CN112438942A

CN112438942A - Pharmaceutical composition containing alkalizer and its synergist and its application

Info

Publication number: CN112438942A
Application number: CN201910813399.8A
Authority: CN
Inventors: 邹方霖; 邹礼常; 王建霞; 王艺羲
Original assignee: Chengdu Kuachang Aopu Medical Technology Co ltd
Current assignee: Chengdu Kuachang Aopu Medical Technology Co ltd
Priority date: 2019-08-30
Filing date: 2019-08-30
Publication date: 2021-03-05

Abstract

The present disclosure relates to a pharmaceutical composition comprising an alkalizing agent and its synergists, and the use of the pharmaceutical composition.

Description

Pharmaceutical composition containing alkalizer and its synergist and its application

Technical Field

Background

Due to the support of a great deal of research work, solid tumors are often used as research models for locally diseased diseases, especially refractory locally diseased diseases. A solid tumor is a neoplastic disease characterized by a tumor mass, which is a characteristic pathological tissue containing tumor cells. In the case of pancreatic cancer tumor bodies, pancreatic cancer cells account for only about 30% by volume of the tumor bodies. It can be seen that in addition to tumor cells, there are often a greater number of other components in tumor body tissue (sometimes also referred to as the microenvironment of the tumor cells), including other various cells, various intercellular substances, various ducts, etc.

Topical administration has the advantage of physically targeting the drug. It has therefore been thought that topical administration of cytotoxic drugs can increase the intratumoral concentration and thus the efficacy of the drug. However, topical administration of cytotoxic drugs has not shown a significant improvement in efficacy. Merely increasing its intratumoral concentration does not appear to significantly improve its efficiency in targeting cancer cells in intratumoral tissues. In addition to resorting to their sustained release forms, cytotoxic drugs are still almost systemically administered clinically. Chemical ablators (high purity ethanol, high concentration of acids and bases) are not characterized by cell destruction but by tissue destruction. Compared with cytotoxic drugs, it has almost no systemic effect of targeting cancer cells, but often shows higher local effect. However, they are often strong disrupters that do not sufficiently distinguish the target tissue from other tissues. This makes their practical application of intervention volumes (e.g., acid-base doses not exceeding 0.2ml/kg) and intervention sites very limited (e.g., restrictions on the organs in which the tumor resides, limited ablation of the tumor margins, etc.). Thus, chemical ablative agents have been clinically faded out of malignant solid tumors in the last decade. In fact, at present, there are few local drugs with high local safety and local curative effect in clinic.

Thus, there is still a need to develop new drugs, especially topical drugs, for the treatment of localized pathological conditions such as solid tumors to meet various clinical needs that the prior art has not yet been able to meet. In fact, there is an urgent need for the prevention and treatment of other localized conditions, particularly intractable localized conditions.

Disclosure of Invention

The invention aims to provide a local medicament for preventing and treating local pathological changes, in particular refractory local pathological changes. More specifically, it is an object of the present invention to provide a topical medicament that physically targets a localized lesion, but has lower side effects and higher efficacy.

According to one aspect of the present disclosure there is provided a topical pharmaceutical composition for the treatment of a topical pathological condition comprising an alkalising agent selected from one or more of a strong base and a weak base, a synergist of said alkalising agent selected from one or more of a cytotoxic drug and/or a conventional ineffective drug, and a suitable solvent, and in said pharmaceutical composition,

the concentration of the strong base is 0.5-5%;

the concentration of the weak base is 2-35%;

the concentration of the cytotoxic drug is 50-100% of the saturation concentration; and/or

The concentration of the conventional ineffective drug is 0.35-40%.

According to another aspect of the present disclosure, a method of treating a localized disease condition comprises administering to a localized diseased area of an individual in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an alkalizing agent, a co-product of the alkalizing agent and a suitable solvent, wherein the alkalizing agent is selected from one or more of a strong base and/or a weak base; the synergist is selected from one or more of cytotoxic drugs and/or conventional ineffective drugs, and in the pharmaceutical composition,

the concentration of the strong base is 0.5-5%;

the concentration of the weak base is 2-35%;

The concentration of the conventional ineffective drug is 0.35-40%.

Embodiments according to the present invention have the following advantages over the prior art for the treatment of localized disease conditions: compared with the existing cytotoxic drugs, the compound has almost non-toxic systemic safety and obviously higher local lesion curative effect; compared with the existing molecular targeted drugs, the compound has less rigorous screening of indications and great potential for rapidly growing tumor bodies, large tumor bodies and blood-poor tumor donors; compared with the existing chemical ablation agents, the chemical ablation agent has higher effectiveness and obviously lower local irritation and damage to surrounding normal tissues, so that the application range of the chemical ablation agent is wider and the application volume is higher. The applications and compositions of the present invention are also not plagued by the problem of drug resistance encountered with existing cytotoxic drugs and existing molecular targeted drugs. In addition, the application and the composition are convenient to prepare and low in cost, and are particularly beneficial to leading the vast population who is difficult to bear high expense to enjoy safe and effective treatment.

Detailed Description

In one aspect of the present disclosure, there is provided a topical pharmaceutical composition for the treatment of a topical pathological condition comprising an alkalizing agent, a synergist of said alkalizing agent and a suitable solvent, wherein said alkalizing agent is selected from one or more of a strong base and a weak base, said synergist is selected from one or more of a cytotoxic drug and/or a conventional ineffective drug, and in said pharmaceutical composition, the concentration of said strong base is 0.5-5%; the concentration of the weak base is 2-35%; the concentration of the cytotoxic drug is 50-100% of the saturation concentration; and/or the concentration of the conventional ineffective drug is 0.35-40%.

In another aspect according to the present disclosure, a method of treating a localized disease condition comprises administering to a localized diseased area of an individual in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an alkalizing agent, a co-product of the alkalizing agent and a suitable solvent, wherein the alkalizing agent is selected from one or more of a strong base and/or a weak base; the synergist is selected from one or more of cytotoxic drugs and/or conventional ineffective drugs, and the concentration of the strong base in the pharmaceutical composition is 0.5-5%; the concentration of the weak base is 2-35%; the concentration of the cytotoxic drug is 50-100% of the saturation concentration; and/or the concentration of the conventional ineffective drug is 0.35-40%.

In one embodiment, the concentration of the strong base is 0.75% or more or 1% or more, or 0.5 to 5%, preferably 0.75 to 5% or 1 to 5%.

In one embodiment, the concentration of the weak base is 2.5% or more, preferably 3.0% or more, or 5% or more, or 2.5 to 35%, preferably 3.0 to 35% or 5 to 35%.

In the context of the present invention, the term "pharmaceutical composition" is used to refer to a mixture of more than one drug uniformly distributed in the same dosage form.

In the context of the present invention, the term "topical active ingredient" is used to refer to an active ingredient in a topical medicament that provides an effective topical effect, typically an effective destructive effect on a topical lesion. The term "local effect" or "local activity" refers to a pharmacological effect or pharmacological activity at a target area that is produced primarily by the drug itself rather than by the drug-bearing blood. The term "topical drug (composition)" refers to a therapeutic drug (composition) that exerts its pharmacological effects primarily through local action. The term "target area" as used herein refers to the target site of administration, e.g., adjacent, interfacial, internal (preferably internal) to a localized lesion, etc.

Within the scope of the present invention, the term "therapeutically effective amount" refers to an amount of a drug that is used to treat a disease (e.g., a tumor) and achieve an effective effect (e.g., reduce or/and alleviate symptoms of the disease).

In the context of the present invention, unless otherwise indicated, the term "concentration" refers to the weight percent concentration (w/w) of the specified component in the topical pharmaceutical composition. The term "local administration concentration" refers to the concentration of a specified component at the time the drug is administered locally, which may be the concentration of the specified component at the site where the drug contacts the target area (e.g., injection needle hole or infusion tube outlet).

In the context of the present invention, the term "alkalinizing agent" is used to indicate basic compounds which are used primarily as adjuvants in the preparation of medicaments, more particularly for pH adjustment, and which generally do not introduce a particular biological activity in addition to providing alkalinity at the time of use. In the compositions disclosed herein, the alkalinizing agent comprises any pharmaceutically acceptable alkalinizing agent, preferably selected from those approved by the chinese, us or european official administrative department (e.g., FDA or chinese food and drug administration), or loaded in the chinese, us or european official pharmacopoeia or guidelines (e.g., "pharmaceutical excipients" in the fourth part of the chinese pharmacopoeia 2015 edition, or the "pharmaceutical excipients manual" fourth edition by r.c. ro et al).

In the context of the present invention, the term "alkalizing agent synergist" (often abbreviated to synergist) refers to a substance which under certain conditions (e.g. concentration and quantitative ratio) can act synergistically with the alkalizing agent.

Within the scope of the present invention, the pharmaceutical composition is a topical synergistic composition. Within the scope of the present invention, the alkalizer co-product is a topical co-product of the alkalizer. Within the scope of the present invention, the alkalizing agent and its synergists are locally synergistic in the same solution.

In the context of the present invention, the term "local synergy" refers to the synergistic effect of the drugs through local effects of local co-usage. The term "synergistic effect" means that the co-use of drugs (e.g., base salt of a polybasic weak acid and acid salt of a polybasic weak acid, strong base and acid salt of a polybasic weak acid) exhibits more therapeutically beneficial pharmaceutical effects than their separate use, including, for example, synergistic efficacy and synergistic safety. The term "synergistic efficacy" means that the active ingredients together exhibit a higher desired efficacy than either ingredient alone and/or that the combination does not exhibit the desired efficacy (e.g., tumor suppression rate) as either ingredient alone. The term "synergistic safety" refers to the combined use of active ingredients that exhibit a desired safety (e.g., irritation, damage to surrounding normal tissues) that is greater than that exhibited by either component alone, even though the combined effect is no greater than the maximum effect alone, it is an effective effect, and the combined safety is significantly greater than that exhibited by the maximum effect alone (e.g., antagonism of side effects), the combination also produces a synergistic effect.

In one embodiment, the synergistic composition is a synergistic safety composition. In one embodiment, the synergistic composition is a synergistic pharmacodynamic composition.

In the present disclosure, the alkalizing agent includes strong bases and weak bases. Wherein the strong base comprises an alkali metal hydroxide and an organic strong base. In the present disclosure, the alkali metal hydroxides include, for example: sodium hydroxide, potassium hydroxide, calcium hydroxide; such as choline.

In one embodiment, the strong base is preferably sodium hydroxide or/and potassium hydroxide.

In one embodiment, the strong base is preferably sodium hydroxide.

Within the scope of the present invention, the weak base is selected from one or more of the following groups: basic inorganic salt of polybasic weak acid, acidic inorganic salt of polybasic weak acid and nitrogenous weak base.

In the context of the present invention, the term "weak polybasic acid type inorganic salt" refers to weak polybasic acid type inorganic salts capable of ionizing hydrogen ions in water, preferably weak polybasic acid type inorganic salts as chemical ablants which are basic in 0.01M aqueous solution, preferably at pH >8.0 (e.g. disodium hydrogen phosphate, sodium hydrogen carbonate, potassium hydrogen carbonate). The term "polybasic weak acid basic inorganic salt" refers to a polybasic weak acid inorganic salt that is not capable of ionizing hydrogen ions in water, and includes the normal salts of a polybasic weak acid strong base inorganic salt. The term "weak nitrogen-containing base" refers to a weakly basic compound comprising nitrogen elements, wherein the weakly basic compound is preferably selected from weakly basic compounds having a solubility in water (w/w) of 2% or more.

In one embodiment, the polybasic weak acid basic inorganic salts include, for example, sodium phosphate, sodium carbonate, potassium carbonate, borax.

In one embodiment, the polybasic weak acid basic inorganic salt is sodium carbonate and/or sodium phosphate.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium carbonate, and the concentration of the sodium hydroxide is more than or equal to 0.5%, preferably 0.75-5%; the concentration of the sodium carbonate is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium phosphate, and the concentration of the sodium hydroxide is more than or equal to 0.5%, preferably 0.75-5%; the concentration of the sodium phosphate is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the polybasic weak acid acidic inorganic salt includes, for example, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, sodium hydrogen sulfate.

In one embodiment, the polybasic weak acid acidic inorganic salt is preferably sodium bicarbonate and/or disodium hydrogen phosphate.

In one embodiment, the weak base containing nitrogen is selected from the group consisting of ammonia, ammonia chloride, 2-aminoethanol, tromethamine, triethanolamine, tris, 2-aminoethanol, tromethamine, triethanolamine, meglumine, and meglumine, for example.

