722 Structure 723 Structure 724 Structure 725 Structure 727 Structure 730 Structure 732 Structure 733 Structure 734 Structure 736 Structure 737 Structure 739 Structure 740 Structure 741 Structure 742 Structure 743 Structure 744 Structure 745 Structure 746 Structure 747 Structure 750 Structure 752 Structure 753 Structure 756 Structure 757 Structure 759 Structure 760 Structure 761 Structure 762 Structure 771 Structure 774 Structure 776 Structure 778 Structure 779 Structure 780 Structure 782 Structure 783 Structure 784 Structure 787 Structure 789 Structure 791 Structure 792 Structure 796 Structure 802 Structure 804 Structure 805 Structure 806 0            0            0            0            0            0 HN--CH—C--N--CH — C--N--CH — C--N--CH — C--N--CH — C--N--CH—C--X I                   H        I                   H        I                   H        I                  H        I                   H        I                   I ch2         h2c-ch2        ch—ch3      ch2           ch2           ch2 r5 c^=o    h2c—ch2       ch3         ch—ch3     c^=o      ch—ch3 nh2          nh2  ha                     ch3                         ch3 R6 0            0 II                    II HA ' ■ H I H I ch2            ch2 ch2 ch2 h3c—s Structure 809 Structure 810 HN--CH—C--N--CH—C--N--CH—C--N CH—C--N--CH—C--N--CH—C--X CH2 C^=O I nh2 H |               H H2C—CH2 H2C--CH2 nh2 ha I H CH—CH3 ch3 I H ch2 CH—CH3 ch3 ch2 c^=o ch2 r5 CH—CH3 ch3 Structure 811 II HN--CH — C--N--CH — C--N--CH—C--N--CH — C--N--CH—C--N--CH — C--X CH2 C^O NH2 H |               H |               H H2C — CH2          CH—CH3 H2C---CH2           CH3 HN---Xg---Rg I H CH2 CH — CH3 CH3 CH2 ch2 r5 O—x6 \ r6 II CH2 ch2 h3c—s I--C---CH—N I H h2c—ch2 o^c NH2 — C--CH—NH2 ch2 ch2 h3c—s HA Structure 812 II II II II II II HN--CH—C--N--CH—C--N--CH—C--N--CH—C--N--CH—C--N--CH—C--X I H I H I H I H I H I I ch2         h2c—ch2      ch—ch3      ch2           ch2           ch2 r5 c^o    h2c—ch2     ch3        ch—ch3    c^o      o—x6 ।     । HA        II       । nh2          nh2 ha                   CH3          x7^             r6 ch2     h2c—ch2           ch2 ch2 o^=c               ch2 I I                                                                                                                              I h3c---s         nh2 h3c—s Structure 813 Structure 814 Structure 815 Structure 816 Structure 817 Structure 818 Structure 820 Structure 822 HA H2N--CH—C--N--CH—C--N--CH—C--NH I                 H        I                 H       I ch3            ch3            h X--C--CH—N--C--CH—N--C--CH—N--C--CH H3C---CH CH3 H I H I CH2 H3C---CH H3C---CH            CH2 ch3            ch3 Structure 827 HA H2N--CH — C--N--CH—C--N--CH—C--N--CH—C--N--CH—C--N--CH—C CH2 CH2 CH — O CH2 CH2 R9 O---X9 CH2 ch3 C^=O CH3 X7 CH2 X8 r7 H3C--S r8 R5 X---C---CH--N---C---CH--N---C---CH--NH H3C---CH H2C—CH2 ch2 CH3 O^=C Re—X@—O nh2 Structure 828 HA H2N--CH—C--N--CH—C--N--CH—C--N--CH—C--N--CH—C--NH CH—CH3 CH—CH3 ch2 ch3 CH—CH3 ch2 ch2 O ,R6 ch3 ch3 ch3 O R5---X---C--CH—N--C--CH—N--C--CH—N--C--CH CH2 H3C---CH H3C---CH H3C---CH CH2 ch3 ch3 ch3 Structure 829 Structure 830 Structure 832 HA H2N---CH—C---1 N--CH — C--N--CH — C--N CH2 CH--CH3 ch2 C^=O ch2 ch2 CH3 C NH CH — C--X CH3 r5 r6----x6 Structure 833 HA H2N--CH — C--N--CH — C--N--CH — C--N--CH-C--X ch2 ch2 CH--CH3 R5 H2C--C--NH H2 I C^=O CH3 C^=NH X6---R6 HN---NO2 Structure 834 HA H2N--CH — C--N--CH — C--N--CH — C--N--CH C--X ch2 ch2 CH--CH3 R5 H2C--C--NH H2 I r8 C^=O CH3 C^=N--X8 HN---X7--R Structure 835 HN / / 0 CH—C--N I H CH2 H2C—C--NH H2 I c= HN — O CH—C H X7---R7 HN CH-CH—CH3 0 I CH—C---NH CH3 CH2 C^=0 X---T Structure 836 Structure 837 Structure 838 o / / HN--------------------------------------C I 0          0          0 CH-CH-CH, II H II । H, I H I H I ch2            h              ch2 H2C--C--NH        R       C^=0 H2 I / I C^=N--X8        X---T HN---X7---R7 Structure 839 HN CH—CH — CH3 CH — C--N--CH — C--N--CH—C--NH CH3 CH2 CH2 H2C—C--NH H2 I r8 C^O Ri C^=N--X8 X---R---N HA HN---X7---R7 R2 Structure 840 HN O / / c CH—CH—CH3 CH—C N--CH—C--N--CH — C--NH CH3 CH2 CH2 H2C—C NH h2 r8 C^=N--X8 R HA C^=O X---R HN----X7---R7 Structure 841 HA H2N--CH—C--N--CH—C--N--CH—C--N--CH—C--X CH2 CH2 ch2 r5 H2C--C--NH H2 I r8 C^=O x9—r9 C^=N--Xg X6---R6 HN---X7---R7 Structure 842 HA H2N--CH — C--N--CH — C---N--CH — C---N--CH — C--X CH2 CH2 ch2 r5 H2C--C--NH H2 I C^=NH HN---NO2 C^=O X6 — R6 Structure 843 x7—r7 Structure 845 Structure 848 Structure 849 Structure 851 Structure 853 HA H2N--CH — C--N--CH—C--N--CH—C--N--CH—C--X H               H               H CH2 r7       CH3           H             CH—O   R5 O---X7                                         CH3 X6---R6 Structure 854 Structure 856 HN--CH—C--N--CH—C--N--CH—C--N--CH—C--N--CH—C--NH I H I H I CH—CH3 H2C--CH2           H ch3 c^=o nh2 h2c—ch2 c^=o I Xu—Ri 1 h2c—ch2 c^o I xio—Rio 0             0             0             0 X--C--CH—N--C--CH — N--C--CH — N--C--CH I                    I H r5        ch2 h2 I h2c---c—ch2 nh2 ha I H ch2 o^=c I x7—r7 I H I j"! R “<2 0^=C       X9--0 Xs---R8 Structure 857 o             o HA II II 0             0             0 H2N--CH — C--N--CH—C--N--CH — C--N--CH — C--N CH — C--NH I                  H I                  H        I H I                  H I CH — ch3 h2c — ch2         h     h2c — ch2    h2c — ch2 ch3 c^=o                c^=o      c^=o I                                                                                                                                                         I                                                                                I NH2                      Xn—Rn      Xio—Rm R5---X---C--CH — N--C--CH — N--C--CH—N--C--CH H H H ch2 r9 ch2 h2 I h2c---c—ch2 CH2 ch2 nh2 ha 0^=C 0^=C X9--0 x7—r7 x8—r8 Structure 858 Structure 860 Structure 864 Structure 865 Structure 867 o^=o Structure 871 Structure 873 Structure 875 Structure 876 Structure 877 HA Structure 878 Structure 879 HA Structure 881 Structure 882 Structure 883 HA Structure 884 Structure 885 Structure 886 Structure 887 Structure 889 HA Structure 891 Structure 893 Structure 897 Structure 899 Structure 904 Structure 905 Structure 906 Structure 908 Structure 910 Structure 913 Structure 914 Structure 915 Structure 916 Structure 917 HA CH2 CH—CH3 ch3 O            0 II C--CH—N--C--CH H I ch2 H3C--CH CH3 Structure 918 HA CH — C--N--CH — C--N--CH — C--N--CH — C--N--CH — C--N--CH—C--NH ch2 CH—CH3 ch3 o CH2 CH — CH3 ch3 r5----X----c---ch2 Structure 919 HA CH — C--N--CH — C--N--CH — C--N--CH — C--N--CH — C--N--CH — C--NH CH2 CH — CH3 ch3 I H I H I ch2            ch2            ch3 I h2 I      h2 H2C — C — NH    H2c--C NH C^=N-X9 — Rg C^=NH HN---X10 — Rio HN---NO2 H |                  H        | ch2        p I        R6   CH —CH3 CH3 o r5---x---c---CH2 Structure 920 HA Structure 922 Structure 924 Structure 925 Structure 926 Structure 928 Structure 929 Structure 930 Structure 931 Structure 933 Structure 935 Structure 936 Structure 937 Structure 939 Structure 940 Structure 941 Structure 943 Structure 944 Structure 945 Structure 946 Structure 947 Structure 948 Structure 951 HA 5                                              Structure 952 HA NH2 9 II Structure 953 Structure 955 HA NH2 O           O          O           O           O           O             O CH—C--N--CH — C--N--CH—C--N--CH —C--N--CH—C--N--CH —C--N--CH---C |                 H       I                 H       |                H        |                H |                  H       |                 H | CH—O       CH2         CH—CH3     CH2    h2c— ch2         ch—ch3 h2c—ch2 ch3 x5                ch2        s c=o         ch3 c^=o 0--x9 0            0            0           0            0 X14—C--CH — N--C--CH — N--C--CH—N--C--CH—N--C--CH—NH /                 | H               | H              | H               | H              | R14 h2c—ch2 h2c—ch2    h2c—ch2       h2c —ch2       ch2 o^=c o^=c       h2c—ch2     o^=c o=c xio—Rio R11 xn          HA NH2               NH2 R-|3   X13 Structure 956 / Xi3—R-|3 HN 0           0          0           0           0           0             0 I II                              II                            II                             II                             II                             II                                  II CH —C--N--CH — C--N--CH—C--N--CH—C--N--CH—C--N--CH —C--N--CH---C CH—0 CH3 X5 R5 H I H2C-CH2 c=o x7—r7 0 II H I H I CH—CH3 H2C—CH2 ch3 c^=o Rs---X8 X14—C--CH — N--C--CH — N--C--CH —N--C--CH—N--C--CH —NH R14   h2c—ch2 h2c—ch2 h2c—ch2 H2C—ch2 ch2 o^=c o^c H2C—CH2 o^c o=c X10—R10 R11----Xi 1 HA NH2 NH2 R13    X13 Structure 957 0            0            0            0            0            0 II                               II                               II                               II                               II                               II HN--CH — C--N--CH — C--N--CH—C--N--CH — C--N--CH — C--N--CH—C--X5 I       "I       "I       H   I       H   I       H   I       I ch3          ch—ch3      ch—ch3 ch2          ch2          ch2 r5 ch3         ch3         c^=o c^=o       ch—ch3 NH2            Xg--Rg        CH3 Structure 958 HA 0          0          0          0 H2N--CH—C--N--CH—C--N--CH—C--N--CH—C--X5 H                  H |            H CH—0       CH2          CH—CH3      ch2      r5 III    I    I ch3 x7—r7  c^o      ch3        c^o x6—Re                    nh2 Structure 959 Structure 960 HA H2N- O II CH--C---N I H CH O—X6 I                                    I ch3     r6 Structure 966 o II —CH C--X5---R5 I h2c—ch2 ch2 NH I C^=NH HN---NO2 C---N---CH—C--X5--R5 HA H2N- Structure 967 h2c—ch2 ch2 I NH        R7 C^=N--X7 I HN---X8--R8 wherein X is selected from the group consisting of nothing, O, C=O, OC(=O), C(=O)O, OC(=O)OCHRiO, OC(=O)OCHRiS, S, SC(=O), C(=O)S, OC(=O)SCHRiO, SC(=O)OCHRiO, NH, NR6, and NR6-C(=O)O; Xi, X2, X3, X4, X5, X6, X7, X8, X9, X10, Xu, X12, X13, Xi4and Xi5 are independently selected from the group consisting of nothing, O, C=O, OC(=O), C(=O)O, OC(=O)OCHRiO, OC(=O)OCHRiS, S, SC(=O), C(=O)S, OC(=O)SCHRiO, SC(=O)OCHRiO, NH, NR6, NR6-C(=O)O, H, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, CH3CH2CH2CH2j 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, substituted and unsubstituted heteroaryl residues having 1 to 12 carbon atoms; Yi is selected from the group consisting of H, F, Br, Cl, I, CH3, CH30, 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; Y4 is selected from the group consisting of H, F, Br, Cl, I, CH3, CF3, OR?, and CH3O; Y5 is selected from the group consisting of H, CH3CO, C2H5CO, and C3H7CO; 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; HA is a pharmaceutically acceptable acid, and can be selected from the group consisting of hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfic acid, bisulfic acid, 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, bitartaric acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid; R is selected from the group consisting of nothing, 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, cycloalkenyl or cycloalkynyl residues having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyl or heterocycloalkenyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkoxyl 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 groups, and any combination thereof; Examples of R are CH2, CHR5, CHR5CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2; R1, R2, R3, R4, Re, Re , R7, R7’, Rs, Rs, R9, R9 , R1O, Rio , R11, R12, R13, R14, and R15 are independently