In one embodiment, the alkali metal salts of organic weak acids include, for example, potassium hydrogen phthalate, sodium acetate, sodium propionate, sodium butyrate, sodium malonate, sodium lactate, sodium citrate, sodium malate, sodium lauryl sulfate.

In one embodiment, the pharmaceutical composition comprises an alkalizing agent.

In one embodiment, the pharmaceutical composition comprises a plurality of basifying agents.

In one embodiment, the pharmaceutical composition comprises a plurality of alkalizing agents and has pH buffering capacity. In one embodiment, the pharmaceutical composition comprises a plurality of basifying agents and has a buffer capacity of>0.01mol·L^-1·pH^-1. In one embodiment, the pharmaceutical composition has a buffer capacity of 0.015 to 0.45 mol.L^-1·pH^-1. In one embodiment, the pharmaceutical composition has a buffer capacity of 0.04 mol.gtoreq.L^-1·pH^-1Preferably not less than 0.05 mol.L^-1·pH^-1. In one embodiment, the pharmaceutical composition has a buffer capacity of 0.04 to 0.45 mol.L^-1·pH^-1Preferably 0.05 to 0.45 mol.L^-1·pH^-1。

In the context of the present invention, the term "buffer capacity" (also known as buffer index) is used to indicate the amount (e.g.xmol) of strong monobasic acid (e.g.hydrochloric acid) or strong monobasic base (e.g.sodium hydroxide) required to be added when the pH of a unit volume (e.g.1L) of the pharmaceutical composition is changed by 1 unit, in mol. L^-1·pH^-1。

In one embodiment, the plurality of alkalizing agents in the pharmaceutical composition includes, for example, a plurality of alkalizing agent combinations listed in table 1 below.

TABLE 1

In one embodiment, the alkalizer comprises sodium hydroxide and sodium bicarbonate, and the concentration of the sodium hydroxide is 0.5% or more, preferably 0.75 to 5%; the concentration of the sodium bicarbonate is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the alkalizing agent comprises sodium hydroxide and sodium dihydrogen phosphate, and the concentration of the sodium hydroxide is 0.5% or more, preferably 0.75-5%; the concentration of the sodium dihydrogen phosphate is more than or equal to 2 percent, and is preferably 2 to 10 percent.

In one embodiment, the alkalizer comprises sodium carbonate and sodium bicarbonate, and the concentration of the sodium carbonate is ≥ 1.5%, preferably 3-10%; the concentration of the sodium bicarbonate is more than or equal to 2.5 percent, and is preferably 4-15 percent.

In one embodiment, the alkalizing agent comprises disodium hydrogen phosphate and sodium dihydrogen phosphate, and the concentration of the disodium hydrogen phosphate is ≥ 1.5%, preferably 2-7%; the concentration of the sodium dihydrogen phosphate is more than or equal to 2 percent, and is preferably 3 to 10 percent.

In one embodiment, the alkalizer comprises sodium hydroxide and potassium chloride, and the concentration of the sodium hydroxide is 0.5% or more, preferably 0.75 to 5%; the concentration of the potassium chloride is more than or equal to 1 percent, and is preferably 1.5 to 10 percent.

Within the scope of the present invention, the said synergist is selected from one or more of cytotoxic drugs and/or conventional ineffective drugs.

In the present disclosure, the term "cytotoxic drug" is used to refer to a drug that is effective in treating a localized disease condition (e.g., a solid tumor) by its cytotoxicity through absorption at a safe dose, and is selected from cytotoxic drugs known in the art, preferably from cytotoxic drugs approved or to be approved by or loaded in chinese, us, or european official administrative departments (e.g., FDA or chinese drug administration) as if they were anti-tumor chemotherapeutic drugs. The term "absorption" as used herein refers to a pharmacological effect resulting from the formation of drug-bearing blood into the target area by blood absorption of the drug; the term "absorbed drug" refers to a therapeutic drug that exerts its pharmacological effect primarily through absorption.

In the context of the present disclosure, the term "conventional ineffective drug" is used in distinction to a conventionally effective drug (e.g., a cytotoxic drug) and refers to a drug that may exhibit an effect against a specific cell (e.g., an antitumor cell effect) in a drug-cell mixture in a cell experiment, but may not exhibit a more effective inhibitory effect than the conventionally effective drug by absorption (via medicated blood in a localized disease) in an animal experiment, and thus may not be approved by a drug administration (e.g., FDA) as a drug effective in treating a specific localized disease, such as a non-anti-localized disease drug, a nutraceutical, a diagnostic drug, a pharmaceutical adjuvant, and the like.

In one embodiment, the concentration of cytotoxic drug is 50% or more, preferably 50 to 100% of its solubility in the pharmaceutical composition.

In one embodiment, the conventional ineffective drug is 0.35% or more, preferably 0.35% to 20%.

In one embodiment, the cytotoxic drug is selected from one or more of the following groups: drugs that disrupt the structure and function of DNA, drugs that interfere with transcribed RNA embedded in DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis, preferably one or more selected from the group consisting of: alkylating agents such as cyclophosphamide, carmustine; metal platinum complexes such as cisplatin, carboplatin; DNA topoisomerase inhibitors such as doxorubicin, topotecan, irinotecan; anti-tumor antibiotics such as actinomycins, daunorubicin; pyrimidine antagonists such as uracil derivatives 5-fluorouracil, furfluorouracil, bifurcofurouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine; taxanes such as paclitaxel, docetaxel.

In one embodiment, the cytotoxic agent is selected from the group consisting of the alkylating agents (e.g., cyclophosphamide, carmustine, etc.), and the concentration (w/v) of the alkylating antineoplastic drug in the topical pharmaceutical composition is 0.5-6%, preferably 0.75-1.5%.

In one embodiment, the cytotoxic agent is selected from the group consisting of the metal platinum complexes (e.g. cisplatin, carboplatin, etc.) and the concentration (w/v) of the metal platinum complex in the topical pharmaceutical composition is from 0.03 to 0.15%, preferably from 0.05 to 0.15%.

In one embodiment, the cytotoxic agent is selected from the group consisting of the DNA topoisomerase inhibitors (e.g. doxorubicin, topotecan, irinotecan, etc.) and the concentration (w/v) of the DNA topoisomerase inhibitor in the topical pharmaceutical composition is from 0.05 to 0.20%, preferably from 0.075 to 0.15%.

In one embodiment, the cytotoxic agent is selected from the group consisting of the anti-tumor antibiotics (e.g., actinomycins, daunorubicin, etc.), and wherein the concentration (w/v) of the anti-tumor antibiotic in the topical pharmaceutical composition is 1-4%, preferably 1-2%.

In one embodiment, the cytotoxic drug is selected from pyrimidine antagonists (e.g. uracil derivatives 5-fluorouracil, furacil, bifacil fluorouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine, etc.) and the concentration (w/v) of the pyrimidine antagonist in the topical pharmaceutical composition is 0.5-2%, preferably 0.75-1.5%.

In one embodiment, the cytotoxic drug is selected from the group consisting of said taxanes (e.g. paclitaxel, docetaxel, etc.) and the concentration (w/v) of said taxanes in said topical pharmaceutical composition is 0.5-2%, preferably 0.75-1.5%.

In one embodiment, the conventional ineffective drug is one or more selected from one or more of the following groups: amino acid nutrients, carbohydrate nutrients, lipid nutrients, pigment aromatic compounds, salicylic acid compounds and quinine compounds.

In one embodiment, the pharmaceutical composition comprises one or more of the basifying agents and one or more of the conventional ineffective drugs.

In one embodiment, the pharmaceutical composition comprises one or more of the basifying agents, one or more of the conventional ineffective drugs, and one or more weak acids.

In one embodiment, the pharmaceutical composition comprises one or more of the basifying agents and a plurality of the conventional ineffective drugs.

In one embodiment, the pharmaceutical composition comprises one or more of the basifying agents, one or more of the cytotoxic agents, and one or more of the conventional ineffective agents.

In one embodiment, the conventional ineffective drug is selected from the amino acid based nutrients.

In one embodiment, the conventional ineffective drug is selected from the group consisting of the carbohydrate nutrients.

In one embodiment, the conventional ineffective drug is selected from the group consisting of the liponutrients.

In one embodiment, the conventional ineffective drug is selected from the group consisting of the pigmented aromatic compounds.

In one embodiment, the conventional ineffective drug is selected from the salicylic acid-based compounds.

In one embodiment, the conventional ineffective drug is selected from the quinines.

In one embodiment, the conventional ineffective drug is selected from the group consisting of the amino acid based nutrient and the carbohydrate nutrient.

In one embodiment, the conventional ineffective drug is selected from the group consisting of the amino acid based nutrients and the pigment aromatic compounds.

In one embodiment, the conventional ineffective drug is selected from the group consisting of the amino acid based nutrients and the quinines.

In one embodiment, the concentration (w/v) of the amino acid based nutrient is not less than 5%, preferably 10-35%.

In one embodiment, the concentration (w/v) of the carbohydrate nutrient is not less than 5%, preferably 5-40%.

In one embodiment, the concentration of the lipid nutrient is greater than 5%, preferably 10-30%.

In one embodiment, the concentration (w/v) of the pigment aroma compound is 0.35% or more, preferably 0.35-10%.

In one embodiment, the concentration (w/v) of the salicylic acid-based compound is not less than 2%, preferably 2-30%.

In one embodiment, the concentration (w/v) of the quinine compound is not less than 2%, preferably 2-10%.

In the context of the present invention, the term "amino acid based nutrient" refers to amino acids and small molecule (molecular weight <3000) derivatives thereof having a nutraceutical effect.

In the context of the present invention, the term "carbohydrate nutrient" is used to indicate a carbohydrate compound having a nutraceutical effect, preferably selected from monosaccharides, carbohydrate polymers and carbohydrate derivatives having a nutraceutical effect, more preferably selected from carbohydrate nutraceuticals and carbohydrate excipients having a nutraceutical effect as carried in the chinese, us or european official pharmacopoeia or guidelines, including for example monosaccharides or their derivatives from the group: glucose, ribose, deoxyribose, xylose, fructose, galactose and fucose.

In the context of the present invention, the term "liponutrient" is used to refer to a lipo-compound having a nutraceutical effect, preferably selected from lipo-compounds having a nutraceutical effect as carried in the chinese, us or european official pharmacopoeia or guidelines, more preferably selected from one or more of the following groups: lipids, fatty acids, fatty milks and lipids.

In the context of the present invention, the term "chromoaromatic compound" refers to a pharmaceutically acceptable aromatic compound capable of selectively absorbing or reflecting light of a specific wavelength at a target region, which may include, for example, vital dyes, photosensitizers, and colored chemotherapeutic agents. The vital dyes may for example comprise one or more of the following organic dyes and derivatives thereof: methylene blue (including its hydrates), patent blue, isothio blue, toluidine blue, trypan blue, basic blue, eosin, basic fuchsin, crystal violet, gentian violet, neutral red, janus green B, safranin, bengal red, and the like. The photosensitizer may include, for example, one or more of the following: mixed porphyrin photosensitizers, porphyrin-based compounds (e.g., porphyrin, porphine, purpurin, endogenous porphyrin) and derivatives thereof, phthalocyanine-based compounds, bacteriochlorin-based compounds, fused ring quinone-based compounds, benzoporphyrin derivatives, 5-aminolevulinic acid, chlorins-based compounds, and the like. The colored chemotherapeutic agent may be, for example, one or more of the following: nitrophenol compounds, flavonoid compounds (e.g., anthocyanins, genistein, etc.), isohexenylnaphthoquinone compounds (e.g., alkannins), and the like. Taking methylene blue as an example, the derivative thereof is also generally a dye, such as 1, 9-dimethylmethylene blue, 1-methylmethylene blue, and the like. Some of the colored aromatic compounds, such as methylene blue, are both vital dyes, photosensitizers, and colored chemotherapeutic agents.

In the context of the present disclosure, the term "salicylic acid-like compounds" is used to refer to salicylic acid and its derivatives. The Salicylic acid (Salicylic acid) has the chemical name of 2-hydroxybenzoic acid. The salicylic acid derivative may be any suitable one known to those skilled in the art, and may be, for example, a salicylic acid derivative including a metal-containing compound and a salicylic acid derivative containing no metal compound. The former may be, for example, sodium salicylate, magnesium salicylate, zinc salicylate, metal element complex (e.g., copper Aspirin), and the like, while the latter may include, for example, acetylsalicylic acid (Aspirin), lysine Aspirin, difluorosalicylic acid, aminosalicylic acid, p-aminosalicylic acid, N-phenylanthranilic acid, salicylanilide, o-ethoxybenzamide, phenyl salicylate, methyl paraben, ethyl paraben, salsalate, dicumarol, and pharmaceutically acceptable derivatives thereof.