selected from the group consisting of H, CH3CO, R5CO, CH3CS, R5CS, CH3OCO, R5OCO, CH3OCS, CH3O, CH3S, CH3NH, R5OCS, substituted and unsubstituted alkyl having 1 to 12 carbon atoms, substituted and unsubstituted alkenyl having 1 to 12 carbon atoms, substituted and unsubstituted alkynyl having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl, cycloalkenyl or cycloalkynyl having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyl or heterocycloalkenyl having 1 to 12 carbon atoms, substituted and unsubstituted alkoxyl or alkenoxyl having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyloxyl or cycloalkenyloxyl having 1 to 12 carbon atoms, substituted and unsubstituted aryl having 1 to 12 carbon atoms, substituted and unsubstituted heteroaryl having 1 to 12 carbon atoms, and any combination thereof; R5 is selected from the group consisting of substituted and unsubstituted alkyl having 1 to 12 carbon atoms, substituted and unsubstituted alkenyl having 1 to 12 carbon atoms, substituted and unsubstituted alkynyl having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyl having 1 to 12 carbon atoms, substituted and unsubstituted alkoxyl having 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyloxyl having 1 to 12 carbon atoms, substituted and unsubstituted aryl having 1 to 12 carbon atoms, substituted and unsubstituted heteroaryl having 1 to 12 carbon atoms, and residues thereof; Z represents CH2=C, CH=CH, C=C, CONH, CSNH, COO, OCO, COS, COCH2, or CH2CO; Every hydrogen in parent drugs or transportational units can be replaced with a deuterium without significant changes in pharmaceutical properties, chemical properties and physical properties; T is a transportational unit, for example, selected from the group consisting of protonated amine groups, especially 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 Structure T-l, Structure T-2, Structure T-3, Structure T-4, Structure T-5, Structure T-6, Structure T-7, Structure T-8, Structure T-9, Structure T-10, Structure T-ll, and Structure T-12: Structure T-l Structure T-2 Structure T-3 Structure T-4 Structure T-5 Structure T-6 HA Structure T-10 Structure T-l 1 Structure T-12 wherein Ri and R2 are defined as above; Rn, Ri2, R13, Rm, R15 and Ri6 are selected from the group consisting of nothing, 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, cycloalkenyl or cycloalkynyl residues having 1 to 12 carbon atoms, substituted and unsubstituted heterocycloalkyl or heterocycloalkenyl residues having 1 to 12 carbon atoms, substituted and unsubstituted alkoxyl or alkenoxyl 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, NRe, or any other pharmaceutically acceptable groups, and any combination thereof; every hydrogen in parent drugs or transportational units can be replaced with a deuterium without significant changes in pharmaceutical properties, chemical properties and physical properties. As used herein, the term "pharmaceutically acceptable salt" means those salts of compounds of the invention that are safe for application in a subject. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. 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, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,11 -methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review on pharmaceutically acceptable salts see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), incorporated herein by reference. As a person of skill in the art would understand, the structures defined above encompass only 5 those stable compounds without violation of covalent bond forming principles. IL Methods for improving the stability of the reconstitution solution of the pharmaceutical composition 10 Unexpectedly, it is discovered that, unlike common ester or ammonium compounds, the stability of the HPDs in a solution varies significantly with the pH value, concentration and temperature of the solution, whereas the acid which forms salt with the amine group, and the substituents on the amine group, only have a slight effect on the stability. The results are illustrated in the following. 15 1. Effect of Concentration on the Stability Table 1: Effect of Concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HCl salt with 1 equivalent sodium acetate in 50% ethanol at 25 °C on the stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at day 0 98.1 98.2 98.5 98.6 98.7 98.7 98.6 98.6 98.8 98.6 98.7 98.7 Purity(%) at Day 30 55.5 65.7 91.1 96.8 97.3 97.6 97.7 97.5 97.7 97.5 97.5 97.7 Purity (%) at Day 90 22.2 31.3 77.3 93.2 94.9 95.2 95.2 95.3 95.3 95.1 95.1 95.3 Purity (%) at Day 180 0 9.6 58.6 87.8 90.5 91.7 91.6 91.7 91.8 91.5 91.6 91.8 20   The concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 2: Effect of Concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt with 1 equivalent sodium acetate in 50% ethanol at 25 °C on the stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at day 0 98.1 98.2 98.5 98.6 98.7 98.7 98.6 98.6 98.8 98.6 98.7 98.7 Purity(%) at Day 30 63.6 78.7 93.3 97.5 98.2 98.3 98.3 98.3 98.3 98.4 98.3 98.3 Purity (%) at Day 90 31.2 49.3 81.9 95.4 97.6 97.7 97.6 97.7 97.6 97.8 97.7 97.6 Purity (%) at Day 180 10.3 25.6 68.6 92.2 95.2 95.5 95.4 95.6 95.3 95.7 95.5 95.5 Purity(%) at Day 360 0 5.1 47.9 84.5 91.9 92.3 92.1 92.3 92.0 92.4 92.3 92.2 The concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 3: Effect of Concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HBr salt with 1 equivalent sodium acetate in 50% ethanol at 25 °C on the stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at day 0 98.0 98.1 98.3 98.4 98.5 98.5 98.5 98.5 98.4 98.5 98.5 98.5 Purity(%) at Day 30 63.9 78.9 93.4 97.5 98.2 98.3 98.2 98.3 98.3 98.2 98.2 98.2 Purity (%) at Day 90 33.9 50.3 82.8 95.6 97.9 98.0 97.9 98.0 97.8 97.8 97.8 98.0 Purity (%) at Day 180 12.3 28.6 69.6 93.5 95.8 95.9 95.7 95.9 95.6 95.8 95.8 95.9 Purity(%) at Day 360 0 8.1 49.5 86.3 92.5 93.1 92.3 92.7 92.8 92.6 92.5 92.6 The concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HBr salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 4: Effect of Concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.citric acid salt with 1 equivalent sodium acetate in 50% ethanol at 25 °C on the stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at day 0 98.1 98.2 98.3 98.4 98.5 98.6 98.5 98.6 98.6 98.5 98.5 98.6 Purity(%) at Day 30 63.1 78.5 93.3 97.6 98.1 98.3 98.2 98.3 98.4 98.3 98.3 98.4 Purity (%) at Day 90 31.2 49.9 81.1 95.3 97.7 97.9 97.8 98.0 98.0 98.1 98.0 98.0 Purity (%) at Day 180 11.0 28.2 67.8 93.2 95.3 95.7 95.6 95.9 95.7 95.6 95.5 95.9 Purity(%) at Day 360 0 7.8 47.9 85.6 92.2 92.8 92.7 92.9 92.8 92.7 92.6 92.8 The concentration of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.citric acid salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 5: Effect of Concentration of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HCl salt with 1 5 equivalent sodium acetate in 50% ethanol at 25 °C on the stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at day 0 98.3 98.4 98.5 98.8 98.9 98.9 98.8 98.9 98.8 98.9 98.9 98.8 Purity(%) at Day 30 55.6 65.7 91.3 96.8 97.1 97.5 97.6 97.6 97.6 97.5 97.6 97.5 Purity (%) at Day 90 21.3 30.2 75.9 92.1 94.4 95.0 95.1 95.2 95.0 95.1 95.1 95.2 Purity (%) at Day 180 0 8.6 56.6 85.8 89.7 91.3 91.4 91.5 91.4 91.5 91.7 91.6 The concentration of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 6: Effect of Concentration of 2-(diethylamino)ethyl (A,5)-2-(6-methoxy-2- 10 naphthyl)propionate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 8% 10% 15% 20% Purity (%) at hr 0 98.3 98.6 98.6 98.8 98.9 98.9 98.8 98.8 98.8 Purity (%) at hr 24 91.7 98.4 98.7 98.7 98.8 98.8 98.8 98.8 98.8 Purity (%) at Day 3 79.6 97.9 98.2 98.5 98.7 98.8 98.8 98.8 98.8 Purity (%) at Day 7 73.4 97.2 97.8 98.3 98.5 98.6 98.6 98.7 98.7 Purity(%) at Day 14 68.7 96.1 97.4 97.9 98.2 98.2 98.3 98.3 98.3 Purity(%) at Day 21 64.5 95.4 96.9 97.6 97.7 97.5 97.4 97.5 97.4 Purity(%) at Day 28 61.4 94.1 96.4 97.1 97.5 97.6 97.6 97.6 97.6 Note: in many cases, (7?,>S)-is omitted before racemic chemical name; 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate is same as 2-(diethylamino)ethyl (7?,5)-2-(6-methoxy-2-naphthyl) propionate. The concentration of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. 15 Table 7: Effect of Concentration of 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2-methyl-l / / -indole-3-acetate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 98.0 98.2 98.3 98.4 98.5 98.5 98.6 98.5 98.5 98.6 98.5 98.6 Purity (%) at Day 3 84.2 96.3 97.2 97.8 98.3 98.4 98.4 98.4 98.4 98.4 98.5 98.5 Purity (%) at Day 7 72.9 93.6 96.1 97.2 98.0 98.2 98.3 98.3 98.2 98.5 98.3 98.4 Purity (%) at Day 14 61.3 88.9 94.0 96.0 97.7 98.0 98.0 98.2 98.1 98.2 98.0 98.1 Purity (%) at Day 21 53.4 84.7 92.4 95.0 97.1 97.7 97.8 98.0 98.0 98.1 98.1 97.9 Purity(%) at Day 28 45.5 78.7 91.2 94.1 96.5 97.4 97.4 97.6 97.5 97.7 97.5 97.6 The concentration of 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2-methyl-l / / -indole-3-acetate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. 5 Table 8: The effect of concentration of 2-(diethylamino)ethyl acetylsalicylate.HCl salt on its stability at 5°C in 15% ethanol. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at day 0 99.1 99.2 99.3 99.5 99.5 99.6 99.7 99.6 99.5 99.5 99.5 99.7 Purity (%) at day 3 93.1 95.8 97.6 98.6 99.3 99.4 99.5 99.7 99.5 99.6 99.5 99.6 Purity (%) at day 7 88.2 93.1 96.9 97.7 99.1 99.3 99.3 99.4 99.3 99.3 99.4 99.5 Purity (%) at day 14 81.4 89.5 95.2 96.4 98.9 99.1 99.3 99.1 99.2 99.2 99.4 99.3 Purity (%) at day 21 74.9 86.6 93.7 94.5 98.5 98.9 98.8 98.7 98.9 99.0 99.0 99.2 Purity (%) at day 28 68.3 83.7 91.5 92.7 98.0 98.7 98.6 98.7 98.7 98.8 98.9 99.0 Purity (%) at day 60 47.1 71.8 82.7 86.1 96.7 98.0 98.0 98.3 98.1 98.1 98.2 98.2 Purity (%) at day 90 30.1 59.9 74.1 80.2 96.1 97.2 97.4 97.2 97.3 97.3 97.4 97.4 The concentration of 2-(diethylamino)ethyl acetylsalicylate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. 10 Table 9: The effect of concentration of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HCl salt on its stability at 5°C in 15% acetone. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at day 0 98.2 98.3 98.4 98.5 98.6 98.7 98.6 98.7 98.6 98.7 98.5 98.7 Purity (%) at day 3 93.9 95.1 97.0 97.7 98.2 98.4 98.5 98.5 98.4 98.5 98.5 98.7 Purity (%) at day 7 88.1 93.1 95.9 96.6 97.8 98.4 98.3 98.5 98.4 98.5 98.4 98.5 Purity (%) at day 15 80.3 89.0 94.0 94.9 97.3 98.0 98.1 98.2 98.3 98.3 98.1 98.3 Purity (%) at day 22 73.7 85.3 92.2 92.1 96.1 97.5 97.4 97.7 97.5 98.0 97.9 97.8 Purity (%) at day 28 67.9 82.3 89.7 91.2 95.5 97.2 97.1 97.3 97.2 97.1 97.3 97.2 Purity (%) at day 60 48.1 70.5 79.4 84.4 94.5 96.2 96.0 96.7 96.5 96.6 96.7 96.9 Purity (%) at day 90 30.0 61.2 71.9 79.2 93.9 95.8 95.9 96.1 96.2 96.0 96.2 96.3 The concentration of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 10: Effect of Concentration of 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2- 5 methyl-lJT-indole-3-acetate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 98.0 98.2 98.3 98.4 98.5 98.5 98.6 98.5 98.5 98.6 98.5 98.6 Purity (%) at Day 3 84.2 96.3 97.2 97.8 98.3 98.4 98.4 98.4 98.4 98.4 98.5 98.5 Purity (%) at Day 7 72.9 93.6 96.1 97.2 98.0 98.2 98.3 98.3 98.2 98.5 98.3 98.4 Purity (%) at Day 14 61.3 88.9 94.0 96.0 97.7 98.0 98.0 98.2 98.1 98.2 98.0 98.1 Purity (%) at Day 21 53.4 84.7 92.4 95.0 97.1 97.7 97.8 98.0 98.0 98.1 98.1 97.9 Purity(%) at Day 28 45.5 78.7 91.2 94.1 96.5 97.4 97.4 97.6 97.5 97.7 97.5 97.6 The concentration of 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2-methyl-l / / -indole-3-acetate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. 10 Table 11: Effect of Concentration of 2-(diethylamino)ethyl 5-fluoro-2-methyl-l-[[4- (methylsulfinyl)phenyl]methylene]-l / / -indene-3-acetate.HCl salt, in water at 25°C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.1 97.2 97.3 97.3 97.5 97.6 97.5 97.5 97.6 97.6 97.7 97.7 Purity (%) at Day 3 82.3 95.7 96.2 96.7 97.3 97.4 97.4 97.5 97.4 97.4 97.5 97.5 Purity (%) at Day 7 71.2 93.6 95.2 96.3 97.1 97.3 97.2 97.3 97.4 97.6 97.5 97.5 Purity (%) at Day 14 59.4 89.8 93.1 95.0 96.7 97.1 96.9 97.0 97.1 97.2 97.3 97.2 Purity (%) at Day 21 50.4 84.4 91.5 94.1 96.2 96.6 96.8 97.0 97.1 97.1 97.0 96.8 Purity(%) at Day 28 43.7 78.9 90.1 93.1 95.4 96.4 96.5 96.7 96.8 96.8 96.7 96.8 The concentration of 2-(diethylamino)ethyl 5-fluoro-2-methyl-l-[[4-(methylsulfinyl)phenyl]methylene]-l / Z-indene-3-acetate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. 5 Table 12: Effect of Concentration of 2-(diethylamino)ethyl 1 -methyl-5-(4-methylbenzoyl)-lH- pyrrole-2-acetate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.4 97.5 97.7 97.9 97.9 98.1 98.1 98.2 98.1 98.0 98.1 98.2 Purity (%) at Day 3 82.3 95.6 95.7 96.5 97.2 97.5 97.7 97.9 97.7 97.6 97.7 97.8 Purity (%) at Day 7 72.2 93.3 94.6 96.2 97.0 97.2 97.3 97.5 97.6 97.5 97.5 97.5 Purity (%) at Day 14 57.4 88.3 92.3 94.8 96.8 97.2 96.9 97.3 97.4 97.2 97.3 97.2 Purity (%) at Day 21 45.4 83.5 90.1 94.0 95.6 96.7 96.9 97.1 97.1 97.1 97.0 96.9 Purity(%) at Day 28 35.7 78.1 88.6 92.7 94.4 96.5 96.6 96.5 96.8 96.8 96.7 96.8 The concentration of 2-(diethylamino)ethyl l-methyl-5-(4-methylbenzoyl)-l / / -pyrrole-2-acetate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. 10 Table 13: Effect of Concentration of 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-l,4-dimethyl- l / / -pyrrole-2-acetate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.5 97.5 97.7 97.9 98.0 98.2 98.1 98.2 98.1 98.0 98.1 98.1 Purity (%) at Day 3 85.3 95.3 95.6 96.5 97.2 97.7 97.7 97.8 97.7 97.6 97.8 97.7 Purity (%) at Day 7 72.9 93.3 94.2 96.3 97.0 97.2 97.3 97.4 97.7 97.5 97.5 97.5 Purity (%) at Day 14 60.1 88.5 92.5 94.7 96.5 97.2 97.0 97.3 97.6 97.2 97.3 97.2 Purity (%) at Day 21 47.4 83.2 90.7 93.8 95.2 96.8 96.9 97.2 97.3 97.3 97.1 97.2 Purity(%) at Day 28 37.7 77.6 88.1 92.5 94.7 96.6 96.5 96.7 96.6 96.8 96.9 96.8 The concentration of 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-l,4-dimethyl-l / / -pyrrole-2-acetate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 14: Effect of Concentration of 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.7 97.9 98.1 98.3 98.4 98.5 98.4 98.5 98.5 98.4 98.5 98.5 Purity (%) at Day 3 84.7 96.7 97.0 97.7 98.2 98.4 98.4 98.4 98.4 98.4 98.4 98.5 Purity (%) at Day 7 73.9 95.5 96.0 97.0 98.0 98.2 98.3 98.3 98.2 98.2 98.3 98.3 Purity (%) at Day 14 62.3 91.1 94.0 96.0 97.6 98.0 98.0 98.2 98.1 98.2 98.1 98.1 Purity (%) at Day 21 53.9 87.2 92.3 94.8 97.0 97.8 97.9 98.0 98.0 98.1 98.1 97.8 Purity(%) at Day 28 45.9 83.8 90.9 93.8 96.3 97.4 97.5 97.5 97.6 97.5 97.5 97.6 The concentration of 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate.HCl salt affects 5 the stability, and it is not stable when the concentration is 0.1% or lower. Table 15: Effect of Concentration of 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 98.4 98.5 98.7 98.9 98.9 99.1 99.1 99.2 99.1 99.0 99.1 99.1 Purity (%) at Day 3 83.4 96.7 96.6 96.5 98.4 98.6 98.7 98.8 98.7 98.8 98.7 98.8 Purity (%) at Day 7 74.2 95.6 95.5 96.2 98.0 98.2 98.3 98.5 98.6 98.5 98.5 98.5 Purity (%) at Day 14 58.4 91.5 92.9 94.8 97.8 98.2 97.9 98.3 98.4 98.2 98.3 98.2 Purity (%) at Day 21 46.5 84.7 90.9 94.0 96.6 97.7 97.9 98.1 98.1 98.1 98.0 98.9 Purity(%) at Day 28 37.5 80.5 89.1 92.7 95.4 97.5 97.6 97.5 97.8 97.7 97.8 97.8 The concentration of 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl 10 salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 16: Effect of Concentration of 2-(diethylamino)ethyl [(1 -benzyl-UT-indazol-3-yl)oxy]acetate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.4 97.5 97.7 97.9 97.9 98.1 98.1 98.2 98.1 98.0 98.1 98.2 Purity (%) at Day 3 83.8 95.7 95.6 95.5 97.4 97.6 97.7 97.8 97.7 97.8 97.7 97.8 Purity (%) at Day 7 73.2 94.6 94.5 95.2 97.0 97.2 97.3 97.5 97.6 97.5 97.5 97.5 Purity (%) at Day 14 58.4 88.5 91.9 93.8 96.8 97.2 96.9 97.3 97.4 97.2 97.3 97.2 Purity (%) at Day 21 45.5 82.7 90.1 93.0 95.6 96.7 96.9 97.1 97.1 97.1 97.0 96.9 Purity(%) at Day 28 36.7 79.5 88.1 91.7 94.4 96.5 96.6 96.5 96.8 96.7 96.8 96.7 The concentration of 2-(diethylamino)ethyl [(l-benzyl-l / / -indazol-3-yl)oxy]acetate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 17: Effect of Concentration of 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5- 5 benzoxazole]propionate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.8 97.9 98.1 98.3 98.5 98.6 98.6 98.5 98.6 98.5 98.6 98.5 Purity (%) at Day 3 84.7 96.7 97.0 97.5 98.0 98.4 98.5 98.4 98.5 98.4 98.5 98.5 Purity (%) at Day 7 73.9 95.5 96.0 97.0 97.9 98.2 98.3 98.3 98.3 98.3 98.3 98.3 Purity (%) at Day 14 62.3 91.1 94.0 95.7 97.6 98.0 98.1 98.2 98.1 98.2 98.0 98.0 Purity (%) at Day 21 52.9 87.2 92.3 94.3 97.0 97.8 97.8 97.7 97.7 97.8 97.7 97.9 Purity(%) at Day 28 42.9 83.0 89.9 92.8 96.3 97.4 97.4 97.3 97.5 97.4 97.3 97.5 The concentration of 2-(diethylamino)ethyl 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. 10 Table 18: Effect of Concentration of 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazolepropionate.HC1 salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.8 97.9 98.0 98.4 98.5 98.8 98.7 98.8 98.8 98.7 98.8 98.8 Purity (%) at Day 3 83.8 94.7 95.3 96.3 98.2 98.6 98.7 98.6 98.7 98.7 98.7 98.7 Purity (%) at Day 7 73.9 90.6 92.9 95.1 97.8 98.2 98.3 98.5 98.4 98.5 98.5 98.5 Purity (%) at Day 14 58.9 83.5 88.9 92.5 97.0 98.0 97.9 98.2 98.1 98.2 98.3 98.2 Purity (%) at Day 21 47.6 75.7 84.6 89.0 96.3 97.7 97.7 97.8 97.9 97.8 97.9 97.8 Purity (%) at Day 28 38.9 65.5 79.2 85.7 95.0 97.4 97.5 97.4 97.5 97.5 97.6 97.5 The concentration of 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazolepropionate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 19: Effect of Concentration of 2-(diethylamino)ethyl 4-[bis(2- 5 chloroethyl)amino]benzenebutyrate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.8 97.9 98.2 98.4 98.5 98.5 98.5 98.6 98.6 98.6 98.5 98.6 Purity (%) at Day 3 83.1 94.1 95.1 96.2 98.2 98.4 98. 98.5 98.5 98.4 98.4 98.4 Purity (%) at Day 7 72.9 89.6 91.9 95.0 97.8 98.2 98.3 98.3 98.4 98.3 98.4 98.3 Purity(%) at Day 14 56.9 81.5 85.9 91.0 97.0 98.0 97.9 98.2 98.1 98.2 98.3 98.2 Purity(%) at Day 21 43.2 73.7 81.9 87.3 96.3 97.6 97.7 97.7 97.7 97.8 97.7 97.8 Purity(%) at Day 28 34.3 62.5 76.9 83.7 95.0 97.4 97.3 97.4 97.3 97.3 97.4 97.4 The concentration of 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. Table 20: Effect of Concentration of 2-(diethylamino)ethyl 4-[bis(2- 10 methylsulfonylethyl)amino]benzenebutyrate.HCl salt, in water at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 7% 8% 10% 15% 20% 30% 50% Purity (%) at hr 0 97.6 97.7 98.0 98.1 98.2 98.4 98.3 98.4 98.4 98.4 98.5 98.4 Purity (%) at Day 3 83.4 93.7 95.1 96.0 97.8 98.3 98.2 98.3 98.4 98.4 98.4 98.3 Purity (%) at Day 7 73.2 88.3 90.8 94.3 97.2 98.1 98.2 98.3 98.2 98.3 98.2 98.2 Purity(%) at Day 14 55.2 80.6 85.1 89.7 95.3 98.0 98.1 98.0 98.1 98.2 98.1 98.2 Purity(%) at Day 21 43.1 71.5 80.3 84.8 93.0 97.5 97.6 97.5 97.7 97.6 97.8 97.7 Purity(%) at Day 28 32.0 60.7 73.8 80.6 90.3 97.0 97.0 97.1 97.2 97.2 97.3 97.3 The concentration of 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate.HCl salt affects the stability, and it is not stable when the concentration is 0.1% or lower. It can be seen that the concentration of HPD affects the stability of pharmaceutical composition significantly. Less than 1% by weight of HPD in aqueous solution is not stable, whereas 1% by weight or a higher concentration of the HPD is desirable. Advantageously, the concentration of the HPD in the composition may be 1-30% by weight, preferably 1-20% by weight, more 5 preferably 3-15%, and most preferably 5-10%. The substituent groups and the type of the salt have shown little effect on the stability. In contrast, the concentration of common esters does not affect the stability significantly. Table 21: Effect of Concentration of ethyl benzoate in 50% ethanol at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 10% Purity (%) at hr 0 97.8 97.9 98.0 97.9 98.0 97.9 Purity (%) at hr 24 97.6 97.7 97.8 97.8 97.8 97.8 Purity (%) at Day 3 97.4 97.6 97.7 97.8 97.8 97.8 Purity (%) at Day 7 96.9 97.5 97.6 97.7 97.7 97.8 Purity(%) at Day 14 96.1 97.2 97.5 97.6 97.6 97.7 Purity(%) at Day 28 95.3 95.9 97.3 97.5 97.6 97.6 10 Ethyl benzoate is very stable at 0.01% to 10% or a higher concentration. The concentration affects the stability slightly. Table 22: Effect of Concentration of isopropyl benzoate in 50% ethanol at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 10% Purity (%) at hr 0 98.4 98.4 98.5 98.4 98.5 98.5 Purity (%) at hr 24 98.3 98.5 98.4 98.6 98.4 98.8 Purity (%) at Day 3 98.1 98.4 98.5 98.4 98.7 98.4 Purity (%) at Day 7 98.3 98.4 98.4 98.4 98.4 98.4 Purity (%) at Day 14 98.2 98.3 98.3 98.4 98.4 98.4 Purity(%) at Day 28 98.2 98.3 98.3 98.4 98.4 98.4 Isopropyl benzoate is very stable at 0.01% to 10% or a higher concentration and more stable than 15 ethyl benzoate. The concentration does not affect the stability. Table 23: Effect of Concentration of t-butyl benzoate (a normal ester) in 50% ethanol at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 10% Purity (%) at hr 0 97.5 97.4 97.5 97.4 97.4 97.8 Purity (%) at hr 2 25.2 31.2 41.3 52.3 56.3 65.5 Purity (%) at hr 24 0.0 0.0 1.6 15.4 20.3 25.1 Purity (%) at Day 3 0.0 0.0 0.0 1.1 3.6 5.1 Purity(%) at Day 7 0.0 0.0 0.0 0.0 0.0 0.0 Purity (%) at Day 14 0.0 0.0 0.0 0.0 0.0 0.0 t-Butyl benzoate is very unstable at any concentration and much less stable than ethyl benzoate 5 and isopropyl benzoate. Table 24: Effect of Concentration of isopropyl 2-amino-3-phenylpropanoate in 50% ethanol at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 10% Purity (%) at hr 0 98.4 98.5 98.7 98.7 98.7 98.8 Purity (%) at hr 24 98.3 98.4 98.5 98.6 98.6 98.7 Purity (%) at Day 3 97.4 97.6 97.9 98.2 98.5 98.6 Purity (%) at Day 7 97.1 97.3 97.6 97.8 98.4 98.5 Purity (%) at Day 14 96.5 96.8 97.2 97.4 98.2 98.3 Purity (%) at Day 21 95.9 96.5 96.8 97.0 97.8 97.9 Purity(%) at Day 28 95.1 95.7 96.1 96.5 97.1 97.3 Isopropyl 2-amino-3-phenylpropanoate is quite stable at 0.01% to 10% and much more stable 10 than ethyl 2-amino-3-phenylpropanoate, perhaps because isopropyl group is more sterically hindered than ethyl group. Table 25: Effect of Concentration of t-butyl 2-amino-3-phenylpropanoate in 50% ethanol at 25 °C on stability. Concentration (wt%) 0.01% 0.1% 1% 3% 5% 10% Purity (%) at hr 0 98.0 98.0 98.1 98.2 98.1 98.2 Purity (%) at hr 24 96.1 96.4 96.7 96.9 97.0 97.6 Purity (%) at Day 3 92.1 93.1 93.9 94.6 94.8 95.9 Purity (%) at Day 7 89.4 91.4 92.2 92.4 93.1 93.9 Purity(%) at Day 14 83.0 86.1 88.9 89.5 90.0 91.0 Purity(%) at Day 21 60.2 64.1 70.9 72.4 73.0 74.9 Purity(%) at Day 28 35.2 41.0 48.9 50.4 56.9 59.2 t-Butyl 2-amino-3-phenylpropanoate is not stable at 0.01% to 10%. 