In the context of the present disclosure, the term "quinine-like compounds" is used to refer to pharmaceutically acceptable quinines and structural analogs thereof, such as quinine and isomers and pharmaceutically acceptable salts thereof. Examples of the quinine isomer include quinidine, cinchonine and cinchonidine, and examples of the salt thereof include quinine hydrochloride, quinine dihydrochloride, and quinine sulfate.

In one embodiment, the pharmaceutical composition comprising the alkalizing agent and its synergists (exemplified only by amino acid based nutrients) includes, for example, the compositions listed in table 2 below.

TABLE 2

In one embodiment, the amino acid based nutrient is selected from one or more of a basic amino acid and/or a non-basic amino acid based nutrient, wherein the basic amino acid based nutrient is for example arginine, lysine, histidine, preferably arginine; such as one or more of the following groups: neutral amino acids, acidic amino acids, amino acid salts, wherein the neutral amino acids are, for example: glycine, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, alanine, valine, leucine, isoleucine, phenylalanine, proline, such as: aspartic acid, glutamic acid, the amino acid salt including the amino acid and acid salt, such as lysine hydrochloride, histidine hydrochloride, glutamic acid hydrochloride, cysteine hydrochloride, arginine hydrochloride, glycine sulfate, lysine hydrochloride, aspartic acid hydrochloride.

In one embodiment, the amino acid nutrient is preferably one or more amino acids selected from the group consisting of: arginine, lysine, glycine, tryptophan, serine, cysteine, glutamine, proline.

In one embodiment, the concentration of the amino acid based nutrient is preferably ≥ 5%, preferably 7.5-35%.

In one embodiment, the amino acid nutrient comprises arginine. In one embodiment, the amino acid nutrient is arginine, and the concentration of arginine is ≥ 10%, preferably 10-20%.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium bicarbonate, the amino acid nutrient is arginine, and the concentration of the sodium hydroxide is 0.5% or more, preferably 0.75-5%; the concentration of the sodium bicarbonate is more than or equal to 2.5 percent, and is preferably 4 to 15 percent; the concentration of the arginine is more than or equal to 10 percent, and preferably 10 to 20 percent.

In one embodiment, the chemical ablative agent is sodium carbonate, the pH adjusting agent is sodium bicarbonate, the amino acid nutrient is arginine, and the concentration of the sodium carbonate is more than or equal to 1.5%, preferably 2-10%; the concentration of the sodium bicarbonate is more than or equal to 1 percent, and is preferably 1 to 5 percent; the concentration of the arginine is more than or equal to 10 percent, and preferably 10 to 20 percent.

In one embodiment, the amino acid based nutrient comprises glycine. In one embodiment, the amino acid based nutrient is glycine and the concentration of glycine is ≥ 10%, preferably 10-25%.

In one embodiment, the amino acid based nutrient comprises lysine hydrochloride.

In one embodiment, the amino acid nutrient is a mixture of 2 or more amino acid nutrients.

In one embodiment, the carbohydrate nutrient is one or more selected from the group consisting of: glucose, fructose, chitosan oligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, xylo-oligosaccharide, fructo-oligosaccharide, manno-oligosaccharide, xylitol, more preferably selected from one or more of the following: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannooligosaccharide and xylitol, wherein the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is more than or equal to 10 percent, and is preferably 10-40 percent.

In one embodiment, the liponutrient is one or more selected from the group consisting of: vegetable oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat milk, medium-chain fat milk, phospholipids, and the concentration (w/v) of the lipid nutrient in the pharmaceutical composition is not less than 4%, preferably 4-25%.

In one embodiment, the pigment aroma compound is one or more selected from the group consisting of: methylene blue, patent blue, isothio blue, bengal red, and in the pharmaceutical composition the concentration (w/v) of the pigmentary aromatic compound is not less than 0.35%, preferably 0.5-10%.

In one embodiment, the salicylate compound is one or more selected from the group consisting of: salicylic acid, acetylsalicylic acid, aspirin-lysine, and in the topical pharmaceutical composition, the concentration (w/v) of the salicylic acid compound is not less than 5%, preferably 5-10%.

In one embodiment, the quinine compound is one or more selected from the group consisting of: quinine hydrochloride, quinine dihydrochloride and quinine sulfate, and in the topical pharmaceutical composition, the concentration (w/v) of the quinine compound is more than or equal to 3 percent, and is preferably 3-6 percent.

The pharmaceutical composition according to the present disclosure may be any dosage form suitable for topical administration which may comprise the active ingredient (the pharmaceutical composition, and optionally other drugs as described above), preferably the following dosage forms: injections (preferably topical injections), external liquids, and aerosols.

In the context of the present invention, the term "injectable formulation" is used to refer to a sterile formulation containing an active ingredient and a liquid carrier and intended for in vivo administration. The injection is classified into a local injection, an intravenous injection, etc. according to the administration mode, and the intravenous injection can be used as the local injection only after the given local administration concentration. The injection is classified into liquid injection, powder injection for injection, etc. according to its commercial form. The powder injection for injection comprises sterile dry powder and a solvent, wherein the sterile dry powder contains part or all of active ingredients, and the solvent contains all of liquid carriers. The concentration of the active ingredient in an injection is the concentration of the active ingredient in its mixture with the entire liquid carrier, usually in the liquid drug at the end point (e.g. needle hole, catheter outlet, etc.) of a topical administration device (syringe, piercer, infusion catheter, etc.). For injectable powder injections, the concentration of the active ingredient is the concentration of the active ingredient in a mixture of sterile dry powder and vehicle (e.g., a reconstituted solution, or the pharmaceutically acceptable liquid carrier).

In the context of the present invention, the term "topical liquid formulation" refers to a liquid medicament comprising an active ingredient and a liquid carrier and intended for topical administration [ e.g., to the skin, mucous membranes (e.g., ocular, nasal, etc.) or/and oral passages (e.g., oral, rectal, vaginal, urethral, nasal, auditory, etc.) ], and includes, e.g., lotions, liniments, drops, gargles, lotions, and the like. When the liquid medicine is locally administered, the liquid medicine is usually from a washing liquid bottle, a dropping liquid pipe, a washing liquid bottle for a person to be cleaned, a cotton swab and other local administration instruments. The concentration of the active ingredient in the external liquid preparation is the concentration of the active ingredient in the liquid medicine.

In the context of the present invention, the term "nebuliser" refers to a dosage form comprising an active ingredient and a liquid carrier and which, in use, is administered by nebulising under pressure a liquid medicament as described above, for administration to the skin, mucous membranes (e.g. ocular, nasal, etc.) or/and the oral tract (e.g. oral, rectal, vaginal, urethral, nasal, auditory etc.), including for example aerosols, sprays, nebulisers and the like. For topical administration, nebulization of liquid drugs is often accomplished by means of topical administration devices such as aerosols, nebulizers, and the like. After the medicine is atomized and sprayed to the target position, the medicine is accumulated to form liquid medicine. The liquid medicament is substantially identical in composition to the liquid medicament prior to aerosolization. Thus, the concentration of the active ingredient in the nebulant may be expressed in terms of the concentration of the active ingredient in the liquid medicament prior to nebulisation.

It will be appreciated by those skilled in the art that according to the present invention, the pharmaceutical composition of the present invention should be formulated for local administration to the target area, preferably as a topical pharmaceutical formulation.

According to the preparation method of the present invention, the preparation of the pharmaceutical composition of the present invention comprises the steps of: a liquid medicament is prepared containing the essential components (e.g. the pharmaceutical composition) and optionally other substances. The liquid drug may be a solution (e.g. a solution in a hydrophilic vehicle, preferably an aqueous solution), a suspension, or an emulsion. When the liquid drug is a suspension, the dispersion medium may be any suitable medium known to those skilled in the art, such as a micro-material or a nano-material. When the liquid drug is an emulsion, the dispersion medium may be any suitable one known to those skilled in the art, such as a vegetable oil, a synthetic oil or a semi-synthetic oil which may be used for injection. Wherein the vegetable oil may be, for example, cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and peanut oil.

According to the preparation method of the present invention, the concentration of the pharmaceutical composition and the other drug is greater than or equal to the concentration thereof in the pharmaceutical composition of the present invention. When the concentration is more than that in the pharmaceutical composition of the present invention, it can be further diluted for use.

According to one embodiment of the preparation method of the present invention, the liquid injection of the pharmaceutical composition of the present invention can be prepared by a method comprising the following steps: 1) the necessary components (e.g. the pharmaceutical composition) and optionally other components in the amounts required in accordance with the concentration for topical administration are added to water to prepare a liquid; 2) adding other optional medicines into the liquid prepared in the step 1) according to the required amount of the local administration concentration, and uniformly mixing to obtain a liquid medicine; 3) sterilizing the liquid medicine prepared in the step 2) and preparing the liquid injection. When in use, the bacteria-removing liquid medicine in the liquid injection can be directly used as a local administration liquid medicine or used as a diluted liquid medicine.

According to one embodiment disclosed herein, the powder injection for injection of the pharmaceutical composition of the present invention may be prepared by a method comprising the steps of: preparing a sterile dry powder containing a desired amount of the pharmaceutical composition according to the topical administration concentration; and preparing a sterile vehicle containing the optional other components in the required amounts according to the concentration for topical administration. The sterile dry powder is preferably sterile freeze-dried powder, and the preparation method comprises the following steps: 1) preparing a solution comprising amino acids as nutrients, poorly water-soluble neutralizing substances and optionally other components; 2) sterilizing, filtering and packaging; 3) freeze drying; 4) and (5) plugging and capping. The freeze-drying process conditions include, for example: the pre-freezing condition is that the temperature is kept at minus 45 ℃ for 4 hours; sublimation drying condition is that the heating rate is 0.1 ℃/min, and the heating is kept for at least 10 hours when the temperature is raised to-15 ℃; the desorption drying conditions were 30 ℃ for 6 hours. When in use, the sterile dry powder of the powder injection for injection is redissolved in a sterile solvent to form a redissolved liquid medicine which can be directly used as a local administration liquid medicine or diluted.

According to one embodiment of the preparation method of the present invention, the external liquid formulation of the pharmaceutical composition of the present invention is prepared by a method comprising the steps of: the liquid medicament is prepared by adding the required amount of the pharmaceutical composition according to the topical administration concentration and optionally other components to the vehicle. In use, the liquid medicine in the liquid preparation for external use may be used as a liquid medicine for topical administration directly or after dilution.

According to one embodiment of the method of preparation of the present invention, the pharmaceutical composition nebulizer of the present invention may be prepared by a method comprising the steps of: 1) adding the required amount of the pharmaceutical composition according to the local administration concentration and the atomization excipient into the solvent to prepare liquid; 2) adding other optional components which are required according to the local administration concentration into the liquid prepared in the step 1) and uniformly mixing to obtain the liquid medicine. Common atomizing excipients include, for example: glycerin, polysorbate-80, benzalkonium chloride, microcrystalline cellulose-sodium carboxymethyl cellulose, and the like. In use, the liquid medicament is applied to an atomiser (e.g. a spray) and is applied topically to a target area in the form of a spray-on stick, under atomisation, which sticks to the target area as liquid medicament.

In accordance with the principles of these methods described above, one skilled in the art can prepare a variety of specific dosage forms comprising the compositions of the present invention by any suitable specific method. For example, variations in the pharmaceutical compositions of the invention include: the composition may contain different kinds and concentrations of the pharmaceutical composition, different kinds and concentrations of other drugs, different kinds and concentrations of other additives (e.g., analgesics, activators, etc.).

In the present disclosure, the pharmaceutical composition is primarily for use in the prevention and treatment of localized disease conditions, especially refractory localized disease conditions, by topical administration.

In the context of the present invention, the term "locally diseased disease" refers to a disease with locally diseased symptoms, whereas the term "locally diseased" refers to structural, morphological or functional abnormalities, native or secondary to a local part of the animal (preferably human) body, which may for example include one or more of the following: tumor body, non-tumor, local inflammation, secretion function disorder of secretory gland, etc. The local site may be any suitable one known to those skilled in the art, and may for example be a local site in an organ comprising one or more of: secretory organs where the secretory system is located, cardiovascular organs where the blood circulatory system is located, skin, and the like.

Local administration requires that the drug composition (local active ingredient, composition ratio and component concentration) be administered by interventional means to the tissue where the local lesion is located and produce the desired therapeutic effect in that tissue. For example, when the lesion is a tumor, the local tissue is the tumor body in which the tumor cells are located; when the lesion is a non-neoplastic mass, the local tissue is an abnormality such as a mass, e.g., a hyperplastic, cyst, nodule, or other lesion mass; when the lesion is local inflammation, the local tissue is an inflamed area, such as a general inflamed mass; when the lesion is abnormal secretion, the local tissue is the source of the abnormality or the secretory gland in which it is located. For another example, when the disease is abnormal insulin secretion, the abnormality is caused in the islets of langerhans, and the local tissue is the islets of langerhans or the pancreas in which the islets of langerhans are located; when the condition is a skin condition, the localized tissue is the diseased skin or an appendage of the diseased skin.

Specifically, in the present disclosure, the local lesions include tumors, non-tumor enlargement, local inflammation, secretory gland dysfunction and skin diseases.

In the context of the present invention, the term "tumor" refers to a mass formed due to abnormal proliferation of cells or mutated cells, which includes solid tumors. The term "solid tumor" refers to a tumor having a tumor body, which may be due to any pathology (malignant and non-malignant) and at any stage of the tumor, including for example the following groups classified by tumor cell type: epithelial cell tumors, sarcomas, lymphomas, germ cell tumors, blastomas; and tumors named as the organ or tissue in which the tumor cell foci are located, including, for example, tumors named as the following organs or tissues: skin, bone, muscle, breast, kidney, liver, lung, gall bladder, pancreas, brain, esophagus, muscle of the shoulder, large intestine, small intestine, spleen, stomach, prostate, emerald, ovary, or uterus.

Specifically, the malignant tumor includes, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, stomach cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer, and the like.

The non-malignant tumor includes, for example, breast tumor, pancreatic tumor, thyroid tumor, prostate tumor, liver tumor, lung tumor, intestinal tumor, oral tumor, esophageal tumor, stomach tumor, nasopharyngeal tumor, laryngeal tumor, testicular tumor, vaginal tumor, uterine tumor, fallopian tube tumor, ovarian tumor, etc.

In one embodiment, the localized disease condition comprises a non-neoplastic enlargement. The term "non-neoplastic enlargement" refers to enlargement other than a tumor, and includes, for example, hyperplasia (e.g., hyperplasia of the breast, pancreas, thyroid, parathyroid, prostate, etc.), cyst (e.g., cyst of the breast, thyroid, parathyroid, etc.), nodule (e.g., nodule of the breast, thyroid, parathyroid, etc.), abnormal vein mass (e.g., hemorrhoid, etc.), localized inflammatory edema, microbial infection edema, etc. The hemorrhoid includes internal hemorrhoid, external hemorrhoid, and mixed hemorrhoid.

In one embodiment, the localized disease condition comprises localized inflammation, particularly refractory inflammation. Within the scope of the present invention, the term "local inflammation" refers to a non-neoplastic inflammation at a local site, including for example, inflammatory inflammation (inflammatory inflammation), exudative inflammation (inflammatory inflammation) and proliferative inflammation, which may be any suitable one known to the skilled person, and may for example include one or more of the following: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, and oophoritis.

In one embodiment, the topical pathological condition includes a skin condition, particularly an intractable skin condition. Within the scope of the present invention, the term "skin disease" refers to a lesion native or secondary to the skin or skin appendages, which may be any suitable one known to a person skilled in the art, and may for example include one or more of the following: skin cancer, non-malignant tumors of the skin, viral skin diseases (e.g., herpes, warts, rubella, hand-foot-and-mouth disease), bacterial skin diseases (e.g., impetigo, furuncle, leprosy), fungal skin diseases (e.g., various ringworm), sexually transmitted diseases (e.g., syphilis, gonorrhea, and condyloma acuminatum), allergic and autoimmune skin diseases (e.g., contact dermatitis, eczema, urticaria), physical skin diseases (e.g., solar skin diseases, chilblain, corns, rhagades of hands and feet, pressure sores), connective tissue diseases (e.g., lupus erythematosus), skin disorders (e.g., freckles, pigmented nevi, various plaques), skin appendages diseases (e.g., acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis, and bromidrosis).

In one embodiment, the localized disease condition comprises secretory dysfunction of a secretory gland. Within the scope of the present invention, the term "secretory gland" refers to a structure composed of gland cells or gland cell groups that performs a secretory function (secretion), which includes exocrine glands and endocrine glands. The secretory gland secretory dysfunction includes secretory gland hyperfunction (for example, hyperthyroidism) and secretory gland hypofunction (for example, hypothyroidism and islet hypofunction (one of diabetes)).

In one embodiment, the localized disease condition comprises cardiovascular disease. Interventional therapy has become an important treatment for cardiovascular diseases. Such cardiovascular diseases include, for example, hemangiomas, hypertrophic obstructive cardiomyopathy, atrial fibrillation, cardiac arrhythmias, arterial emboli, and the like.

The topical drug in the present invention is a therapeutic drug, which, when used for the prevention and treatment of a localized disease, can also be administered in combination with other interventions, systemic chemotherapy, immunotherapy, photodynamic therapy, sonodynamic therapy, surgical intervention or a combination of such therapies to further enhance the therapeutic effect.

In the present disclosure, the pharmaceutical composition is primarily for use in the prevention and treatment of localized disease conditions by topical administration.

In the use and method for the topical treatment and prevention of locally varying diseases according to the present disclosure, the one containing the alkalizing agent and its local co-product is administered locally in their concentration or amount ratio in the topical pharmaceutical composition. The concentration or amount provides a synergistic effect on the local response compared to local administration.

Based on the studies described in more detail below, although the specific mechanism remains to be further studied, the pharmaceutical composition of the present invention exhibits a pharmaceutical effect of promoting effective destruction of the relevant structures of the tissues in which the local lesion is located (e.g., the lesion tissue, the lesion cells, and any structure involved in constituting them), while minimizing damage to the normal tissues of the patient, thereby achieving safe and effective treatment of the local lesion disease.

Examples

The present invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention thereto. In the following examples, all experimental animals were performed according to the relevant regulations and industry discipline. Unless otherwise specified, all tests were carried out according to the usual methods.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified. The partial alkalizing agents, water-soluble electrolytes and antitumor agents used in the following examples are listed in Table 3.

TABLE 3

Class (c): 1 is strong base, 2 is polybasic weak acid type inorganic salt, 3 is polybasic weak acid type inorganic salt, 4 is other weak base, 5 is amino acid type nutrient, 6 is other medicine

The experimental animals used in the following examples were all purchased from professional laboratory animals company and were all SPF (Specific Pathogen Free) grade animals. Taking mice as an example, there are 2 species: BALB/c mouse, nude mouse, wherein the nude mouse is mutation line (BALB/c-nu) mouse obtained by introducing nude gene (nu) into BALB/c mouse. The mice are healthy females with the age of 6-8 weeks and the body weight of 17.5-20.5 g.

In the following examples, unless otherwise indicated, subcutaneous transplantation of tumor animals was performed according to the general practice of subcutaneous inoculation of solid tumor cells according to the guidelines issued by the drug administration. Unless otherwise indicated, solid tumors grow to the desired volume (e.g., mice carry tumors 30-500 mm)³) Then for successful modeling, the model was randomly divided into experimental groups of 6 animals each using PEMS 3.2 software (compiled by the national institutes of public health, western, university, Sichuan). Items for experimental observation, measurement and analysis include general state, body weight, food intake, animal graft versus host disease, solid tumor volume, tumor weight, survival time, and the like.

The tumor volume calculation formula is as follows:

tumor volume (V) ═ l/2 × a × b²Wherein a represents the tumor length and b represents the tumor width.

The tumor growth inhibition rate (abbreviated as tumor inhibition rate in the invention) is calculated by the following formula:

tumor inhibition rate Y (%) ═ (CW-TW)/CW × 100%, where TW is the average tumor weight of the study group; CW is the average tumor weight of the negative control group.

In the following examples, experimental results (e.g. tumor weights) are expressed as means ± standard deviation (x ± s), differences between two experimental animal groups and group means are compared by significance test using statistical software SPSS 13.0 or SPSS 19.0, tests are performed using statistic t, test level α is 0.05, P <0.05 indicates that the difference is statistically significant, otherwise it is not statistically significant.

Within the scope of the present invention, the combination of drug A and drug B is designated as B/A. The effect (including efficacy and safety) of the combination of drugs can be theoretically determined according to the judgment of q:

q-actual combined effect/theoretical purely additive expected effect.

When q is 1, the actual combined effect is in accordance with theoretical expectations, showing additive effect; when q is<1, the actual combined effect is weaker than the theoretical expectation, and the antagonism is shown; when q is>1, the actual combined action is over the theoretical expectation, and the synergistic effect is shown. A, B Single use efficacy (denoted respectively as E) unless otherwise indicated_A、E_B) Actual combined drug effects of A and B (denoted as E)_A+B) All are tumor inhibition rates. The q calculation formula has many calculation methods for simply adding the expected drug effect theoretically, and most methods aim at the cell experimental effect.

Improving the drug effect of antitumor drugs is always the biggest medical problem in the world. Even a few percent of efficacy is difficult and difficult to improve, so that the theoretical expectation of drug combination in animal experiments is usually not high, and once the drug combination is realized, the significance is great. A method for judging the drug effect of an anti-tumor combined drug commonly used in animal experimental literature is based on the hypothesis that: the actual combined action is obviously superior to the single-medicine action, which is the super-theoretical expectation. The concrete judgment is as follows: (E)_A+B>E_AAnd E_A+B>E_B) And the tumor weight difference of the composition group and each group has statistical significance (all are p)<0.005)。

Another method for determining the combined effect in animal experiments is the Burgi method (Burgi Y. Pharmacology; Drug actions and reactions. cancer res.1978, 38 (2); 284) 285). The Burgi method is improved by Jinzheng (Jinzheng, the addition of the combined medicines, Chinese pharmacology newspaper 1980; 1(2), 70-76), and q is calculated as:

q＝E_A+B/(E_A+E_B-E_A·E_B)，

wherein (E)_A+E_B-E_A·E_B) The expected effect is simply added for the pharmacology theory of A drug and B drug.

The determination of the effect of the combination of drugs in the following antitumor animal experiments is shown in Table 4:

TABLE 4

Example 1: preparation of the composition

Numerous different topical pharmaceutical compositions of the present invention can be formulated according to the above-described method of preparing the pharmaceutical composition of the present invention. Several examples of the preparation tests of the pharmaceutical composition of the present invention are listed below.

1. Preparation of liquid injection

The essential components (such as 1g of sodium hydroxide as an alkalizer and 25g of arginine as a synergist and 1g of 5-fluorouracil) in the pharmaceutical composition, optional other components and a liquid carrier (such as water for injection) which is constant to the total volume (such as 100ml) are measured according to the required concentration, slowly mixed uniformly, sterilized, filtered and distributed into required quantities (such as 10 ml/bottle) for storage and standby. The preparation (e.g. 1% 5-fluorouracil/20% arginine/1% aqueous sodium hydroxide) can be administered topically as a liquid drug.

2. Preparation of powder injection for injection

The necessary components (such as 1g of sodium hydroxide as an alkalizer and 1g of 5-fluorouracil as a synergist) and other optional components in the pharmaceutical composition are measured according to the required concentration, and a liquid carrier (such as water for injection) is added to a total volume (such as 100ml), and the components are slowly mixed uniformly, sterilized, filtered, subpackaged to the required volume (such as 10 ml/bottle), freeze-dried, corked and capped, and prepared into sterilized dry powder for later use.

The desired amount of sterile dry powder (e.g., 1 vial of the dry powder described above) is reconstituted with the desired amount of sterile liquid (e.g., water for injection) to the desired reconstituted solution (e.g., 1% 5-fluorouracil/1% aqueous sodium hydroxide) at the desired concentration for each component and then topically administered as a liquid medicament.

3. Preparation of external liquid preparation

The essential components of the pharmaceutical composition (e.g. 1g of sodium hydroxide as alkalizer, 15g of arginine as synergist and 20g of xylitol), optionally other components and a liquid carrier (e.g. water for injection) up to a total volume (e.g. 100ml) are measured out in the desired concentration and mixed slowly and homogeneously. The preparation (e.g. 15% arginine/20% xylitol/1% sodium hydroxide aqueous solution) can be directly used as a liquid drug for topical liquid formulation for topical administration.