2. Effect of pH value on the Stability 5 Table 26: Stabilities of 5% solution of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt in 25% ethanol at different pH for 30 days at 25°C. 25% ethanol with HC1 pH 1.0 25% ethanol with HC1 pH 2.0 25% ethanol (after multiple recrystalization pH 3.7 25% ethanol pH 3.0 25% ethanol with 0.5 equivalent sodium acetate pH 3.7 25% ethanol with 1 equivalent sodium acetate pH 4.6 25% ethanol with 1.5 equivalent sodium acetate pH 5.6 25% ethanol with NaOH pH 7 25% ethanol with NaOH pH 8 Purity(%) at day 1 98.3±0.2 98.4±0.2 98.6±0.2 98.5±0.1 98.6±0.2 98.6±0.2 98.5±0.2 98.3±0.3 98.0±0.3 Purity(%) at day 30 85.0±0.2 91.7±0.2 98.1±0.2 97.4±0.2 98.2±0.1 98.2±0.2 97.0±0.2 78.1±0.4 56.3±0.3 Purity(%) at day 90 59.5±0.2 84.7±0.3 97.2±0.1 94.7±0.1 97.1±0.2 97.0±0.1 93.8±0.1 44.1±0.4 32.3±0.4 Purity(%) at day 180 43.5±0.3 71.7±0.3 95.4±0.1 90.7±0.2 95.6±0.2 95.6±0.2 88.1±0.2 25.1±0.4 3.9±0.4 Purity(%) at day 360 17.6±0.3 52.7±0.3 92.1±0.2 82.7±0.3 92.0±0.2 92.1±0.2 80.1±0.3 0 0 The solution of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt is only stable at pH 3-6 and can be stored for about 1 year at room temperature. Table 27: Stabilities of 5% solution of H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2.HC1 salt in 25% ethanol at different pH for 30 days at 25°C. 25% ethanol with HC1 pH 2.0 25% ethanol (after multiple recry stalizations pH 3.7 25% ethanol pH 3.0 25% ethanol with 0.5 equivalent sodium acetate pH 3.7 25% ethanol with 1 equivalent sodium acetate pH 4.6 25% ethanol with 1.5 equivalent sodium acetate pH 5.6 25% ethanol with NaOH pH 7 25% ethanol with NaOH pH 8 Purity (%) at day 1 98.7±0.1 98.9±0.2 98.8±0.2 98.9±0.1 98.9±0.2 98.8±0.2 98.6±0.3 98.4±0.3 Purity (%) at day 30 91.2±0.2 97.6±0.2 97.H0.2 97.9±0.1 97.8±0.2 97.0±0.2 77.0±0.2 52.3±0.2 Purity (%) at day 90 83.9±0.2 96.9±0.1 94.H0.1 96.9±0.2 97.0±0.1 93.4±0.1 41.1±0.3 29.3±0.3 Purity (%) at day 180 69.8±0.2 95.0±0.1 89.3±0.2 95.0±0.2 95.0±0.2 86.9±0.2 21.1±0.3 2.9±0.3 Purity (%) at day 360 48.7±0.3 91.9±0.2 81.3±0.3 92.2±0.2 92.0±0.2 79.8±0.3 0 0 The solution of H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2.HCl salt is stable at pH 3-6 and can be stored for about 1 year at room temperature. Table 28: Stabilities of 5% solution of H-Tyr-Gly-Gly-Phe-Leu-OCH2CH3.HC1 salt in 25% ethanol at different pH for 30 days at 25°C. 25% ethanol with HC1 pH 1.0 25% ethanol with HC1 pH 2.0 25% ethanol (after multiple recry stalization pH 3.7 25% ethanol pH 3.0 25% ethanol with 0.5 equivalent sodium acetate pH 3.7 25% ethanol with 1 equivalent sodium acetate pH 4.6 25% ethanol with 1.5 equivalent sodium acetate pH 5.6 25% ethanol with NaOH pH 7 25% ethanol with NaOH pH 8 Purity(%) at day 1 98.3±0.2 98.4±0.2 98.5±0.1 98.4±0.1 98.5±0.1 98.5±0.1 98.5±0.2 98.2±0.3 98.2±0.2 Purity(%) at day 30 68.3±0.1 85.6±0.2 97.8±0.2 96.1±0.2 97.7±0.2 97.7±0.2 95.2±0.2 57.3±0.3 25.1±0.3 Purity(%) at day 90 37.3±0.2 71.9±0.2 95.4±0.3 93.3±0.3 95.3±0.2 95.3±0.3 92.3±0.3 33.9±0.4 0 Purity(%) at day 180 14.5±0.2 44.5±0.3 91.9±0.2 86.9±0.2 91.8±0.3 91.7±0.3 85.1±0.3 0 0 The solution of H-Tyr-Gly-Gly-Phe-Leu-OCH2CH3.HC1 salt is stable only at pH 3-6 and can be stored for only about 3 months at room temperature. Table 29: Stabilities of 5% solution of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HCl salt in 25% 5 ethanol at different pH for 30 days at 25°C. 25% ethanol with HC1 pH 2.0 25% ethanol (after multiple recry stali zation pH 3.7 25% ethanol pH 3.0 25% ethanol with 0.5 equivalent sodium acetate pH 3.7 25% ethanol with 1 equivalent sodium acetate pH 4.6 25% ethanol with 1.5 equivalent sodium acetate pH 5.6 25% ethanol with NaOH pH 7 25% ethanol with NaOH pH 8 Purity (%) at day 1 97.8±0.1 98.1±0.2 98.H0.2 98.2±0.1 98.2±0.2 98.1±0.2 97.9±0.2 97.5±0.1 Purity (%) at day 30 84.2±0.2 97.3±0.2 95.7±0.3 97.4±0.2 97.3±0.2 94.7±0.2 55.2±0.3 22.6±0.2 Purity (%) at day 90 69.6±0.2 95.0±0.1 92.8±0.3 95.1±0.3 95.0±0.3 91.5±0.3 31.3±0.3 0 Purity (%) at day 180 39.9±0.3 91.2±0.3 86.0±0.3 91.2±0.3 91.H0.3 83.7±0.3 0 0 The solution of H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HCl salt is stable only at pH 3-6 and can be stored for only about 3 months at room temperature. Table 30: Stabilities of 5% solution of H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HC1 salt in 25% 10 ethanol at different pH for 30 days at 25°C. 25% ethanol with HC1 pH 2.0 25% ethanol (after multiple recry stali zation pH 3.7 25% ethanol pH 3.0 25% ethanol with 0.5 equivalent sodium acetate pH 3.7 25% ethanol with 1 equivalent sodium acetate pH 4.6 25% ethanol with 1.5 equivalent sodium acetate pH 5.6 25% ethanol with NaOH pH 7 25% ethanol with NaOH pH 8 Purity (%) at day 1 98.5±0.1 98.9±0.2 98.7±0.2 98.9±0.1 98.9±0.2 98.8±0.2 98.5±0.3 98.2±0.2 Purity (%) at day 30 92. l±0.2 98.3±0.2 97.9±0.2 98.4±0.1 98.4±0.2 97.2±0.2 77.9±0.2 56.2±0.2 Purity (%) at day 90 85.1±0.2 97.2±0.1 95.H0.1 97.3±0.2 97.4±0.2 94.1±0.1 43.6±0.2 33.3±0.3 Purity (%) at day 180 71.9±0.2 95.4±0.1 90.9±0.2 95.5±0.2 95.5±0.2 88.7±0.2 24.3±0.3 5.8±0.3 Purity (%) at day 360 51.8±0.2 92.3±0.2 82.8±0.3 92.5±0.2 92.4±0.2 81.1±0.3 0 0 The solution of H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HC1 salt is only stable at pH 3-6 and can be stored for about 1 year at room temperature. The results show that the reconstitution solution is stable only at pH 3-6, preferably at pH 3-5, 5 more preferably at pH 3.5-4.5. The pH of the solution can be adjusted with any acid or base, such as HC1 or NaOH, preferably with weak base. The pH adjusting and buffering agent can be sodium, potassium, calcium, lithium, or magnesium salt of an organic acid, for example, 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. 10 Table 31: Stabilities of 7% solution of 2-(diethylamino)ethyl (2?,5)-2-(6-methoxy-2-naphthyl) propionate.HCl salt (C-l), 2-(diethylamino)ethyl (2?,5)-2-(6-methoxy-2-naphthyl) propionate.HBr salt (C-2), and 2-(diethylamino)ethyl (2?,5)-2-(6-methoxy-2-naphthyl) propionate.citric acid salt (C-3) at various pH values in water (pH was adjusted with 3N HC1 or 15 3N NaOH) at 25°C for 28 days. PH solvent Purity(%) from day 0-28 (C-l) Purity(%) from day 0-28 (C-2) Purity(%) from day 0-28 (C-3) 1.0 water 98.5±0.3—>68.9±0.3 98.3±0.3^69.7±0.3 98.0±0.3—>68.2±0.4 2.0 water 98.6±0.2—>80.9±0.4 98.5±0.3—>80.1 ±0.3 98.2±0.4—>80.1±0.3 3.0 water 98.6±0.2—>90.3±0.3 98.6±0.4^90.7±0.3 98.2±0.2—>90.3±0.3 3.7 water 98.8±0.3—>97.2±0.2 98.6±0.3—>97.1 ±0.3 98.3±0.4—>96.8±0.2 4.0 water 98.8±0.2—>97.8±0.2 98.7±0.4^97.7±0.2 98.4±0.3—>97.1 ±0.2 4.3 water 98.8±0.3—>97.9±0.2 98.8±0.2^97.8±0.2 98.3±0.4—>97.1±0.3 4.6 water 98.8 ±0.2—>97.9±0.1 98.7±0.3^97.8±0.2 98.3±0.2—>97.0±0.3 5.0 water 98.7±0.3^96.3±0.2 98.7±0.2^96.5±0.3 98.1±0.3—>96.0±0.3 6.0 water 98.6±0.2^89.9±0.3 98.7±0.3^89.0±0.4 98.1±0.3—>88.4±0.3 7.0 water 98.5±0.3^65.8±0.3 98.6±0.3^65.5±0.3 98.0±0.3—>55.8±0.4 8.0 water 98.3±0.3—>45.8±0.4 98.5±0.3—>45.5±0.5 98.0±0.2—>35.8±0.5 The results show that only pH values, but not the acid, such as HC1, HBr or citric acid, which formed the salt with 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate, affect the stability of the 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate salt significantly. 5 Table 32: Stabilities of 7% of 2-(diethylamino)ethyl (K<S)-2-(p-isobutylphenyl)propionate.HCl salt (C-4), 2-(dimethylamino)ethyl (R,Ay2-(p-isobutylphenyl)propionate.HCl salt (C-5), and 2-(dibutylamino)ethyl (R,Ay2-(p-isobutylphenyl)propionate.HCl salt (C-6) at various pH values in 25% ethanol (pH was adjusted with 3N HC1 or 3N NaOH) at 25°C for 28 days. PH solvent Purity(%) from day 0-28 (C-4) Purity(%) from day 0-28 (C-5) Purity(%) from day 0-28 (C-6) 1.0 25% ethanol 98.2±0.3—>69.1±0.2 98.0±0.3—>65.3±0.3 97.9±0.3^68.4±0.3 2.0 25% ethanol 98.3±0.3—>80.8±0.4 98.2±0.4—>77.4±0.3 98.0±0.3—>79.2±0.4 3.0 25% ethanol 98.5±0.2—>92.5±0.3 98.3±0.3—>88.4±0.2 98.2±0.4—>91.2±0.3 3.7 25% ethanol 98.6±0.3—>97.2±0.4 98.5±0.4—>95.7±0.3 98.3±0.3—>96.9±0.2 4.0 25% ethanol 98.6±0.2—>97.8±0.3 98.5±0.3—>96.6±0.4 98.4±0.3—>97.3±0.2 4.3 25% ethanol 98.7±0.3—>97.7±0.2 98.6±0.3—>96.8±0.3 98.4±0.3—>97.3±0.3 4.6 25% ethanol 98.6±0.2^97.3±0.3 98.5±0.2—>96.8±0.2 98.3±0.3^97.1±0.3 5.0 25% ethanol 98.5±0.3^94.3±0.2 98.5±0.3—>93.1±0.4 98.3±0.3^94.5±0.3 6.0 25% ethanol 98.4±0.3^89.9±0.3 98.4±0.3—>85.3±0.2 98.2±0.4^89.2±0.4 7.0 25% ethanol 98.2±0.3^52.8±0.4 98.2±0.3—>47.1±0.3 98.0±0.3^51.5±0.3 8.0 25% ethanol 98.0±0.4^35.3±0.3 98.0±0.3—>34.9±0.5 97.8±0.4—>35.1±0.3 The results show that the size of Ri, R2 and R on the amino group does not affect the stability of 10 aminoalkyl (R,5)-2-( / ?-isobutylphenyl)propionate significantly. Table 33: Stabilities of 7% of 2-pyrrolidinemethyl (2?,5)-2-( / ?-isobutylphenyl)propionate.HCl salt (C-7), 4-piperidineethyl (7?,5)-2-( / ?-isobutylphenyl)propionate.HCl salt (C-8), 1-pyrrolidineethyl (R,5)-2-( / >-isobutylphenyl)propionate.HCl salt (C-9), and 1-piperidineethyl (R,S)-2-(p- 15 isobutylphenyljpropionate.HCl salt (C-10) at various pH values and temperature in 25% ethanol (pH was adjusted with 3N HC1 or 3N NaOH) at 25°C for 28 days. PH solvent Purity(%) from day Purity(%) from day Purity(%) from day Purity(%) from day 0-28 (C-7) 0-28 (C-8) 0-28 (C-9) 0-28 (C-10) 1.0 25% ethanol 97.8X0.4—>66.8X0.3 97.6X0.4—>68.4X0.4 98.0X0.3—>68.3X0.2 97.6X0.3^68.1X0.3 2.0 25% ethanol 98.1X0.3—>86.0X0.4 98.0X0.3—>87.3X0.3 98.2X0.4—>87.7X0.3 97.9X0.4^-87.0X0.3 3.0 25% ethanol 98.3X0.3—>86.0X0.3 98.1X0.2—>87.3X0.3 98.5X0.3—>87.7X0.2 98.0X0.3^-87.0X0.2 3.7 25% ethanol 98.5X0.2—>94.3X0.3 98.3X0.3—>95.0X0.2 98.6X0.4—>95.5X0.3 98.2X0.3—>95.1X0.3 4.0 25% ethanol 98.6X0.3—>95.8X0.3 98.4X0.3—>96.1X0.3 98.6X0.3—>96.3X0.3 98.2X0.2^-95.8X0.3 4.3 25% ethanol 98.5X0.3—>96.5X0.4 98.4X0.2—>96.3X0.3 98.7X0.2—>96.4X0.2 98.3X0.3^-95.9X0.2 4.6 25% ethanol 98.5X0.2—>96.2X0.3 98.3X0.2—>96.3X0.2 98.6X0.3—>96.4X0.3 98.2X0.4^-95.8X0.3 5.0 25% ethanol 98.4X0.3—>89.3X0.2 98.3X0.4—>89.7X0.3 98.5X0.4—>88.6X0.3 98.2X0.3^-88.5X0.4 6.0 25% ethanol 98.4X0.4—>86.2X0.3 98.2X0.3—>87.3X0.3 98.4X0.5—>89.0X0.4 98.1X0.3^-87.9X0.3 7.0 25% ethanol 98.2X0.3—>48.0X0.3 97.9X0.3—>48.3X0.4 98.1X0.5—>48.1X0.3 97.8X0.3^47.8X0.3 8.0 25% ethanol 97.7X0.3—>34.3X0.4 97.6X0.5—>34.2X0.3 97.9X0.5—>34.4X0.4 97.5X0.5^34.1X0.4 The results show that the size of Ri, R2 and R on the amino group does not affect the stability of aminoalkyl (2?,5)-2-( / ?-isobutylphenyl)propionate significantly. Table 34: Stabilities of 7% of 2-(diethylamino)ethyl acetylsalicylate.maleic acid salt (A-l), 2 5 (diethylamino)ethyl acetylsalicylate.benzoic acid salt (A-2), 2-(diethylamino)ethyl acetylsalicylate.lactic acid salt (A-3), and 2-(diethylamino)ethyl acetylsalicylate.valeric acid (A-4) salt at various pH values in water (pH was adjusted with 3N HC1 or 3N NaOH) at 25°C for 14 days. PH solvent Purity(%) from day 014 (A-l) Purity(%) from day 014 (A-2) Purity(%) from day 014 (A-3) Purity (%) from day 0-14 (A-4) 1.0 water 98.1X0.3—>59.1±0.4 98.2X0.2—60.5X0.3 97.8X0.3—57.9X0.4 97.8X0.2—>58.1X0.3 2.0 water 98.2X0.3—>78.8X0.3 98.4X0.2—79.7X0.4 98.0X0.2—>77.0X0.4 98.1X0.2—>77.3X0.2 3.0 water 98.4X0.1—>90.9X0.2 98.5X0.1—>91.0X0.2 98.2X0.1—>88.7X0.2 98.3X0.1—>87.5X0.3 3.7 water 98.5X0.1—>94.0X0.3 98.6X0.1—94.1X0.2 98.2X0.2—>93.1X0.3 98.4X0.1—>93.2X0.3 4.0 water 98.6X0.1—>94.5X0.2 98.6X0.2—95.0X0.3 98.3X0.1—>94.1X0.4 98.4X0.2—>94.2X0.4 4.3 water 98.5X0.2—>94.6X0.3 98.7X0.2—95.0X0.4 98.2X0.1—>94.4X0.2 98.5X0.1—>94.7X0.2 4.6 water 98.5±0.3^94.3±0.2 98.6X0.3—94.4X0.3 98.2X0.3^94.1X0.2 98.4X0.3^94.0X0.2 5.0 water 98.4X0.1—86.9X0.3 98.5X0.2^87.3X0.2 98.2X0.2^85.6X0.4 98.3X0.2^85.5X0.4 6.0 water 98.3X0.2—78.9X0.3 98.4X0.3—78.3X0.3 98.0X0.1^78.3X0.3 98.2X0.2^77.3X0.3 7.0 water 98.2X0.2—57.8X0.4 98.2X0.2^56.0X0.4 98.0X0.2—55.1X0.3 98.0X0.3^52.5X0.4 8.0 water 98.0±0.3^16.1±0.4 98.0±0.3^17.7±0.4 97.8±0.2^15.0±0.4 97.9±0.2^15.2±0.4 The results show that only pH values, but not the acid, such as maleic acid, benzoic acid, lactic acid, or valeric acid, which formed the salt with 2-(diethylamino)ethyl acetyl salicylate, affect the stability of the 2-(diethylamino)ethyl acetyl salicyl ate salt significantly. 5 The results further show that only pH values, but not the acid, such as HC1, HBr, citric acid, maleic acid, benzoic acid, or lactic acid, which forms the protonated amine groups, affect the stability of the solution significantly. In addition, the size of the groups on the amino group, such as Ri, R2 and R, does not affect the stability significantly. 10   3. Effect of Temperature on the Stability Table 35: Stabilities of 5% solution of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt with 1 equivalent sodium acetate (T-l), H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt with 1 equivalent sodium acetate (T-2), and H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)- 15 OCH(CH3)2.HC1 salt with 1 equivalent sodium acetate (T-3) at various temperature in 25% ethanol. PH solvent Purity (%) at day 0 Purity (%) at day 30 (5°C ) Purity(%) at day 30 (25°C ) Purity (%) at day 30 (40°C ) Purity (%) at day 30 (60°C ) T-l 4.50 25% ethanol 98.7±0.2 98.5±0.3 97.7±0.2 71.6±0.2 32.4±0.4 T-2 4.51 25% ethanol 98.9±0.2 98.8±0.2 97.8±0.3 71.3±0.2 32.8±0.2 T-3 4.49 25% ethanol 99.H0.1 98.9±0.2 97.9±0.3 71.9±0.2 33.2±0.3 PH solvent Purity (%) at day 0 Purity (%) at day 90 (5°C ) Purity(%) at day 90 (25°C ) Purity (%) at day 90 (40°C ) Purity (%) at day 90 (60°C ) T-l 4.50 25% ethanol 98.7±0.2 98.4±0.3 97.0±0.3 32.7±0.3 0 T-2 4.51 25% ethanol 98.9±0.2 98.5±0.3 97.0±0.2 33.6±0.2 0 T-3 4.49 25% ethanol 99.H0.1 98.6±0.3 97.2±0.3 34.2±0.3 0 PH solvent Purity(%) at day 0 Purity(%) at day 180 (5°C ) Purity(%) at day 180 (25°C ) Purity(%) at day 180 (40°C ) Purity (%) at day 180 (60°C ) T-l 4.50 25% ethanol 98.7±0.2 97.8±0.3 95.H0.3 12.2±0.3 0 T-2 4.51 25% ethanol 98.9±0.2 97.8±0.2 95.2±0.3 13.6±0.2 0 T-3 4.49 25% ethanol 99.H0.1 97.9±0.2 95.2±0.3 13.5±0.3 0 PH solvent Purity (%) at day 0 Purity (%) at day 360 (5°C ) Purity(%) at day 360 (25°C ) Purity (%) at day 360 (40°C ) Purity (%) at day 360 (60°C ) T-l 4.50 25% ethanol 98.7±0.2 97.3±0.3 92.2±0.2 0 0 T-2 4.51 25% ethanol 98.9±0.2 97.4±0.3 92.3±0.3 0 0 T-3 4.49 25% ethanol 99.H0.1 97.4±0.3 92.5±0.4 0 0 The solutions of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt(T-l), 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.HC1 salt (T-3) are more stable at lower temperature and can be stored for more than 1 years at 25°C and 5°C. Table 36: Stabilities of 7% solution of (A,5)-2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.02 water 98.6±0.2 93.8±0.2 72.2±0.2 18.1=1=0.3 0 2.09 water 98.6±0.3 98.1±0.2 86.3±0.2 30.2±0.4 0 3.00 water 98.7±0.2 98.4±0.2 96.3±0.2 56.7±0.2 7.9±0.2 3.68 water 98.8±0.3 98.6±0.1 98.0±0.1 63.7±0.2 15.3±0.4 4.07 water 98.7±0.4 98.7±0.1 98.3±0.2 72.5±0.3 21.5±0.3 4.35 water 98.8±0.3 98.7±0.1 98.2±0.1 72.3±0.2 18.7±0.2 4.67 water 98.8±0.3 98.7±0.1 98.2±0.2 58.5±0.2 10.6±0.2 4.95 water 98.7±0.2 97.9±0.2 95.5±0.3 50.6±0.2 3.1=1=0.3 5.98 water 98.8±0.3 96.1±0.2 90.7±0.3 30.3±0.3 0 6.98 water 98.±50.2 90.9±0.2 70.8±0.2 19.9±0.3 0 8.01 water 98.3±0.3 81.9±0.2 58.8±0.2 0 0 The results show that the solution of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) 10 propionate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. Table 37: Stabilities of 7% solution of 2-(diethylamino)ethyl (R,S)-2-(p-isobutylphenyl)propionate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.02 water 98.0±0.4 93.7±0.3 73.0±0.4 18.6±0.4 0 2.09 water 98.2±0.4 97.6±0.4 86.H0.3 30.4±0.3 0 3.00 water 98.5±0.3 98.0±0.4 96.5±0.4 56.3±0.4 8.8±0.3 3.68 water 98.5±0.2 98.4±0.3 98.H0.4 64.3±0.4 16.4±0.4 4.07 water 98.6±0.3 98.5±0.3 98.2±0.2 72.7±0.3 22.6±0.4 4.35 water 98.6±0.2 98.6±0.4 98.2±0.3 72.6±0.3 18.8±0.2 4.67 water 98.5±0.1 98.5±0.4 98.H0.4 58.2±0.4 10.3=1=0.3 4.95 water 98.5±0.3 97.5±0.4 95.4±0.4 50.2±0.4 3.9±0.3 5.98 water 98.4±0.3 96.1±0.3 90.7±0.3 29.9±0.2 0 6.98 water 98.3±0.4 90.7±0.4 78.6±0.4 19.7±0.4 0 8.01 water 98.0±0.4 81.6±0.5 52.5±0.5 0 0 The results show that the solution of 2-(diethylamino)ethyl (R,S)-2-(p- 5 isobutylphenyljpropionate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. Table 38: Stabilities of 7% solution of 2-(diethylamino)ethyl (R)-2-(p-isobutylphenyljpropionate.HCl salt at various pH values and temperature in water (pH was 10 adjusted with 3N HC1 or 3N NaOH). PH solvent Purity(%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity(%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.02 water 97.8±0.4 93.H0.3 70.7±0.4 18.5±0.3 0 2.09 water 98.0±0.4 97.0±0.4 86.0±0.4 30.6±0.4 0 3.01 water 98. l±0.3 97.8±0.4 96.1 ±0.3 56.H0.4 8.4±0.3 3.68 water 98.2±0.2 98.H0.3 97.7±0.3 64.H0.5 16.0±0.4 4.07 water 98.2±0.3 98.0±0.4 97.8±0.4 72.6±0.4 22.7±0.4 4.35 water 98.3±0.2 98.1±0.4 97.8±0.3 72.6±0.5 18.3±0.3 4.67 water 98.2±0.3 98.H0.2 97.5±0.4 58.3±0.4 10.4±0.5 4.96 water 98. l±0.3 97.0±0.4 95.1±0.4 50.5±0.5 4.0±0.3 5.98 water 98.0±0.4 95.8±0.4 90.2±0.4 29.9±0.4 0 6.99 water 97.9±0.4 90.0±0.5 77.1±0.4 19.9±0.4 0 8.01 water 97.6±0.5 81.H0.5 52.3±0.4 0 0 The results show that the solution of 2-(diethylamino)ethyl (R)-2-(p-isobutylphenyl)propionate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6, and there is no significant difference between (R,S)- and (R-isomer. Table 39: Stabilities of 7% solution of 2-(diethylamino)ethyl 2-(2,4-dichlorophenoxy)benzeneacetate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity(%) at day 0 Purity (%) at day 21 (5°C ) Purity (%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 97.9±0.3 91.3±0.3 67.3±0.3 15.1±0.3 0 2.0 water 98.0±0.2 95.1±0.3 82. l±0.3 27.0±0.3 0 3.0 water 98.3±0.2 97.0±0.2 93.5±0.2 48.3±0.3 0 3.7 water 98.4±0.1 97.6±0.2 96.9±0.3 57.2±0.2 13.3±0.5 4.0 water 98.5±0.1 98.0±0.1 97.0±0.2 68.1±0.3 18.2±0.3 4.3 water 98.5±0.2 98.0±0.1 97.0±0.3 68.1±0.3 17.2±0.2 4.6 water 98.6±0.1 98.1±0.2 96. l±0.2 54.5±0.2 14.3±0.3 5.0 water 98.4±0.2 96.9±0.2 93.1±0.3 40.8±0.3 1.2±0.2 6.0 water 98.2±0.2 95.0±0.2 86.7±0.2 27.8±0.2 0 7.0 water 98.0±0.3 90.0±0.3 59.3±0.3 11.0±0.4 0 8.0 water 97.8±0.3 78.3±0.3 47.1±0.3 0 0 The results show that 2-(diethylamino)ethyl 2-(2,4-dichlorophenoxy)benzeneacetate.HCl salt is 10 not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. Table 40: Stabilities of 7% solution of 2-(diethylamino)ethyl (R,5)-2-(2-fluoro-4- biphenyljpropionate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity(%) at day 0 Purity(%) at day 21 (5°C) Purity(%) at day 21 (25°C ) Purity(%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 98.2±0.3 94.0±0.3 72.0±0.3 18.5±0.3 0 2.0 water 98.3±0.3 97.8±0.2 86.1±0.3 30.H0.4 0 3.0 water 98.4±0.2 98.0±0.2 96.0±0.2 56.5±0.3 8.7±0.3 3.7 water 98.5±0.3 98.2±0.1 97.5±0.1 64.5±0.3 16.2±0.3 4.0 water 98.5±0.2 98.3±0.1 97.7±0.2 72.3±0.3 22.4±0.3 4.3 water 98.5±0.3 98.3±0.1 97.8±0.1 72.2±0.3 18.3±0.2 4.6 water 98.4±0.2 98.3±0.1 97.7±0.1 58.H0.4 10.4±0.3 5.0 water 98.5±0.3 97.6±0.2 96.7±0.2 50.H0.3 3.0±0.3 6.0 water 98.3±0.3 95.4±0.2 90.5±0.3 29.7±0.4 0 7.0 water 98.H0.4 89.7±0.3 75.1±0.3 19.8±0.3 0 8.0 water 98.0±0.4 81.9±0.3 52.8±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl (R,5)-2-(2-fluoro-4-biphenyl)propionate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. 5 Table 41: Stabilities of 7% solution of 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2-methyl-U / -indole-3-acetate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 98.H0.3 92.3±0.3 69.0±0.3 15.3±0.3 0 2.0 water 98.3±0.4 95.9±0.3 83.H0.3 27.5±0.3 0 3.0 water 98.5±0.2 97.3±0.3 94.5±0.2 49.3±0.3 0 3.7 water 98.5±0.2 97.7±0.2 97.3±0.3 57.9±0.2 16.3±0.5 4.0 water 98.7±0.1 98.1±0.3 97.5±0.2 68.7±0.3 19.6±0.3 4.3 water 98.8±0.2 98.3±0.3 97.3±0.3 70.H0.3 17.7±0.2 4.6 water 98.7±0.1 98.2±0.2 96.4±0.2 56.3±0.2 15.3±0.3 5.0 water 98.6±0.3 97.0±0.2 94.H0.3 42.8±0.3 1.9±0.2 6.0 water 98.5±0.4 95.3±0.3 87.8±0.2 27.6±0.2 0 7.0 water 98.4±0.3 90.2±0.3 59.9±0.3 11.4±0.4 0 8.0 water 98.0±0.5 79.3±0.4 47.6±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2- methyl-U / -indole-3-acetate.HCl salt in water is not stable at a temperature higher than 40°C and 10 a pH lower than 3 or greater than 6. Table 42: Stabilities of 7% solution of 2-(diethylamino)ethyl 5-fluoro-2-methyl-l-[[4-(methylsulfinyl)phenyl]methylene]-l / / -indene-3-acetate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 97.2±0.3 91.1±0.4 67.5±0.4 10.4±0.4 0 2.0 water 97.3±0.3 94.7±0.3 81.1±0.3 23.6±0.3 0 3.0 water 97.6±0.2 96.3±0.2 92.2±0.2 45.7±0.3 0 3.7 water 97.6±0.2 97.3±0.2 96.8±0.2 55.5±0.2 13.5±0.3 4.0 water 97.9±0.1 97.4±0.1 96.9±0.1 60.3±0.2 19.7±0.3 4.3 water 97.7±0.2 97.3±0.1 96.7±0.1 63.H0.1 16.8±0.2 4.6 water 97.8±0.1 97.3±0.2 95.9±0.2 57.3±0.2 15.5±0.3 5.0 water 97.7±0.3 96.1±0.2 93.9±0.3 38.9±0.3 1.5±0.3 6.0 water 97.5±0.3 94.4±0.3 88.9±0.2 21.6±0.2 0 7.0 water 97.3±0.3 89.0±0.3 59.8±0.3 5.4±0.3 0 8.0 water 96.9±0.4 77.1±0.3 44.5±0.4 0 0 5 The results show that the solution of 2-(di ethyl aminojethyl 5-fluoro-2-methyl-l-[[4-(methylsulfinyl)phenyl]methylene]-U / -indene-3-acetate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. Table 43: Stabilities of 7% solution of 2-(diethylamino)ethyl l-methyl-5-(4-methylbenzoyl)-UT-10 pyrrole-2-acetate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3NNaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 97.4±0.4 90.3±0.3 65.5±0.3 9.4±0.3 0 2.0 water 97.6±0.3 93.5±0.3 78.H0.3 20.6±0.3 0 3.0 water 97.8±0.2 95.3±0.3 91.2±0.2 41.7±0.2 0 3.7 water 97.9±0.2 96.4±0.2 95.6±0.2 56.6±0.2 11.5±0.3 4.0 water 98.H0.1 96.8±0.1 95.7±0.2 58.3±0.2 23.0±0.3 4.3 water 98.H0.2 96.9±0.1 95.4±0.1 60.H0.1 25.8±0.2 4.6 water 97.9±0.1 96.3±0.2 94.9±0.2 55.3±0.2 13.5±0.3 5.0 water 97.8±0.2 96.1±0.2 92.H0.3 37.8±0.3 1.7±0.3 6.0 water 97.6±0.3 94.4±0.2 79.5±0.3 19.5±0.2 0 7.0 water 97.4±0.3 90.0±0.3 59.7±0.3 5.7±0.3 0 8.0 water 97.H0.3 78.1±0.3 43.6±0.4 0 0 The results show that the solution of 2-(diethylamino)ethyl l-methyl-5-(4-methylbenzoyl)-IT / -pyrrole-2-acetate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. 5 Table 44: Stabilities of 7% solution of 2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 98.0±0.3 92.7±0.3 69.H0.3 16.3±0.3 0 2.0 water 98.H0.3 95.9±0.3 83.5±0.3 27.5±0.3 0 3.0 water 98.3±0.2 97.4±0.3 94.6±0.2 49.3±0.2 0 3.7 water 98.4±0.2 97.7±0.2 97.3±0.2 59.9±0.2 19.3±0.3 4.0 water 98.5±0.1 98.2±0.2 97.5±0.2 70.7±0.2 23.6±0.3 4.3 water 98.5±0.2 98.2±0.2 97.6±0.1 70.1±0.2 27.7±0.2 4.6 water 98.5±0.1 98.2±0.2 97.5±0.2 59.3±0.2 22.3±0.2 5.0 water 98.4±0.2 97.5±0.2 94.9±0.2 45.8±0.3 5.9±0.2 6.0 water 98.2±0.2 95.3±0.2 88.8±0.2 28.6±0.2 0 7.0 water 98.0±0.3 90.2±0.3 60.9±0.2 17.4±0.3 0 8.0 water 97.7±0.3 79.7±0.3 49.9±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl 3-(6-methoxy-2- naphthyljpropionate.HCl salt in water is not stable at a temperature higher than 40°C and a pH 10 lower than 3 or greater than 6. Table 45: Stabilities of 7% solution of 2-(di ethylaminojethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 98.5±0.3 90.9±0.3 66.5±0.3 9.9±0.3 0 2.0 water 98.7±0.2 93.9±0.2 78.9±0.3 21.6±0.3 0 3.0 water 98.8±0.2 96.8±0.2 92.3±0.2 42.3±0.2 0 3.7 water 98.9±0.2 98.5±0.2 96.6±0.2 57.6±0.2 10.5±0.3 4.0 water 99.H0.1 98.6±0.1 96.7±0.2 60.2±0.2 25.2±0.2 4.3 water 99.H0.1 98.7±0.2 95.4±0.1 60.8±0.1 26.8±0.2 4.6 water 98.9±0.1 98.5±0.1 95.8±0.1 55.9±0.1 15.5±0.1 5.0 water 98.8±0.2 96.9±0.2 92.8±0.2 37.3±0.2 4.6±0.3 6.0 water 98.6±0.2 94.7±0.2 79.9±0.3 21.5±0.2 0 7.0 water 98.5±0.3 90.3±0.3 60.7±0.3 7.7±0.2 0 8.0 water 98.3±0.3 78.4±0.3 44.8±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. 