4. Preparation of nebulant

The essential components of the pharmaceutical composition (e.g. 3g sodium hydroxide, 7g sodium bicarbonate, 15g arginine) were measured at the desired concentration (as described in table 1) and the following adjuvants for nebulisers: glycerin (2.5g), polysorbate-80 (1.5g), benzalkonium chloride (0.02g), and microcrystalline cellulose-sodium carboxymethyl cellulose (1.5g), then a vehicle (e.g., water for injection) with a constant volume to a total volume (e.g., 100ml) is added, and they are slowly mixed until uniform for use. The preparation (such as 15% arginine/7% sodium bicarbonate/3% sodium hydroxide aqueous solution) can be used as spray stock solution, and can be directly sprayed on target area to form liquid medicine after being added into a sprayer.

Example 2: pharmaceutical composition synergy study

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 317 mm)³) The groups were randomly divided into 2 negative control groups (01, 02) and 20 drug study groups (1-20). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The negative control and study drug were injected intraperitoneally (groups 02, 11, 15) and intratumorally (other study groups), respectively. All the groups take the medicine one every 3 daysThe injection was performed intratumorally 3 times, and the injection amount was 150. mu.l/tube. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 5.

TABLE 5

In the above table, the tumor inhibition rates of the composition study groups 5 and 10 were lower than the conventional effective tumor inhibition standard (40%) in the intraperitoneal injection series, and the tumor weight difference between the study group 5 and the negative control group (02 group) was not statistically significant (p > 0.005). Surprisingly, study group 4 had more than 25-fold higher tumor inhibition than study group 5 (86%: 3%) and study group 9 had more than 25-fold higher tumor inhibition than study group 10 (86%: 36%) using the same composition. Thus, different modes of administration of the same composition show significantly different targeting and pharmacology through disparate drug effects. After different modes of administration (i.e., intraperitoneal and local), the composition of the same composition may vary completely in the target area (local lesion). The composition injected intraperitoneally enters the blood and reaches the local lesion, where it is administered in a composition that is completely diluted or even dissolved by the blood (e.g., different retention of different compositions in certain organs). While the target composition of a topically administered composition is the same as (at least over a period of time) that it is administered. Conversely, compositions administered in different ways should have different compositional characteristics to achieve synergistic efficacy.

This phenomenon, which is less desirable in general terms (systemic versus topical administration shows a very different effect), obviously necessitates a less common technical solution. In the above table, in the topical administration series, although the component amount ratios of the respective compositions were the same, the tumor inhibition rate of the composition study group 12 was only 38% (33%: 86%) of the composition study group 10, and the difference in tumor weights of the two groups was statistically significant (p < 0.005). The tumor inhibition rate of the composition study group 16 was only 27% (22%: 83%) of the composition study group 14, and the tumor weight difference of the two groups was statistically significant (p < 0.005). In fact, the tumor inhibition rates of the composition research group 12 and the single-drug research group 2 and the tumor weight difference of the composition research group 14 and the single-drug research group 4 are not different greatly, the tumor weight difference is not statistically significant (p is greater than 0.005), and the composition research group does not show a synergistic effect. However, between study groups 10, 1, 5, composition group 10 had q ═ 1.04>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between groups 1 and 5, respectively, thus showing significant synergistic efficacy. Between study groups 14, 3, and 8, composition group 14 had q ═ 1.13>1.00, and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 8, respectively, thus showing significant synergistic efficacy. These results further illustrate that compositions administered in different ways may require entirely different components in order to achieve synergistic efficacy. Compositions for systemic administration usually require component-to-component ratio (which are instead diluted into the blood), whereas compositions for topical administration give no other characteristic (e.g. concentration) than the component-to-component ratio.

Furthermore, between study groups 18, 1, 17, composition group 18 had q ═ 1.19>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between groups 1 and 17, respectively, thus showing significant synergistic efficacy. Between study groups 20, 3, 19, composition group 14 had q ═ 1.20>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 19, respectively, thus showing significant synergistic efficacy.

In summary, the compositions of the present invention appear to exhibit a pharmacological profile when administered topically that is significantly different from systemic administration. For example, instead of being molecularly distributed in the blood to attack pathogens within the diseased tissue (e.g., tumor cells within a tumor), the primary pharmacology is distributed as a drug solution to the interstitial space of the tissue at the site of administration to attack the diseased tissue (e.g., intratumoral tissue).

According to the above studies and more similar studies, the requirements of the application technical scheme of the composition of the present invention as a topical active ingredient in the preparation of topical medicaments for the treatment of locally diseased diseases can be derived:

the composition of the pharmaceutical composition of the present invention must be such that it can be administered topically and above a certain concentration threshold such that the ratio of the amounts of the components of the pharmaceutical composition produces a synergistic effect. Specifically, in the pharmaceutical composition, the concentration of the alkalizer is equal to or more than the threshold of the synergistic effect concentration (for example, the concentration of strong alkali is equal to or more than 0.5%, and the concentration of weak alkali is equal to or more than 2.5%). On the basis of the concentration of the alkalizer, the quantity ratio condition of each necessary component is as follows: the concentration of the alkalizing agent is as described above, and the concentration of the synergist is such that the pharmaceutical composition exerts a synergistic effect.

In addition, the composition comprising a plurality of alkalizers that showed synergistic efficacy in the above experiments was also determined to have a buffer capacity of>0.01mol·L^-1·pH^-1The buffer solution of (1). Based on the above requirements, the composition of the present invention can further improve the drug effect, even the synergistic drug effect, by increasing the types of alkalizers and/or the synergistic species.

The following examples further investigate this synergistic approach based on the above requirements.

Example 3: synergistic study of pharmaceutical composition containing an alkalinizing agent

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 317 mm)³) The groups were randomly divided into 1 negative control group (0) and 17 drug study groups (1-17). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injection was carried out at an injection rate of 150. mu.l/injection. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 6.

TABLE 6

Group of	Research medicine	Tumor weight (x + -s) (g)	Tumor inhibition rate
				0	Physiological saline	2.36±0.35	0
1	7％NaOH	0.59	75％
				2	1％NaOH	1.39	41％
3	0.5％NaOH	1.54	31％
				4	1% 5-Fluorouracil	1.09	55％
5	0.35% 5-Fluorouracil	1.70	28％
				6	0.35% 5-Fluorouracil/7% NaOH	0.61	74％
7	1% 5-Fluorouracil/1% NaOH	0.45	81％
				8	20% arginine	1.72	27％
9	10% arginine	1.91	19％
				10	4% arginine	2.31	2％
11	4% arginine/7% NaOH	0.57	76％
				12	20% arginine/1% NaOH	0.64	73％
13	10% arginine/0.5% NaOH	0.99	58％
				14	3% methylene blue	0.78	67％
15	1% methylene blue	1.79	24％
				16	3% methylene blue/0.5% NaOH	0.73	69％
17	1% methylene blue/1% NaOH	0.52	78％

In the above table, the tumor inhibition rates of the composition group 6 and the study group 1 were not greatly different between the study groups 6, 1, 5, and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), and thus no synergistic efficacy was shown. Between study groups 7, 2, 4, composition group 7 had q ═ 1.11>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 4, respectively, thus showing significant synergistic efficacy. Between study groups 11, 1, 10, the tumor inhibition rates of composition group 11 and study group 1 were not significantly different and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), thus showing no synergistic efficacy. Between study groups 12, 2, 8, composition group 12 had q ═ 1.14>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 8, respectively, thus showing significant synergistic efficacy. Between study groups 13, 3, 9, composition group 12 had q ═ 1.31>1.00, and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 9, respectively, thus showing significant synergistic efficacy. Between study groups 12, 2, 8, composition group 12 had q ═ 1.14>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 8, respectively, thus showing significant synergistic efficacy. Between study groups 16, 14, 3, the tumor inhibition rates of composition group 16 and study group 14 were not significantly different and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), thus showing no synergistic efficacy. Between study groups 17, 2, 15, composition group 17 had q ═ 1.42>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 15, respectively, thus showing significant synergistic efficacy.

Example 4: synergistic study of pharmaceutical compositions comprising multiple alkalizers

Indeed, according to the results of example 2, a synergistic combination of a plurality of basifying agents can be formed, thereby enhancing the local activity of the pharmaceutical composition.

In one experiment, successfully modeled test animals (S180-bearing mice, mean tumor volume 314mm³) The groups were randomly divided into 2 negative control groups (01, 02) and 8 drug study groups (1-8). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The negative control and study drug were injected intraperitoneally (02, 6 groups) and intratumorally (other study groups), respectively. Each group was administered once every 3 days for a total of 3 times, and the injection amount was 150. mu.l/tube. 5 days after the administration, the animals were euthanized, the tumor weight was determined after dissection,and tumor inhibition rate was calculated from the negative control group, and the results are shown in Table 7.

30 mice, male and female unlimited, were randomized into 5 groups (1, 3, 4, 7, 8 in the table below), with 6 mice per group. Each group of experimental animals was injected with 100. mu.l of study drug as shown in the following table in the quadriceps muscle of the right leg. After 24h of injection, animals were euthanized and the degree of congestion, edema, degeneration, necrosis, etc. at the injection site was observed and scored for a stimulus response. The scoring criteria were calculated based on the negative control group phenomenon being 0 points and the 3% NaOH group phenomenon being 5 points. The results of the stimulation response scores are shown in table 7.

30 New Zealand white rabbits with the weight of 2.0-2.5kg and unlimited male and female parts. Experimental rabbits were randomly divided into 5 groups (1, 3, 4, 7, 8 groups in the table below), with 6 rabbits per group. The experimental rabbit is anesthetized by intravenous injection of anesthetic at the ear margin, then is fixed on a rabbit frame in a supine position, a small incision on the right side is made under aseptic conditions to open the abdomen and expose the liver, then a PTC (positive temperature coefficient) needle of 22G is punctured into the center of the thickest liver right lobe of the liver, the depth of the needle point from a liver envelope of a puncture point is 1.5cm, and research medicines are slowly injected at a constant speed respectively. One intrahepatic injection was administered to each rabbit, and study drug 1, OmL, as shown in the table below, was injected. After the administration, the rabbits were fed with conventional feed, euthanized 1 week later, and then the necrotic area in the liver was determined after dissection. The liver was dissected along the center of the necrotic area, and the maximal and minimal diameters of the necrotic area were measured on the maximum level. The average diameter of the liver tissue necrosis area is (maximum diameter + minimum diameter)/2. The results of the average diameter of the necrotic area in liver tissue are shown in table 7.

TABLE 7

In the above table, the tumor inhibition rate of the composition study group 6 was lower than the conventional effective tumor inhibition standard (40%) in the intraperitoneal injection series, and it had no statistical significance in the tumor weight difference from the negative control group (02 group) (p > 0.005). Surprisingly, with the same composition, the tumor inhibition rate of study group 4 was more than 20 times higher (68%: 3%. thus, the same composition showed significantly different targeting and pharmacology with different modes of administration than study group 6 by virtue of completely different drug effects after different modes of administration (i.e., i.p. injection and topical administration), the target (local lesion) composition of the same composition of administration may be completely different.

In the prior art, locally administered alkalizing agents (e.g. sodium hydroxide, sodium carbonate, sodium bicarbonate) above a certain concentration threshold are used as chemoablative agents. The increase in pH of the basic chemical ablative agent is believed to be a positive correlation to its chemical ablative effect. At extreme pH conditions (e.g., approaching 14), strong undifferentiated tissue destruction is believed to underlie the pharmacological effects of conventional alkaline chemical ablative agents. It is generally believed that the greater the damage to normal tissue, the greater the damage to diseased tissue. Many basic chemical ablative agents are screened for damage to normal tissues, such as liver tissue. In the above table, the results of the single drug study groups 1, 2 are consistent with the knowledge of the prior art: the higher the stimulation response score, the larger the necrotic surface diameter of the liver tissue and the higher the tumor suppression effect.

Thus, the addition of a weaker alkalizer that would tend to neutralize the pH of the stronger alkalizer should ideally exhibit an antagonistic, rather than a synergistic, effect on tissue destruction. The addition of 7% sodium bicarbonate (pH6.9) reduced the pH of 3% sodium hydroxide (pH11.8) by 1.6 and the composition was significantly neutralized (7% sodium bicarbonate/3% NaOH, pH 10.2). Study group 4 did show a reduction in the stimulation response score and in the necrotic surface diameter of liver tissue as predicted compared to 1, and the composition group showed local stimulation antagonism and normal tissue disruption antagonism. However, in the above table, the tumor inhibition rate of study group 4 was greater than that of study group 1. Between study groups 4, 3, 1, composition group 4 had q ═ 1.11>1.00, and it was statistically significant (both p <0.05) in the residual tumor weight differences between groups 3 and 1, respectively, thus showing significant synergistic efficacy. These results indicate that the addition of more pH neutral substances may result in compositions that exhibit higher tissue destruction specificity, thereby reducing the risk of local irritation, showing synergistic safety, and may even provide synergistic efficacy at the same time.