5 Table 46: Stabilities of 7% solution of 2-(diethylamino)ethyl l-(4-chlorobenzoyl-5-methoxy-2-methyl-lH-indole-3-acetoxyacetate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 98.H0.3 91.9±0.3 67.3±0.3 15.6±0.3 0 2.0 water 98.3±0.3 95.7±0.2 82.2±0.2 26.7±0.3 0 3.0 water 98.5±0.2 98.0±0.2 93.0±0.2 47.7±0.3 0 3.7 water 98.7±0.1 98.2±0.1 97.H0.1 57.6±0.2 13.9±0.3 4.0 water 98.7±0.1 98.4±0.1 97.4±0.2 68.7±0.3 19.2±0.3 4.3 water 98.8±0.2 98.5±0.1 97.5±0.1 68.6±0.3 17.9±0.2 4.6 water 98.8±0.2 98.4±0.2 96.5±0.2 53.7±0.2 14.8±0.3 5.0 water 98.6±0.2 97.1±0.2 93.8±0.2 39.8±0.3 3.2±0.2 6.0 water 98.4±0.2 95.8±0.2 86.9±0.2 28.8±0.2 0 7.0 water 98.H0.2 90.2±0.3 59.7±0.3 11.2±0.4 0 8.0 water 97.7±0.3 78.5±0.2 47.9±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl l-(4-chlorobenzoyl-5-methoxy-2-methyl-lH-indole-3-acetoxyacetate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. 5 Table 47: Stabilities of 7% solution of 2-(diethylamino)ethyl [(1 -benzyl-U / -indazol-3-yl)oxy]acetate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3NNaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 97.5±0.3 89.9±0.3 63.5±0.3 9.1±0.3 0 2.0 water 97.7±0.2 93.0±0.2 77.8±0.3 19.6±0.3 0 3.0 water 97.8±0.2 96.8±0.2 91.3±0.2 40.4±0.2 0 3.7 water 97.9±0.1 97.5±0.1 95.6±0.2 55.6±0.2 8.5±0.2 4.0 water 98.H0.1 97.6±0.1 95.7±0.1 57.2±0.2 23.2±0.2 4.3 water 98.H0.1 97.7±0.2 95.5±0.1 58.8±0.3 25.8±0.2 4.6 water 97.9±0.1 97.6±0.1 95.H0.1 54.7±0.2 16.5±0.2 5.0 water 97.8±0.2 95.9±0.2 91.8±0.2 36.H0.2 4.2±0.2 6.0 water 97.6±0.3 93.7±0.2 78.9±0.2 18.5±0.2 0 7.0 water 97.5±0.3 89.3±0.2 59.7±0.3 7.1±0.3 0 8.0 water 97.4±0.4 77.5±0.3 39.8±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl [(1 -benzyl-U / -indazol-3-yl)oxy]acetate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower 10 than 3 or greater than 6. Table 48: Stabilities of 7% solution of 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 98.1±0.3 92.9±0.3 69.2±0.3 11.3±0.3 0 2.0 water 98.2±0.3 96.1±0.3 83.0±0.3 20.5±0.3 0 3.0 water 98.3±0.2 97.5±0.2 94.0±0.3 45.3±0.2 0 3.7 water 98.5±0.1 97.6±0.2 96.6±0.2 51.9±0.2 11.3±0.3 4.0 water 98.6±0.1 98.0±0.1 96.7±0.2 62.7±0.2 18.6±0.2 4.3 water 98.6±0.1 98.0±0.1 96.7±0.1 63.H0.2 17.7±0.2 4.6 water 98.6±0.1 98.0±0.1 96.6±0.1 50.3±0.2 12.3±0.2 5.0 water 98.4±0.2 97.1±0.2 92.9±0.2 39.8±0.2 2.9±0.2 6.0 water 98.2±0.2 94.8±0.2 86.8±0.2 20.6±0.3 0 7.0 water 98.0±0.2 89.1±0.3 60.9±0.2 7.4±0.3 0 8.0 water 97.7±0.3 78.7±0.3 47.9±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. 5 Table 49: Stabilities of 7% solution of 2-(diethylamino)ethyl 4,5-diphenyl-2-oxazolepropionate.HC1 salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3NNaOH). PH solvent Purity (%) at day 0 Purity(%) at day 21 (5°C ) Purity(%) at day 21 (25°C ) Purity (%) at day 21 (40°C ) Purity (%) at day 21 (60°C ) 1.0 water 98.2±0.3 90.1±0.3 59.9±0.3 7.9±0.3 0 2.0 water 98.4±0.3 93.0±0.2 74.8±0.2 17.6±0.2 0 3.0 water 98.6±0.1 96.9±0.2 88.9±0.2 36.4±0.2 0 3.7 water 98.7±0.2 97.8±0.1 94.5±0.2 50.6±0.2 7.3±0.3 4.0 water 98.8±0.1 97.9±0.1 95.H0.1 53.2±0.2 20.2±0.2 4.3 water 98.8±0.2 97.9±0.2 95.2±0.2 54.8±0.1 21.8±0.3 4.6 water 98.7±0.1 97.8±0.2 95.0±0.1 54.7±0.2 15.5±0.3 5.0 water 98.6±0.3 96.3±0.2 89.8±0.1 30.H0.2 3.2±0.2 6.0 water 98.4±0.2 93.4±0.2 73.9±0.2 16.5±0.2 0 7.0 water 98.2±0.3 89.2±0.3 59.7±0.2 7.1±0.3 0 8.0 water 98.0±0.3 77.1±0.3 40.8±0.3 0 0 The results show that the solution of 2-(diethylamino)ethyl 4,5-diphenyl-2- oxazolepropionate.HC1 salt in water is not stable at a temperature higher than 40°C and a pH 10 lower than 3 or greater than 6. Table 50: Stabilities of 7% solution of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HCl salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3NNaOH). PH solvent Purity (%) at day 0 Purity(%) at day 14 (5°C ) Purity(%) at day 14 (25°C ) Purity (%) at day 14 (40°C ) Purity (%) at day 14(60°C) 1.0 water 99.1 90.2 61.2 0 0 2.0 water 99.1 95.8 82.7 0 0 3.0 water 99.1 97.5 87.7 2.3 0 3.7 water 99.1 98.2 95.5 14.1 0 4.0 water 99.1 98.4 95.9 14.3 0 4.3 water 99.1 98.4 95.8 12.8 0 4.6 water 99.1 98.3 95.6 3.4 0 5.0 water 99.1 97.0 91.0 0.9 0 6.0 water 99.1 91.6 84.1 0 0 7.0 water 99.1 87.3 60.3 0 0 8.0 water 99.1 57.3 21.2 0 0 The results show that the solution of 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2- 5 acetoxybenzoate.HC1 salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. The results show that the solutions are more stable at a lower temperature and should be stored at temperatures no more than 25°C, preferably 2-8°C. 0 4. Effect of Solvent on the Stability Table 51: Stabilities of 7% solution of 2-(diethylamino)ethyl acetylsalicylate.HC1 salt at various pH values and temperature in water (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 14 (5°C ) Purity(%) at day 14 (25°C ) Purity (%) at day 14 (40°C ) Purity (%) at day 14(60°C) 1.0 water 99.1±0.3 90.8±0.3 62.2±0.4 0 0 2.0 water 99.3±0.2 96.3±0.2 83.3±0.3 0 0 3.0 water 99.5±0.2 98.1±0.1 88.5±0.2 2.5±0.2 0 3.7 water 99.5±0.1 98.7±0.1 96.1±0.1 14.5±0.3 0 4.0 water 99.6±0.1 98.8±0.1 96.6±0.2 14.5±0.3 0 4.3 water 99.7±0.1 98.9±0.1 96.6±0.1 12.9±0.2 0 4.6 water 99.5±0.2 98.5±0.2 96.5±0.2 3.6±0.2 0 5.0 water 99.5±0.1 97.3±0.1 92.5±0.2 1.0 0 6.0 water 99.4±0.3 92.1±0.2 84.7±0.3 0 0 7.0 water 99.2±0.3 87.9±0.3 59.8±0.3 0 0 8.0 water 99.0±0.3 57.9±0.3 21.7±0.4 0 0 The results show that the solution of 2-(diethylamino)ethyl acetylsalicylate.HCl salt in water is not stable at a temperature higher than 40°C and a pH lower than 3 or greater than 6. Table 52: Stabilities of 7% solution of 2-(diethylamino)ethyl acetylsalicylate.HCl salt at various 5 pH values and temperature in 15% ethanol (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Punty(%) at day 0 Purity(%) at day 14 (5°C ) Purity(%) at day 14 (25°C ) Purity (%) at day 14 (40°C ) Purity (%) at day 14(60°C) 1.0 15% ethanol 99.1±0.2 92.1±0.3 62.7±0.3 0 0 2.0 15% ethanol 99.4±0.2 96.5±0.2 83.8±0.3 0 0 3.0 15% ethanol 99.5±0.1 98.3±0.3 88.8±0.2 2.9±0.3 0 3.7 15% ethanol 99.6±0.1 98.9±0.2 96.2±0.3 15.2±0.3 0 4.0 15% ethanol 99.7±0.2 98.9±0.1 96.7±0.2 15.7±0.3 0 4.3 15% ethanol 99.7±0.1 98.9±0.1 96.7±0.1 13.6±0.3 0 4.6 15% ethanol 99.6±0.2 98.6±0.2 96.5±0.2 4.1±0.3 0 5.0 15% ethanol 99.5±0.2 97.4±0.2 92.9±0.2 1.3±0.3 0 6.0 15% ethanol 99.4±0.2 92.3±0.3 84.9±0.3 0 0 7.0 15% ethanol 99.2±0.1 87.9±0.3 60.2±0.3 0 0 8.0 15% ethanol 99.1±0.2 58.7±0.4 22.7±0.3 0 0 The results show that the solvent (15% ethanol) did not affect the stability of the solution of 2-(diethylamino)ethyl acetylsalicylate.HCl salt significantly, but somewhat improved the stability. Because 15% ethanol can inhibit bacteria growth, it is a good selection for 2-(diethylamino)ethyl acetylsalicylate.HCl medical uses. Table 53: Stabilities of 7% solution of 2-(diethylamino)ethyl acetylsalicylate.HC1 salt at various pH values and temperature in 25% ethanol (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity(%) at day 0 Purity(%) at day 14 (5°C ) Purity(%) at day 14 (25°C ) Purity (%) at day 14 (40°C ) Purity (%) at day 14(60°C) 1.0 25% ethanol 99.1±0.3 92.3±0.3 63.5±0.3 0 0 2.0 25% ethanol 99.4±0.3 96.9±0.3 84.2±0.3 0 0 3.0 25% ethanol 99.5±0.2 98.5±0.2 88.9±0.2 2.9±0.2 0 3.7 25% ethanol 99.6±0.1 99.1±0.2 96.3±0.2 15.1±0.3 0 4.0 25% ethanol 99.8±0.1 99.1±0.1 96.9±0.1 15.2±0.3 0 4.3 25% ethanol 99.7±0.2 99.1±0.2 96.8±0.2 13.8±0.3 0 4.6 25% ethanol 99.7±0.2 98.8±0.1 96.5±0.2 4.2±0.1 0 5.0 25% ethanol 99.6±0.2 98.0±0.2 92.8±0.2 1.6±0.1 0 6.0 25% ethanol 99.5±0.3 92.7±0.2 85.0±0.3 0 0 7.0 25% ethanol 99.4±0.3 88.0±0.3 61.2±0.3 0 0 8.0 25% ethanol 99.1±0.3 59.8±0.3 23.1±0.3 0 0 The results show that the solvent (25% ethanol) did not affect the stability of the solution of 2- (diethylamino)ethyl acetylsalicylate.HC1 salt significantly. Table 54: Stabilities of 7% solution of 2-(diethylamino)ethyl acetylsalicylate.HC1 salt at various pH values and temperature in 50% ethanol (pH was adjusted with 3N HC1 or 3N NaOH). PH solvent Purity (%) at day 0 Purity(%) at day 14 (5°C ) Purity(%) at day 14(25°C) Purity(%) at day 14 (40°C ) Purity (%) at day 14(60°C) 1.0 50% ethanol 99.2±0.3 92.4±0.3 63.8±0.4 0 0 2.0 50% ethanol 99.5±0.2 96.9±0.3 84.7±0.3 0 0 3.0 50% ethanol 99.6±0.3 98.6±0.3 89.5±0.3 3.2±0.3 0 3.7 50% ethanol 99.7±0.2 99.1±0.3 96.6±0.2 16.9±0.3 0 4.0 50% ethanol 99.8±0.2 99.2±0.3 97.2±0.3 16.8±0.4 0 4.3 50% ethanol 99.7±0.2 99.1±0.2 97.2±0.2 14.9±0.3 0 4.6 50% ethanol 99.7±0.3 99.0±0.3 96.9±0.3 4.9±0.3 0 5.0 50% ethanol 99.6±0.2 98.2±0.3 93.1±0.3 2.3±0.2 0 6.0 50% ethanol 99.5±0.3 92.9±0.4 85.5±0.3 0 0 7.0 50% ethanol 99.4±0.3 88.2±0.3 61.9±0.4 0 0 8.0 50% ethanol 99.2±0.3 60.3±0.4 23.9±0.4 0 0 The results show that the solvent (50% ethanol) did not affect the stability of 2-(diethylamino)ethyl acetylsalicylate.HC1 salt significantly. From tables 51-54, it can be seen that the amount of ethanol did not affect the stability of 7% solution of 2-(diethylamino)ethyl acetyl salicyl ate. HC1 salt significantly. Compared with pure water as the solvent, the solvents with different concentrations of ethanol make the solutions somewhat more stable. The concentration of ethanol may be 0-70% v / v, preferably 10-35% v / v, more preferably 15-25% v / v. For example, aqueous solution containing 15% ethanol, which can inhibit bacteria growth, is a good selection for medical uses. Experiments with other solvents, such as aqueous solution containing different concentration of acetone or DMSO also gave similar results, i.e., the solvent did not affect the stability of the solution significantly. Other HPDs also have very similar behavior. The other HPDs are, for example: HPDs of peptides such as 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.HC1, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HC1; and other HPDs such as 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HC1, 2-(diethylamino)ethyl (7?,5)-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-l / / -indole-3-acetate.HCl, 2-(diethylamino)ethyl 5-fluoro-2-methyl-l-[[4-(methylsulfinyl)phenyl]methylene]-l / / -indene-3-acetate.HCl, 2-(diethylamino)ethyl l-methyl-5-(4-methylbenzoyl)-17 / -pyrrole-2-acetate.HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-l,4-dimethyl-1 JT-pyrrole-2-acetate.HCl, 2-(diethylamino)ethyl 3 -(6-methoxy-2-naphthyl)propionate.HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl, 2-(diethylamino)ethyl l-(4-chlorobenzoyl-5-methoxy-2-methyl-lH-indole-3-acetoxyacetate.HCl, 2-(diethylamino)ethyl [(l-benzyl-IT / -indazol-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, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxyb enzoate .HC1. It should be understood that the above-mentioned general, preferable, or more preferable feature(s) in one aspect of the invention can be combined with other general, preferable, or more preferable feature(s) in another aspect of the invention. For example, the concentration of the HPD in the reconstitution solution is 3-10%, the pH is 3-5 and the pharmaceutically acceptable carrier is 15-35% ethanol in pure water. 