This phenomenon, which is not so much in accordance with the usual belief (a composition in which the pH of the alkalizer tends to be neutralized shows a synergistic effect or even a significant synergistic effect against the diseased tissue), obviously necessitates a less general solution. In the above table, in the topical administration series, although the component amount ratios of the respective compositions were the same, the tumor inhibition rate of the composition study group 5 was only 47% (32%: 68%) of the composition study group 4, and the difference in tumor weights of the two groups was statistically significant (p < 0.005). Between study groups 5 and 2, their tumor inhibition rates did not reach the 40% universal standard and the remaining tumor weight differences were not statistically significant (p >0.05), thus no synergistic efficacy was shown. The compositions used in study groups 5 and 4 had the same composition and ratio of amounts, but different concentrations of alkalizing agent and its alkalizing agent resulted in different shared effects. These results further illustrate that compositions administered in different ways may require entirely different components in order to achieve synergistic efficacy. Compositions for systemic administration usually require component-to-component ratio (which are instead diluted into the blood), whereas compositions for topical administration give no other characteristic (e.g. concentration) than the component-to-component ratio.

In the above table, the pH of 15% arginine/7% sodium bicarbonate/3% NaOH was slightly increased over 7% sodium bicarbonate/3% NaOH, whereas the addition of 15% arginine resulted in a decrease in the stimulation response score and the necrotic surface diameter of liver tissue, indicating the potential formation of local stimulation and normal tissue destruction antagonisms. However, between study groups 8, 7, 4, composition group 8 had q ═ 1.15>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between groups 7 and 4, respectively, thus showing significant synergistic efficacy. These results indicate that the addition of the synergist can be used to make the composition show synergistic efficacy by changing the properties of the composition (perhaps e.g. increasing the buffer capacity) without a substantial change in pH.

Based on the above and more similar studies, a preferred embodiment of the pharmaceutical composition of the present invention can be derived: as the alkalizer, various alkalizers having synergistic effects can be used. The necessary conditions of the technical scheme of the multi-alkalizer are as follows: the polybasifying agents of the present invention produce synergistic efficacy at a certain ratio above a certain concentration threshold.

In addition, the solution of the polybasifier which shows synergistic effect is determined to have a buffer capacity of>0.01mol·L^-1·pH^-1The buffer solution of (1). The following examples further investigate this synergistic approach based on the above requirements.

The following experiments further investigated the different polybasifier protocols.

In another experiment, the experimental animals were BALB/c mice, the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 325 mm)³) The groups were randomly divided into 1 negative control group (0) and 9 drug study groups (1-9). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injection was carried out at an injection rate of 150. mu.l/injection. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 8.

TABLE 8

In the above table, the tumor inhibition rates of the composition group 7 and the study group 1 were not greatly different between the study groups 7, 1, 6, and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), and thus no synergistic efficacy was shown. Between study groups 8, 2, 5, composition group 8 had q 1.04>1.00 and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 5, respectively, thus showing significant synergistic efficacy. Between study groups 9, 3, 4, the tumor inhibition rates of composition group 9 and study group 3 were not significantly different and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), thus showing no synergistic efficacy.

According to the above studies and more similar studies, the preferred conditions for the strong base/weak base alkalizer combination of the present invention are:

the concentration of the strong base is more than or equal to 0.5 percent, and preferably 0.75 to 7.5 percent;

the concentration of the weak base is more than or equal to 1 percent, and preferably 2 to 15 percent; and

the ratio of the amount of the strong base to the weak base (w: w) is <1, preferably 1/20-1/1.25.

Further, the pH of the composition is preferably 10.0 ± 2.0, more preferably 10.0 ± 1.0.

In another experiment, the experimental animals were BALB/c mice, the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (average tumor volume 307 mm)³) The groups were randomly divided into 1 negative control group (0) and 13 drug study groups (1-13). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injection was carried out at an injection rate of 150. mu.l/injection. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 9.

TABLE 9

In the above table, the tumor inhibition rates between the study groups 7, 1, 6 were not greatly different between the composition group 7 and the single drug group 1, and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), so that no synergistic efficacy was exhibited. Between study groups 8, 1, 4, composition group 8 had q ═ 1.43>1.00, and it was statistically significant (both p <0.05) in the residual tumor weight differences between groups 1 and 4, respectively, thus showing significant synergistic efficacy. Between study groups 9, 2, 5, composition group 9 had q ═ 1.43>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 5, respectively, thus showing significant synergistic efficacy. Similarly, composition group 10 also showed significant synergistic efficacy, but its tumor suppression rate was only 60% of that of composition group 9. The tumor suppression rates between the study groups 11, 3, 5 were not very different between the composition group 11 and the single drug group 5, and the remaining tumor weights between the two groups were not statistically significant (p >0.05), thus showing no synergistic efficacy.

In addition, between study groups 13, 12, and 9, composition group 13 had q ═ 1.16>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between 12 and 9 groups, respectively, thus showing significant synergistic efficacy. Again, the results show that the addition of the synergist allows the composition to show synergistic efficacy by changing the properties of the composition (perhaps e.g. increasing the buffer capacity) without a substantial pH shift.

According to the above and further similar studies, preferred conditions for the weak base/other weak base alkalizing agent combination of the present invention according to the above and further similar studies are:

the concentration of the weak base is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 20 percent, preferably more than or equal to 3.0 to 20 percent or more than or equal to 5 to 20 percent; and

the concentration of the other alkalizers is more than or equal to 1 percent, and preferably 2 to 15 percent.

Further, the pH of the composition is preferably 9.0 ± 2.0, more preferably 9.0 ± 1.3.

When the weak base/other weak bases are a basic polybasic acid salt/acidic polybasic acid salt, the ratio of the basic polybasic acid salt to the acidic polybasic acid salt (w: w) is greater than 0.56 and less than 7, preferably 1 to 2.

Example 5: synergistic study of compositions comprising alkalizing agents and other pH adjusting agents

Indeed, according to the results of example 2, the basifying agent may also form a synergistic combination with other pH modifying agents, thereby enhancing the local activity of the pharmaceutical composition. These pH adjusting agents include, for example, strong acid, strong base salts (suitable for strong bases) and weak acids (suitable for weak bases).

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 325 mm)³) The groups were randomly divided into 1 negative control group (0) and 5 drug study groups (1-5). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injection was carried out at an injection rate of 150. mu.l/injection. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 10.

Watch 10

In the above table, composition group 3 has q of 1.34>1.00 between study groups 3, 1, 2, and it has statistical significance (both p <0.05) from the remaining tumor weight differences between groups 1 and 2, respectively, thus showing significant synergistic efficacy. Between study groups 5, 3, 4, composition group 5 had q ═ 1.08>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 4, respectively, thus showing significant synergistic efficacy.

According to the above and more similar studies, the preferred conditions for the alkalinizing agent combination of the strong base/strong acid strong base salt of the present invention are:

the concentration of the strong acid strong alkali salt is more than or equal to 1 percent, and preferably 2 to 15 percent;

the amount ratio (w: w) of said strong base to said strong acid strong base salt is <1, preferably 1/20-1/1.25.

Furthermore, the preferred pH of the composition is 11.0. + -. 2.0, more preferably 11.0. + -. 1.0.

In another experiment, the experimental animals were BALB/c mice, the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 316 mm)³) The groups were divided into 1 negative control group (0) and 5 drug study groups (1-5). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injection was carried out at an injection rate of 150. mu.l/injection. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 11.

TABLE 11

In the above table, composition group 3 has q 1.04>1.00 between study groups 3, 1, 2, and it has statistical significance (both p <0.05) from the remaining tumor weight differences between groups 2 and 1, respectively, thus showing significant synergistic efficacy. In addition, between study groups 5, 3, 4, composition group 5 had q of 1.05>1.00 and had statistical significance (both p <0.05) to the remaining tumor weight differences between groups 3 and 4, respectively, thus showing significant synergistic efficacy. Again, the results demonstrate that the addition of the synergistic agent allows the composition to exhibit synergistic efficacy by altering the properties of the composition (perhaps, for example, by increasing the buffer capacity).

According to the above and more similar studies, the preferred conditions for the pharmaceutical composition of the invention comprising a combination of a weak base and a weak acid are:

the concentration of said weak acid is > 3%, preferably 5-25%.

Furthermore, the pH of the composition is preferably 4.0. + -. 1.5, preferably 4.0. + -. 1.0.

Example 6: further study of the synergistic technical scheme of the pharmaceutical composition of the present invention

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 336 mm)³) The groups were divided into 1 negative control group (0) and 24 drug study groups (1-24). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injection was carried out at an injection rate of 150. mu.l/injection. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 12.

TABLE 12

In the above table, between study groups 15, 1, 5, composition group 15 had q 1.01>1.00 and had statistical significance (both p <0.05) to the remaining tumor weight differences between groups 1 and 5, respectively, thus showing significant synergistic efficacy. Between study groups 16, 2, 6, composition group 16 had q ═ 1.02>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 6, respectively, thus showing significant synergistic efficacy. The tumor suppression rate was greatest in the composition group 17 among study groups 17, 1, and 7, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 1 and 7, respectively, thus showing synergistic efficacy. The tumor suppression rate was greatest in the composition group 18 among study groups 18, 1, and 8, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 1 and 8, respectively, thus showing synergistic efficacy. Between study groups 19, 1, 9, composition group 19 had q ═ 1.11>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 1 and 9, respectively, thus showing significant synergistic efficacy. Between study groups 20, 1, 10, composition group 20 had q 1.04>1.00 and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 1 and 10, respectively, thus showing significant synergistic efficacy. The tumor suppression rate was greatest in composition group 21 among study groups 21, 1, 11, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 1 and 11, respectively, thus showing synergistic efficacy. The tumor suppression rate was greatest for composition group 22 among study groups 22, 3, 12, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 3 and 12, respectively, thus showing synergistic efficacy. Between study groups 23, 3, 13, composition group 23 had q ═ 1.08>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 13, respectively, thus showing significant synergistic efficacy. Between study groups 24, 3, 14, composition group 24 had q 1.06>1.00 and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 14, respectively, thus showing significant synergistic efficacy.

From the above studies and further similar studies, the requirements for the technical solution of the pharmaceutical composition of the present invention can be derived:

the synergistic effect produced by the pharmaceutical composition of the invention must be mainly, even completely, a local synergistic effect of the alkalinizing agent and its synergists:

the alkalizing agent in the pharmaceutical composition of the present invention must satisfy the concentration conditions for the local synergistic effect to occur (e.g., concentration of strong base or strong acid chemical ablator is 0.5% or more, and concentration of weak base or weak acid chemical ablator is 2.5% or more);

the composition of the pharmaceutical composition of the present invention must satisfy the quantitative ratio conditions for the local synergy (e.g., the local synergist concentration is 5% or more or 25% or more of its saturation solubility in the composition when the alkalizing agent concentration is as described above).

In addition, compositions exhibiting synergistic efficacy have been determined to also have a buffer capacity of>0.01mol·L^-1·pH^-1The buffer solution of (1).

Example 7: the pharmaceutical composition of the invention has more anti-tumor applications

In this series of experiments, the successfully modeled nude mice bearing human cancer cells were randomly divided into 1 negative control group and 3 study groups. The corresponding negative control was normal saline, and the 3 study drugs were: 15% arginine/7% sodium bicarbonate/3% sodium hydroxide, 2% KCl/1% NaOH/20% arginine/20% xylitol, 20% glycine/3% sodium bicarbonate/10% acetic acid. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was injected intratumorally, once every 3 days for a total of 3 times, 150. mu.l/patient. On day 5 after the end of the administration, the animals were euthanized, and tumor weights were determined after dissection, and the tumor inhibition rates were calculated from the respective negative control groups.

1) Application of the compound in treating breast tumor

In this study, a successfully modeled nude mouse bearing human breast cancer cells (MDA-MB231) (tumor mean volume 303 mm)³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 92 percent, 97 percent and 91 percent of the total content of the extract meet the commonly considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40 percent).