5. Stability of the Pure HPDs Table 55: Stabilities of H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HCl salt(T-l), 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.HC1 salt (T-3) at 25°C / RH60% Time Day 0 3 month 6 month 9 month 12 month 18 month 24 month Purity(T-l) 98.7±0.2 98.8±0.2 98.6±0.2 98.5±0.2 98.4±0.3 98.2±0.3 98.2±0.2 Purity(T-2) 98.9±0.1 98.9±0.3 98.6±0.2 98.6±0.3 98.5±0.2 98.5±0.2 98.4±0.2 Purity(T-3) 99. l±0.2 99.0±0.2 99.0±0.2 98.8±0.2 98.7±0.0 98.6±0.0 98.5±0.2 The results show that the pure powder 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 for years at room temperature. Table 56: Stabilities of H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2.HC1 (U-l) and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HC1 salt (U-2) at 25°C / RH60% Time Day 0 3 month 6 month 9 month 12 month 18 month 24 month Purity(U-l) 98.5±0.2 98.5±0.2 98.4±0.2 98.3±0.2 98.2±0.3 98.2±0.3 98.0±0.2 Purity(U-2) 98.9±0.1 98.9±0.3 98.6±0.2 98.6±0.3 98.5±0.2 98.5±0.2 98.4±0.2 The results show that the pure powder of H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2.HC1 (U-l) and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HC1 salt (U-2) are very stable and can be stored for years at room temperature. Table 57: Stabilities of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HC1 salt (A-1-1), 2-(diethylamino)ethyl (5)-2-(6-methoxy-2-naphthyl) propionate.HC1 salt (A-1-2), 2-(diethylamino)ethyl (A)-2-(6-methoxy-2-naphthyl) propionate.HCl salt (A-1-3), 2 5 (diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HBr salt (A-1-4), 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate, ci trie acid salt (A-1-5), 2-(dimethylamino)ethyl 2-(6-methoxy-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- 10 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) at 25°C / RH60% Time Day 0 3 month 6 month 12 month 18 month 24 month Purity(A-l-l) 98.8±0.2 98.6±0.1 98.8±0.1 98.5±0.2 98.3±0.2 98.2±0.2 Purity(A-l-2) 98.6±0.3 98.5±0.3 98.4±0.2 98.3±0.2 98.2±0.2 98.0±0.1 Purity(A-l-3) 98.5±0.2 98.4±0.2 98.5±0.2 98.2±0.1 98.H0.2 97.9±0.2 Purity(A-l-4) 98.6±0.3 98.9±0.1 98.6±0.4 98.4±0.2 98.2±0.1 98.0±0.4 Purity(A-l-5) 99.0±0.2 99.0±0.4 98.9±0.1 98.7±0.2 98.4±0.2 98.2±0.2 Purity(A-2) 98.5±0.2 98.4±0.1 98.2±0.2 97.9±0.1 97.6±0.2 97.H0.2 Purity(A-3) 98.3±0.1 98.4±0.2 98.2±0.2 97.9±0.2 97.3±0.1 96.8±0.2 Purity(A-4) 98.6±0.2 98.5±0.1 98.6±0.1 98.0±0.2 97.9±0.2 97.2±0.1 Purity(A-5) 98.5±0.3 98.3±0.3 98.4±0.2 97.9±0.1 97.6±0.2 97.H0.2 Purity(A-6) 98.3±0.2 98.5±0.2 98.0±0.1 97.8±0.2 97.4±0.2 97.H0.2 Purity(A-7) 98.H0.2 98.0±0.1 98.2±0.2 97.4±0.2 97.H0.2 96.7±0.1 The solid of 2-(6-methoxy-2-naphthyl) propionate.HA salt is very stable and can be stored for more than 2 years ar room temperature. The size and shape of alkyl group on amino group and 15 A' did not affect the stability significantly. The dry drug substances can be stored for 2 years or more at 25°C without significant changes. Table 58: Stabilities of 2-(diethylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate.HCl salt(B-l-l), 2-(diethylamino)ethyl (5)-2-(2-fluoro-4-biphenyl)propionate.HCl salt (B-l-2), 2- (diethylamino)ethyl (7?)-2-(2-fluoro-4-biphenyl)propionate.HCl salt(B-l-3), 2- (diethylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate.HBr salt (B-l-4), 2-(diethylamino)ethyl 2-(2-fluoro-4-biphenyl)propionate. citric acid salt (B-l-5), 2-(dimethylamino)ethyl 2-(2-fluoro-4- biphenyl)propionate.HCl salt (B-2), 2-(dibutylamino)ethyl 2-(2-fluoro-4- 5 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) at 25°C / RH60% Time Day 0 3 month 6 month 12 month 18 month 24 month Purity (B-l-1) 98.5±0.2 98.4±0.1 98.1±0.1 98.2±0.1 98.1±0.1 98.0±0.1 Purity (B-l -2) 98.7±0.2 98.6±0.1 98.5±0.2 98.4±0.2 98.3±0.1 98.2±0.1 Purity (B-l -3) 98.4±0.1 98.3±0.1 98.3±0.1 98.2±0.1 98.1 ±0.2 98.0±0.1 Purity (B-l-4) 98.6±0.2 98.5±0.1 98.4±0.1 98.3±0.1 98.1±0.1 97.9±0.1 Purity (B-l-5) 98.3±0.2 98.2±0.1 98.2±0.1 98.1±0.1 98.0±0.1 97.9±0.1 Purity (B-2) 98.1±0.3 98.0±0.1 97.9±0.1 98.0±0.1 97.6±0.1 97.4±0.2 Purity (B-3) 98.3±0.2 98.3±0.1 98.1±0.1 98.2±0.1 97.6±0.1 97.5±0.1 Purity (B-4) 98.0±0.2 98.0±0.1 97.9±0.1 97.8±0.1 97.5±0.3 97.2±0.1 Purity (B-5) 98.2±0.3 98.1±0.1 98.1±0.1 98.1±0.1 97.8±0.1 97.7±0.2 Purity (B-6) 98.1±0.2 98.1±0.1 98.0±0.1 97.9±0.2 97.8±0.2 97.6±0.1 Purity (B-7) 98.3±0.3 98.2±0.1 98.2±0.1 98.1±0.1 98.0±0.1 97.9±0.1 10 The solid of 2-(2-fluoro-4-biphenyl)propionate.HCl salt is very stable and can be stored for more than 2 years ar room temperature. The size of alkyl group on amino group and A' did not affect the stability significantly. The dry drug substances can be stored for 2 years or more at 25°C without significant changes. 15 Table 59: 2-(diethylamino)ethyl (R,5)-2-( / >-isobutylphenyl)propionate.HCl salt (C-l-1), 2-(diethylamino)ethyl (5)-2-( / ?-isobutylphenyl)propionate.HCl salt (C-l-2), 2-(diethylamino)ethyl (A)- 2-( / ?-isobutylphenyl)propionate.HCl salt (C-l-3), 2-(diethylamino)ethyl (R,S)-2-(p-isobutylphenyl)propionate.HBr salt (C-l-4), 2-(diethylamino)ethyl (R,S)-2-(p-isobutylphenyl)propionate.citric acid salt (C-l-5), 2-(dimethylamino)ethyl (R,S)-2-(p- isobutylphenyl)propionate.HCl salt (C-2), 2-(dibutylamino)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- 5 isobutylphenyl)propionate.HCl salt (C-6), and 2-(di-2-(2-methoxyethoxy)ethylamino)ethyl (R,S)-2-( / ?-isobutylphenyl)propionate.HCl salt (C-7) at 25°C / RH60% Time Day 0 3 month 6 month 9 month 12 month 18 month 24 month Purity(C-l-l) 99.8±0.1 99.9±0.2 99.8±0.2 99.8±0.3 99.5±0.3 99.8±0.3 99.7±0.4 Purity(C-l-2) 98.5±0.1 98.5±0.3 98.4±0.4 98.5±0.3 98.3±0.4 98.2±0.1 98.0±0.5 Purity(C-l-3) 98.2±0.1 98.2±0.2 98.1±0.3 98.0±0.1 98.0±0.3 97.9±0.3 97.8±0.2 Purity(C-l-4) 98.5±0.2 98.4±0.1 98.5±0.3 98.3±0.1 98.3±0.3 98.2±0.4 98.0±0.5 Purity(C-l-5) 98.8±0.1 98.7±0.2 98.8±0.3 98.5±0.1 98.7±0.1 98.4±0.4 98.3±0.3 Purity(C-2) 98.5±0.1 98.4±0.2 98.4±0.1 98.1±0.1 98.2±0.3 97.9±0.3 97.7±0.4 Purity(C-3) 98.4±0.2 98.3±0.1 98.2±0.3 98.4±0.3 98.1±0.3 97.9±0.4 97.8±0.3 Purity(C-4) 98.3±0.1 98.4±0.2 98.2±0.3 98.2±0.1 98.1±0.3 98.0±0.1 97.9±0.3 Purity(C-5) 98.2±0.1 98.1±0.2 98.1±0.3 98.2±0.1 98.0±0.4 97.9±0.1 97.7±0.4 Purity(C-6) 98.5±0.1 98.5±0.3 98.4±0.4 98.4±0.1 98.3±0.2 98.3±0.3 98.1±0.2 Purity(C-7) 98.3±0.2 98.2±0.1 98.2±0.2 98.1±0.1 98.2±0.3 98.0±0.3 97.9±0.1 The solid of 2-( / ?-isobutylphenyl)propionate.HA salt is very stable and can be stored for more than 2 years ar room temperature. The size and shape of alkyl group on amino group and A' did not affect the stability significantly. 10 Other HPDs have very similar behavior. The other HPDs are, for example, 2-(diethylamino)ethyl l-(4-chlorobenzoyl)-5-methoxy-2-methyl-IT / -indole-3-acetate.HCl, 2-(diethylamino)ethyl 5-fluoro-2-methyl-l-[[4-(methylsulfinyl)phenyl]methylene]-l / 7-indene-3-acetate.HCl, 2-(diethylamino)ethyl l-methyl-5-(4-methylbenzoyl)-l / / -pyrrole-2-acetate.HCl, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-l,4-dimethyl-l / / -pyrrole-2-acetate.HCl, 2 15 (diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate.HCl, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl, 2-(diethylamino)ethyl l-(4-chlorobenzoyl-5-methoxy-2-methyl-lH-indole-3-acetoxyacetate.HCl, 2-(diethylamino)ethyl [(1 -benzyl- 1H-indazol-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)ethyl acetylsalicylate.HC1, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HCl. III. Administering HPDs via penetrating a biological barrier Another aspect of the invention relates to a method of using the pharmaceutical composition in penetrating one or more biological barriers in a biological subject. The method comprises a step of administering the pharmaceutical composition to a biological subject. The term "biological barrier" as used herein refers to a biological layer that separates an environment into different spatial areas or compartments, which separation is capable of modulating (e.g., restricting, limiting, enhancing or taking no action in) the passing through, penetrating or translocation of substance or matter from one compartment / area to another. The different spatial areas or compartments as referred to herein may have the same or different chemical or biological environment(s). The biological layer as referred herein includes, but is not limited to, a biological membrane, a cell layer, a biological structure, an inner surface of subjects, organisms, organs or body cavities, an external surface of subjects, organisms, organs or body cavities, or any combination or plurality thereof. Examples of a biological membrane include a lipid bilayer structure, eukaryotic cell membrane, prokaryotic cell membrane, and intracellular membrane (e.g., nucleus or organelle membrane, such as membrane or envelope of Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome, nucleus, chloroplasts, plastids, peroxisomes or microbodies). The lipid bilayer referred to herein is a double layer of lipid-class molecules, including, but not limited to, phospholipids and cholesterol. In a particular embodiment, lipids for bilayer are amphiphilic molecules consisting of polar head groups and non-polar fatty acid tails. The bilayer is composed of two layers of lipids arranged so that their hydrocarbon tails face one another to form an oily core held together by the hydrophobic effect, while their charged heads face the aqueous solutions on either side of the membrane. In another particular embodiment, the lipid bilayer may contain one or more embedded protein and / or sugar molecule(s). Examples of a cell layer include a lining of eukaryotic cells (e.g., epithelium, lamina propria and smooth muscle or muscularis mucosa (in gastrointestinal tract)), a lining of prokaryotic cells (e.g., surface layer or S-layer which refers to a two dimensional structure monomolecular layer composed of identical proteins or glycoproteins, specifically, an S-layer refers to a part of a cell envelope commonly found in bacteria and archaea), a biofilm (a structured community of microorganisms encapsulated within a self-developed polymeric matrix and adherent to a living or inert surface), and a plant cell layer (e.g., empidermis). The cells may be normal cells or pathological cells (e.g. disease cells, cancer cells). Examples of biological structures include structures sealed by tight or occluding junctions which provide a barrier to the entry of toxins, bacteria and viruses, e.g. blood milk barrier, blood-cerebrospinal fluid (CSF) barrier, blood-synovial fluid (SF) barrier and blood brain barrier (BBB). In particular, BBB is composed of an impermeable class of endothelium, which presents both a physical barrier through tight junctions adjoining neighboring endothelial cells and a transport barrier comprised of efflux transporters. The biological structure may also include a mixture of cells, proteins and sugars (e.g. blood clots), for example, a myelin sheath, which is a layer around the axon of a neuron formed by a dielectric material, myelin. Examples of the inner surface of subjects, organisms, organs or body cavities include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrium (the mucosa of the uterus, inner layer of the wall of a pollen grain or the inner wall layer of a spore), or a combination or plurality thereof. Examples of the external surface of subjects, organisms, organs or body cavities include capillaries (e.g. capillaries in the heart tissue), mucous membranes that are continuous with skin (e.g. such as at the nostrils, the lips, the ears, the genital area, and the anus), outer surface