2) Application of the compound in lung tumor treatment

In the study, a nude mouse with human lung cancer cells (A549) successfully modeled (average tumor volume 326 mm)³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 92%, 95% and 89% all meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

3) Application of the compound in thyroid tumor treatment

In the study, the nude mouse with human thyroid carcinoma cells (SW579) (mean tumor volume 341 mm) was successfully modeled³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 92%, 97% and 88% all meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

4) Use in the treatment of prostate tumors

In this study, human prostate cancer cell (LNCaP/AR) bearing nude mice (mean tumor volume 348 mm) were successfully modeled³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 93 percent, 97 percent and 92 percent, all meet the commonly considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40 percent).

5) Application of the compound in liver tumor treatment

In the study, the nude mice (average tumor volume 309 mm) with human hepatoma cells (HepG2) successfully modeled³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 92%, 95% and 89% all meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

6) Application of the compound in treating head and neck tumors

In the present study, nude mice with human head and neck cancer cells (F μ da) successfully modeled (mean tumor volume 305 mm)³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 93 percent, 97 percent and 86 percent, all meet the commonly considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40 percent).

7) Application of the compound in treatment of nasopharyngeal tumors

In the present study, nude mice (mean tumor volume 327 mm) with human nasopharyngeal carcinoma cells (CNE1) successfully modeled³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 91%, 95% and 88% which meet the commonly considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

8) Application of the compound in treating gastric tumor

In the study, nude mice (average tumor volume 314 mm) with human gastric carcinoma cells (BGC823) successfully modeled³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 88 percent, 91 percent and 93 percent, all meet the commonly considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40 percent).

9) Application of the compound in ovarian tumor treatment

In the study, nude mice with successfully modeled human ovarian carcinoma cells (PA1) (mean tumor volume 311 mm)³) The groups were randomized into a negative control group and 3 study groups (D, E, F groups). D. The tumor inhibition rates of E, F groups were: 91%, 93% and 85% which meet the commonly considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

Similar results were obtained with some other compositions of the invention prepared by the method of example 1 (e.g. the synergistic pharmaceutical compositions of the examples) for use in the treatment of each of the above-mentioned tumors.

Locally administered interventions for diseases with locally diseased symptoms, especially intractable diseases, are often modeled as tumors. Among the diseases associated with localized lesions, the mechanisms of tumors are extremely complex and the most difficult to treat. Local administration protocols obtained using tumor models are generally applicable to other diseases associated with local lesions. The following experiments investigated further applications of the compositions of the present invention.

Example 8: application of anti-non-tumor and non-inflammatory local lesion diseases

In one experiment, the non-pregnant female rats (weighing 150-180g) were randomly divided into a blank control group and a molding group. Taking mammary gland hyperplasia as a model, the model group is injected with estradiol benzoate (0.5mg/kg, 1 time/day, continuous for 20 days), and then progesterone (5mg/kg, 1 time/day, continuous for 5 days). Successfully modeled test animals were randomly divided into a negative control group, a positive control group and 3 study groups (1, 2, 3 groups), with 6 animals per group. The administration was started on the day of the group. The negative control was physiological saline, the positive control was tamoxifen (rottendorf phanna GmhH), and the 3 study drugs were: 15% arginine/7% sodium bicarbonate/3% sodium hydroxide, 2% KCl/1% NaOH/20% arginine/20% xylitol, 20% glycine/3% sodium bicarbonate/10% acetic acid. The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The negative control group and the study group are injected once in the swelling area every 3 days, each time is 100 mu l, and the total dose is 5 times. The positive control group is administrated by gavage with tamoxifen 2 times a day, 0.1mg/kg gavage each time, and administration is carried out for 30 days. The items observed, measured and analyzed in the experiment include nipple enlargement inhibition rate and pathological changes of mammary tissue, in addition to the conventional food intake, body weight, general state. The calculation of pathological changes of mammary tissue and evaluation criteria of drug effect are the same as those in the previous experiment. The nipple enlargement inhibition ratio (R%) was calculated as follows:

R％＝[(△D01-△Dn)/△D01]％＝1-△Dn/△D01

wherein, Delta D01 is the difference (D01-D0) between the nipple diameter (D01) of the negative control group and the nipple diameter (D0) of the blank control group at the 33 th day after the first administration, and Delta Dn is the difference (Dn-D0) between the nipple diameter (Dn) of the study group and the nipple diameter (D0) of the blank control group.

The evaluation criteria of the drug efficacy of the nipple enlargement inhibition rate (R%) are as follows:

(R%) < 40% is invalid and (R%) > 40% is valid.

The results of the teat growth inhibition ratio are shown in the following Table 13.

Watch 13

Group of	Medicine	Nipple diameter (mm)	Nipple enlargement inhibition rate
				0	Blank control group	0.76±0.17	(100％)
01	Physiological saline	1.71±0.32	(0)
				02	Triphenoxy amine	1.16±0.25	58％
1	15% arginine/7% sodium bicarbonate/3% sodium hydroxide	0.92±0.21	83％
				2	2% KCl/1% NaOH/20% arginine/20% xylitol	0.96±0.24	79％
3	20% glycine/3% sodium bicarbonate/10% acetic acid	1.04±0.18	71％

In the above table, the papilla diameters of the 1, 2, 3 and positive control groups were all much smaller than those of the negative control group at day 33 after the first administration, and the differences were statistically significant (all P < 0.05). In this case, the inhibition rates of nipple enlargement in groups 02, 1, 2 and 3 were 58%, 83%, 79% and 71%, respectively, and all were effective drug effects.

On the 33 th day after the first administration, the pathological scores of the groups 1, 2 and 3 are respectively 0.71 +/-0.25, 0.73 +/-0.21 and 0.82 +/-0.21, which are all less than or equal to 1, are close to the blank control group (0.32 +/-0.15), and are obviously different from the pathological scores of the negative control group (3.76 +/-0.36) and have statistical significance (all are less than 0.05). While the positive control group had a pathology score greater than 1(1.74 ± 0.28). The safety observations of the drugs were essentially the same.

Similar results can be obtained with some other compositions of the present invention prepared using the method of example 1 (e.g., synergistic compositions in each example).

In another experiment, infertile female rats were randomly divided into a placebo group and a molding group. The non-inflammatory goiter is used as a model, the building module is raised for more than 3 months in the environment of low-iodine feed feeding, and urine iodine is obviously reduced, and thyroid gland is obviously enlarged to successfully build the model. Successfully modeled test animals were randomly divided into a negative control group, a positive control group and 3 study groups, each group of 6 animals. The administration was started on the day of the group. The negative control was physiological saline, the positive control was potassium iodate, and the 3 study drugs were: 15% arginine/7% sodium bicarbonate/3% sodium hydroxide, 2% KCl/1% NaOH/20% arginine/20% xylitol, 20% glycine/3% sodium bicarbonate/10% acetic acid. The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1.

The negative control group (group 01) and the study groups (groups 1, 2 and 3) were injected once every 3 days into the swollen area, 100. mu.l/body each time, and a total of 5 times. The positive control group (02 group) was administered potassium iodate (KIO3) at 27 times at a daily dose of 0.4. mu.g/kg per dose. Items observed, measured and analyzed in the experiment include thyroid relative weight and thyroid pathology examination, in addition to regular food intake, body weight, general state. The observation of thyroid pathological changes and evaluation criteria of drug efficacy are the same as in the previous experiment. 30 days after the first administration, the rats were euthanized, the thyroid gland was detached, the wet weight was weighed, and the relative thyroid mass was calculated (thyroid relative mass w ═ thyroid mass/rat mass).

calculation formula for the inhibition of increase of adenoid gland (R%) is as follows:

R％＝[(△w₀₁-△w_n)/△w₀₁]％＝1-△w_n/△w₀₁

in the formula, delta w₀₁The difference in relative thyroid mass (w) between the negative control group (01) and the blank control group (0)₀₁-w₀)，△w_nTo investigate the difference (w) between the relative masses of thyroid glands of group (n) and blank control group (0)_n-w₀)。

evaluation criteria for drug efficacy of the increase inhibition rate (R%) of the glandular gland are: (R%) < 40% is invalid and (R%) > 40% is valid. The -like gland increase inhibition rate (R%) obtained in the experiment is shown in Table 14 below.

TABLE 14

In the above table, the relative masses of the thyroid glands in groups 1, 2, 3 and 02 were all much smaller than those in the negative control group at day 30 after the first administration, and the differences between the groups and the negative control group were statistically significant (all P < 0.05). In this case, the inhibition rates of increase in -like glands in groups 1, 2, 3 and 02 were 85%, 81%, 71% and 62%, respectively, and all were effective.

On day 30 after administration, the difference between groups 1, 2 and 3 and the blank control group in terms of follicular morphology and size, epithelial cells, and inter-leaflet fibrous tissue was less than 15%, and was close to the positive control group. The safety observations for each group of drugs were essentially the same.

Mastoplasia (MGH), also known as mammary dysplasia, is characterized by painful swelling of the breast with lumps. Goiter is one of the most common non-neoplastic, non-inflammatory focal disease states. Given that the compositions of the present invention target diseased tissue beyond the causative agent (e.g., pathogen) itself, goiter can serve as a localized disease model for proliferative lesions that are neither inflammatory nor malignant. Such diseases include: non-malignant tumors, hyperplasia (e.g., hyperplasia of breast, pancreas, thyroid, parathyroid, prostate, etc.), cyst (e.g., cyst of breast, thyroid, parathyroid, etc.), abnormal vein mass (e.g., hemorrhoid, etc.), other nodules (e.g., nodules of breast, thyroid, parathyroid, etc.). The hemorrhoid includes internal hemorrhoid, external hemorrhoid, and mixed hemorrhoid.

Example 9: study of anti-local inflammation

In one experiment, adult male rats (weighing approximately 150-180g) were randomly divided into a blank control group and a building block. Using allergic rhinitis as model, the model group uses Ovalbumin (OVA) sensitizing solution (each milliliter contains 0.5mgOVA and 30mg Al (OH)₃) The allergen was sensitized by intraperitoneal injection (once a day, 7 times total), and then the mixture was subjected to nasal drip (once a day, 7 times total) with ovalbumin molding solution (3% OVA) to mold. Successfully modeled test animals were randomly divided into a negative control group, a positive control group and 3 study groups, each group of 6 animals. The administration was started on the day of the group. The negative control was physiological saline, the positive control was budesonide nasal drops (AstraZeneca Pty Ltd), and the 3 study drugs were sprays containing the following components: 15% arginine/7% sodium bicarbonate/3% sodium hydroxide, 2% KCl/1% NaOH/20% arginine/20% xylitol, 20% glycine/3% sodium bicarbonate/10% acetic acid. The liquid stock solutions all contain water and the following auxiliary materials: glycerol (2.5%), polysorbate-80 (1.5%), benzalkonium chloride (0.02%), microcrystalline cellulose-sodium carboxymethylcellulose (1.5%). The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1.

Each group is made into a mould, nasal cavity spraying is carried out once a day, each time is 300 mul/body, and the medicine is taken 7 times. Items observed, measured and analyzed in the experiment included nasal symptom scores in addition to regular food intake, weight, general status. Nasal symptoms were scored the next day after completion of the treatment, using the overlap-add method to score nasal symptoms (nasal scratching, sneezing, watery nasal discharge) observed within 30min after nasal administration with ovalbumin. Scratching the nose: the number of times of scratching the nose is 1 minute, the repeated scratching of the nose surface is more than 2 minutes, and the rubbing of the nose surface is 3 minutes everywhere. Sneezing: 1 to 3 are 1 minute, 4 to 10 are 2 minutes, and more than 11 are 3 minutes. Running nose: until the anterior nares is 1 point, 2 points through the anterior nares, and 3 points full of nasal discharge. Nasal symptom scores obtained from the experiments are shown in table 15 below.

Watch 15

Group of	Medicine	Nasal symptom scoring prior to dosing	Nasal symptom scoring after dosing
				0	Blank control group	0.00±0.00	0.00±0.00
01	Physiological saline	0.57±0.53	7.14±0.81
				02	Budesonide nasal drops	0.57±0.53	1.64±0.41
1	15% arginine/7% sodium bicarbonate/3% sodium hydroxide	0.57±0.53	0.69±0.51
				2	2% KCl/1% NaOH/20% arginine/20% xylitol	0.57±0.53	0.71±0.53
3	20% glycine/3% sodium bicarbonate/10% acetic acid	0.57±0.53	0.83±0.63

In the above table, on day 8 after the first administration, except the blank control group, the other groups all showed nasal scratching, sneezing, nasal discharge, etc. after the nasal drip of ovalbumin solution. Compared with the negative control group, nasal symptom scores of 1, 2, 3 and 02 groups are all reduced remarkably, and the difference between each group and the negative control group is statistically significant (P < 0.05).