of an organ (e.g. liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, the anorectum and pruritus ani), skin, cuticle (e.g., dead layers of epidermal cells or keratinocytes or superficial layer of overlapping cells covering the hair shaft of an animal, a multi-layered structure outside the epidermis of many invertebrates, plant cuticles or polymers cutin and / or cutan), external layer of the wall of a pollen grain or the external wall layer of a spore), and a combination or plurality thereof. In addition, a biological barrier further includes a sugar layer, a protein layer or any other biological layer, or a combination or plurality thereof. For example, skin is a biological barrier that has a plurality of biological layers. A skin comprises an epidermis layer (outer surface), a demis layer and a subcutaneous layer. The epidermis layer contains several layers including a basal cell layer, a spinous cell layer, a granular cell layer, and a stratum corneum. The cells in the epidermis are called keratinocytes. The stratum corneum ("horny layer") is the outmost layer of the epidermis, wherein cells here are flat and scale-like ("squamous") in shape. These cells contain a lot of keratin and are arranged in overlapping layers that impart a tough and oilproof and waterproof character to the skin's surface. In certain embodiments, since the HPD of the present disclosure has enhanced ability of crossing one or more biological barriers, it can be administered locally (e.g., topically or transdermally) to reach a location where a condition occurs without the necessity of a systematic administration (e.g., oral or parenteral administration). A local administration and penetration of the HPD allows it to reach the same level of local concentration of an agent or drug with a much smaller amount or dosage in comparison to a systematic administration of a parent drug; alternatively, a higher level of local concentration which may not be afforded in the systematic administration, or if possible, requires significantly higher dosage of an agent in the systematic administration. The local administration of the HPD may allow a biological subject to reduce potential sufferings from a systemic administration, e.g., adverse reactions associated with the systematic exposure to the agent, gastrointestinal / renal effects. Additionally, the local administration may allow the HPD to cross a plurality of biological barriers and reach systematically through, for example, general circulation and thus avoid the needs for systematic administration (e.g., injection) and obviate the pain associated with the parenteral injection. The HPD of this disclosure exhibited high penetration rate through a biological barrier (e.g., about >10 times, about >50 times, about >100 times, about >200 times, about >300 times, about >500 times, about >1,000 times, about >10,000 times or higher than the penetration rate of prostaglandins or prostaglandin analogs if administered alone). No side effect was observed from 27953306.1:DCC-22 / 12 / 2025 2021236811  22 Dec 2025 the subjects to which were administered a HPD, while side effects were observed from the subjects to which the parent drug or anolog thereof was administered at the similar dosage. 5 It will be understood by those of skill in the art that numerous and various modifications can be made to the compounds, compositions, and / or methods of the present invention without departing from the spirit of the invention. Therefore, the various embodiments of the present invention described herein are illustrative only, and are not intended to limit the scope of the invention in any way. All patent or non-patent references cited 10 herein are incorporated by reference in their entirety. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers 15 or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or 20 information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A method for improving the stability of a pharmaceutical composition which comprises a high penetration drug substance and a pharmaceutically acceptable carrier, the method comprising:5       packaging the high penetration drug substance and the pharmaceuticallyacceptable carrier in separate containers; andreconstituting 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;10        wherein the reconstitution solution is applied transdermally, the high penetrationdrug substance comprises protonated amine group and ester bond in its molecule, the pharmaceutically acceptable carrier is an aqueous carrier, the concentration of the high penetration drug substance in the reconstitution solution is in the range of 3%-30% by weight, the pH of the reconstitution solution of the pharmaceutical15        composition is modified within the range of 3 to 6, andthe high penetration drug substance is selected from the group consisting of 2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl) propionate.HA, 2-(diethylamino)ethyl (R,S)-2-(2-fluoro-4-biphenyl)propionate.HA, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propionate.HA, 2-(dimethylamino)ethyl20       2-(p-isobutylphenyl)propionate.HA, 2-(dibutylamino)ethyl 2-(p-isobutylphenyl)propionate.HA, 2-pyrrolidinemethyl (R,S)-2-(p-isobutylphenyl)propionate.HA, 4-piperidineethyl (R,S)-2-(p-isobutylphenyl)propionate.HA, 1-pyrrolidineethyl (R,S)-2-(p-isobutylphenyl)propionate.HA, 1-piperidineethyl (R,S)-2-(p-25       isobutylphenyl)propionate.HA, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indole-3-acetate.HA, 2-(diethylamino)ethyl 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate.HA, 2-(diethylamino)ethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.HA, 2-(diethylamino)ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate.HA,30       2-(diethylamino)ethyl 3-(6-methoxy-2-naphthyl)propionate.HA, 2-(diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HA, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.HA, 2-(diethylamino)ethyl [(1-benzyl-1H-indazol-3-yl)oxy]acetate.HA, 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-35       benzoxazole]propionate.HA, 2-(diethylamino)ethyl 4,5-diphenyl-2-2021236811   23 Jun 2026oxazolepropionate.HA, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate.HA, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate.HA, 2-(diethylamino)ethyl acetylsalicylate.HA, 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-5       acetoxybenzoate.HA, H-Val-Pro-Gly-Pro-Arg(NO2)-OCH(CH3)2.HA, H-Ala-Pro-Gly-Pro-Arg(NO2)-OCH2CH3.HA, H-Val-Pro-Asp[OCH(CH3)2]-Pro-Arg(NO2)-OCH(CH3)2.HA, H-Tyr-Gly-Gly-Phe-Leu-OCH(CH3)2.HA, and H-Tyr-Gly-Gly-Phe-Met-OCH(CH3)2.HA, wherein HA is a pharmaceutically acceptable acid.10   2. The method according to claim 1, wherein the pharmaceutically acceptablecarrier is a mixture of water with alcohol, acetone, or DMSO.

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

4. The method according to any one of claims 1 to 3, wherein the pharmaceutically 15       acceptable carrier is an aqueous solution containing 10-35% ethanol by volume.

5. The method according to any one of claims 1 to 4, wherein the reconstitution solution is applied transdermally as a spray solution.

6. The method according to any one of claims 1 to 5, further comprising storing the reconstitution solution in a refrigerator at a temperature of 2-8oC after20        preparation.

7. The method according to any one of claims 1 to 6, wherein the pharmaceutical composition further comprises a pH adjusting and buffering agent in the pharmaceutically acceptable carrier.

8. The method according to claim 7, wherein the high penetration drug substance is 25       high penetration peptide; and the pH adjusting and buffering agent is a sodium,potassium, calcium, lithium, or magnesium salt of an organic acid.

9. The method according to claim 7, wherein the pH adjusting and buffering agent is sodium, potassium, or lithium salt of an organic acid selected from the group consisting of acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, 30        lactic acid, salicylic acid, citric acid, ascorbic acid, succinic acid, and maleic acid.

10. The method according to any one of claims 1 to 9, wherein the pH of the reconstitution solution of the pharmaceutical composition is modified within the range of 3 to 5.2021236811   23 Jun 202611. The method according to any one of claims 1 to 0, wherein the pH of the reconstitution solution of the pharmaceutical composition is modified within the range of 3.5 to 4.5.

12. The method according to any one of claims 1 to 11, wherein the concentration 5         of the high penetration drug substance in the reconstitution solution is in therange of 3%-20% by weight.

13. The method according to any one of claims 1 to 0, wherein the concentration of the high penetration drug substance in the reconstitution solution is in the range of 3%-10% by weight.10   14. The method according to any one of claims 1 to 0, wherein the high penetrationdrug substance is selected from the group consisting of 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)-5-15         methoxy-2-methyl-1 H-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, 220         (diethylamino)ethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl, 2-(diethylamino)ethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.HCl, 2-(diethylamino)ethyl [(1-benzyl-1H-indazol-3-yl)oxy]acetate.HCl, 2-(diethylamino)ethyl 2-[(4-chlorophenyl)-5-benzoxazole]propionate.HCl, 2-(diethylamino)ethyl 4,5-diphenyl-2-25         oxazolepropionate.HCl, 2-(diethylamino)ethyl 4-[bis(2-chloroethyl)amino]benzenebutyrate.HCl, 2-(diethylamino)ethyl 4-[bis(2-methylsulfonylethyl)amino]benzenebutyrate.HCl, 2-(diethylamino)ethyl acetylsalicylate.HCl, and 2-(diethylamino)ethyl 5-(2,4-difluorophenyl)-2-acetoxybenzoate.HCl.30   15. The method according to claim 0, wherein the concentration of the highpenetration drug substance in the reconstitution solution is 3-8% by weight, the pH of reconstitution solution is 3.5-4.5, and the pharmaceutically acceptable carrier is 15-35% ethanol in water by volume.

16. The method according to any one of claims 1 to 0, wherein the high penetration 35         drug substance is selected from the group consisting of H-Val-Pro-Gly-Pro-2021236811   23 Jun 2026Arg(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.

17. The method according to claim 16, wherein the concentration of the high5         penetration drug substance in the reconstitution solution is 3-8%, the pH ofreconstitution solution is 3.5-4.5, the pH adjusting and buffering agent is sodium acetate, and the pharmaceutically acceptable carrier is 15-35% ethanol in water by volume.

18. A reconstitution solution obtained from any one of the preceding claims 1 to 17.10   19. A treatment kit when used for improving the stability of a pharmaceuticalcomposition, comprising: a high penetration drug substance as described in claim 1 in a first container, a pharmaceutically acceptable carrier as described in claim 1 in a second container, and optionally a pH adjusting and buffering agent in the first container, the second container, or a separate third container, wherein15         the high penetration drug substance, the pharmaceutically acceptable carrier,and the optional pH adjusting and buffering agent are to be mixed together to form a reconstitution solution with a concentration of 3%-30% by weight and a pH value of 3 to 6.20

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