Allergic rhinitis is one of the most common inflammatory focal diseases. Given that the compositions of the present invention target diseased tissue beyond the causative agent (e.g., pathogen) itself, allergic rhinitis may serve as a model of inflammatory localized disease. Such diseases include: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, and oophoritis.

Example 10: studies on secretion disorders of antisecretory glands

In one experiment, adult male rats (weighing approximately 150-180g) were randomly divided into a blank control group and a building block. Using hyperthyroidism as a model, the modeling module is modeled by levothyroxine (intraperitoneal injection, dosage of 50 mug/100 g body weight, continuous injection for 10 days). The successfully modeled test animals were randomly divided into a negative control group (group 01), a positive control group (group 02) and 3 study groups, 6 animals per group, except for the unmodeled blank control group (group 0). The administration was started on the day of the group. The negative control was physiological saline, the positive control was thioimidazole, and the 3 study drugs were: 20% glycine/3% sodium bicarbonate/10% acetic acid, 2% KCl/1% NaOH/20% arginine/20% xylitol, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide. The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1.

The negative control group and the study group are injected once in the swelling area every 3 days, each time is 100 mu l, and the total dose is 7 times. The positive control group is drenched with methyl-lucimidazole 1 time a day, and the medicine is drenched with 10mg/kg stomach every time for 21 days. Items observed, measured and analyzed in the experiment include serological examinations (thyroid hormone levels) in addition to regular food intake, body weight, general state. Thyroid hormone levels were determined as follows: on the 5 th day after the administration, the rats were fasted without water, and blood was collected from the abdominal aorta the next day to centrifuge the serum. T3 and T4 were measured by enzyme-linked immunosorbent assay according to the kit instructions (Beijing northern Biotechnology Co., Ltd.). The results of the measurements are given in Table 16 below.

Watch 15

In the above table, on day 26 after the first administration, the levels of thyroid hormones in groups 1, 2, 3, and 02 were significantly decreased compared to the negative control group, and the difference between each group and the negative control group was statistically significant (all P < 0.05).

Hyperthyroidism is one of the most common local pathological diseases with abnormal secretion of secretory glands. Considering that the composition of the invention targets diseased tissue beyond the causative agent (e.g., pathogen) itself, hyperthyroidism may serve as a model for such localized disease. Such diseases include, for example: hyperthyroidism, hypothyroidism and islet function depression.

Example 11: anti-skin disease study

In this study, 20 volunteers with athlete's foot who participated in the study were divided into 4 groups, including 1 positive control group and 3 study groups (A, B, C groups), with 5 persons each. The positive control was dacron cream (siennan poplar pharmaceutical co., ltd.) and the 3 study drugs were liquid stock solutions of the following compositions as active ingredients: 20% glycine/3% sodium bicarbonate/10% acetic acid, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide, 2% KCl/1% NaOH/20% arginine/20% xylitol. The preparation method of the spray is shown in example 1. The liquid stock solution contains the following auxiliary materials besides the active ingredients: glycerol (2.5%), polysorbate-80 (1.5%), benzalkonium chloride (0.02%), microcrystalline cellulose-sodium carboxymethylcellulose (1.5%). The aerosol liquid raw liquid storage device is stored in a container of the aerosol device before use. The positive control group is applied with Daktarin cream on affected part once a day for 7 times. The negative control group and 3 study groups sprayed the affected part with the corresponding spray once a day for 7 times. The therapeutic effect judgment standard is as follows: curing: skin lesions subsided > 90%, effective: regression of skin lesions > 50%, no effect: the skin lesions subsided < 50%.

Significant regression of skin lesions occurred 7 days after dosing in both the positive control group and the 3 study groups. The results 10 days after administration are shown in Table 17 below.

TABLE 17

Group of	Number of cases	Number of healed diseases	Effective number	Number of invalid	Inefficiency (%)
						Positive control group	5	0	3	2	40
Group A	5	1	3	1	20
						Group B	5	2	3	0	0
Group C	5	2	3	0	0

Similar results were obtained using a spray of the same composition as the other compositions of the invention prepared in example 1 (e.g. synergistic compositions in each example).

Tinea pedis is a fungal skin disease, which is one of the most common skin diseases in south China. Given that the compositions of the present invention target diseased tissue beyond the pathogen itself, tinea pedis can be used as a model for skin disease. Such diseases may for example include one or more of the following: skin cancer, non-malignant tumors of the skin, viral skin diseases (e.g., herpes, warts, rubella, hand-foot-and-mouth disease), bacterial skin diseases (e.g., impetigo, furuncle, leprosy), fungal skin diseases (e.g., various ringworm), sexually transmitted diseases (e.g., syphilis, gonorrhea, and condyloma acuminatum), allergic and autoimmune skin diseases (e.g., contact dermatitis, eczema, urticaria), physical skin diseases (e.g., solar skin diseases, chilblain, corns, rhagades of hands and feet, pressure sores), connective tissue diseases (e.g., lupus erythematosus), skin disorders (e.g., freckles, pigmented nevi, various plaques), skin appendages diseases (e.g., acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis, and bromidrosis).

The present disclosure includes the following items:

item 1, a topical pharmaceutical composition for the treatment of a topical pathological condition comprising an alkalinizing agent, a synergist of said alkalinizing agent selected from one or more of a strong base and a weak base, and a suitable solvent, wherein said synergist is selected from one or more of a cytotoxic drug and/or a conventionally ineffective drug, and wherein in said pharmaceutical composition,

the concentration of the strong base is 0.5-5%;

the concentration of the weak base is 2-35%;

The concentration of the conventional ineffective drug is 0.35-40%.

Item 2, a method of treating a localized disease condition comprising administering to a localized diseased area of an individual in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an alkalizing agent, a co-product of the alkalizing agent and a suitable solvent, wherein the alkalizing agent is selected from one or more of a strong base and/or a weak base; the synergist is selected from one or more of cytotoxic drugs and/or conventional ineffective drugs, and in the pharmaceutical composition,

the concentration of the strong base is 0.5-5%;

the concentration of the weak base is 2-35%;

The concentration of the conventional ineffective drug is 0.35-40%.

Item 3, the pharmaceutical composition or the method according to item 1 or 2, wherein the concentration of the strong base is 0.75% or more or 1% or more, or 0.5 to 5%, preferably 0.75 to 5% or 1 to 5%.

Item 4, the pharmaceutical composition or the method according to one of items 1 to 3, wherein the concentration of the weak base is ≥ 2.5%, preferably ≥ 3.0% or ≥ 5%, or 2.5-35%, preferably 3.0-35% or 5-35%.

Item 5, the pharmaceutical composition or method according to one of items 1 to 3, wherein the strong base comprises an alkali metal hydroxide, wherein the alkali metal hydroxide comprises, for example: sodium hydroxide, potassium hydroxide, calcium hydroxide.

Item 6, the pharmaceutical composition or method according to one of items 1 to 4, wherein the weak base comprises a weak basic inorganic salt of a polybasic acid, an inorganic salt of a weak acidic polybasic acid, a weak base containing nitrogen.

Item 7, the pharmaceutical composition or method of item 6, wherein the polybasic weak acid basic inorganic salt comprises sodium phosphate, sodium carbonate, potassium carbonate, borax.

Item 8, the pharmaceutical composition or method of item 6, wherein the polybasic weak acid inorganic salt comprises monobasic sodium phosphate, dibasic sodium phosphate, sodium bicarbonate, potassium bicarbonate, dibasic calcium carbonate, sodium hydrogen sulfate.

Item 9, the pharmaceutical composition or method of item 6, wherein the weak base comprising nitrogen is selected from the group consisting of ammonia, ammonia chloride, 2-aminoethanol, tromethamine, triethanolamine, tris, 2-aminoethanol, tromethamine, triethanolamine, meglumine, and glufosinate.

Item 10, the pharmaceutical composition or method according to one of items 1 to 9, wherein the cytotoxic drug is selected from one or more of the following group: drugs that disrupt the structure and function of DNA, drugs that interfere with transcribed RNA embedded in DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis, preferably one or more selected from the group consisting of: alkylating agents such as cyclophosphamide, carmustine; metal platinum complexes such as cisplatin, carboplatin; DNA topoisomerase inhibitors such as doxorubicin, topotecan, irinotecan; anti-tumor antibiotics such as actinomycins, daunorubicin; pyrimidine antagonists such as uracil derivatives 5-fluorouracil, furfluorouracil, bifurcofurouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine; taxanes such as paclitaxel, docetaxel.

Item 11, a pharmaceutical composition or a method according to one of items 1 to 10, wherein the cytotoxic drug is preferably selected from one or more of a pyrimidine antagonist such as uracil derivative 5-fluorouracil, furflurouracil, bifurcofiurfuraluracil and/or a metal platinum complex; such as cisplatin, carboplatin.

Item 12, a pharmaceutical composition or a method according to one of items 1 to 11, wherein the conventional ineffective drug is one or more selected from one or more of the following groups: amino acid nutrients, carbohydrate nutrients, lipid nutrients, pigment aromatic compounds, salicylic acid compounds and quinine compounds.

Item 13, the pharmaceutical composition or method according to item 12, wherein the amino acid based nutrient is selected from one or more of a basic amino acid based nutrient such as arginine, lysine, histidine, preferably arginine, and/or a non-basic amino acid based nutrient; such as one or more of the following groups: neutral amino acids, acidic amino acids, amino acid salts, wherein the neutral amino acids are, for example: glycine, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, alanine, valine, leucine, isoleucine, phenylalanine, proline, such as: aspartic acid, glutamic acid, said amino acid salts including salts of the amino acids with acids as described above, such as lysine hydrochloride, histidine hydrochloride, glutamic acid hydrochloride, cysteine hydrochloride, arginine hydrochloride, glycine sulfate iron, lysine hydrochloride, aspartic acid hydrochloride, and the concentration (w/v) of the amino acid nutrients in the pharmaceutical composition is ≥ 5%, preferably 10-30%.

Item 14, the pharmaceutical composition or method according to item 12, wherein the carbohydrate nutrient is selected from one or more of the following: glucose, fructose, chitosan oligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, xylo-oligosaccharide, fructo-oligosaccharide, manno-oligosaccharide, xylitol, more preferably selected from one or more of the following: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannooligosaccharide and xylitol, wherein the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is more than or equal to 10 percent, and is preferably 10-40 percent.

Item 15, the pharmaceutical composition or method of item 12, wherein the liponutrient is selected from one or more of the group consisting of: vegetable oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat milk, medium-chain fat milk, phospholipids, and the concentration (w/v) of the lipid nutrient in the pharmaceutical composition is not less than 4%, preferably 4-25%.

Item 16, the pharmaceutical composition or method of item 12, wherein the pigment aromatic compound is one or more selected from the group consisting of: methylene blue, patent blue, isothio blue, bengal red, and in the pharmaceutical composition the concentration (w/v) of said pigment aromatic compound is not less than 0.35%, preferably 0.5-10%

Item 17, the pharmaceutical composition or method of item 12, wherein the salicylate compound is selected from one or more of: salicylic acid, acetylsalicylic acid, aspirin-lysine, and in the topical pharmaceutical composition, the concentration (w/v) of the salicylic acid compound is not less than 5%, preferably 5-10%;

item 18, the pharmaceutical composition or method of item 12, wherein the quinine compound is selected from one or more of: quinine hydrochloride, quinine dihydrochloride and quinine sulfate, and in the topical pharmaceutical composition, the concentration (w/v) of the quinine compound is more than or equal to 3 percent, and is preferably 3-6 percent.

Item 19, the pharmaceutical composition according to one of items 1 to 18, or the method, wherein the local lesion comprises a tumor, a non-tumor enlargement, a local inflammation, a secretory gland dysfunction and a skin disease.

Item 20, the pharmaceutical composition, the use or the method according to item 19, wherein the neoplasm comprises a malignant neoplasm and a non-malignant neoplasm.

Item 21, the pharmaceutical composition of or the method of item 20, wherein the malignant tumor comprises breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, gastric cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer.

Item 22, the pharmaceutical composition or method of item 20, wherein the non-malignant tumor comprises a breast tumor, a pancreatic tumor, a thyroid tumor, a prostate tumor, a liver tumor, a lung tumor, an intestinal tumor, an oral tumor, an esophageal tumor, a gastric tumor, a nasopharyngeal tumor, a laryngeal tumor, a testicular tumor, a vaginal tumor, a uterine tumor, a fallopian tube tumor, an ovarian tumor.

Item 23, the pharmaceutical composition or method of item 19, wherein the non-neoplastic mass comprises a hyperplasia (e.g., hyperplasia of breast, pancreas, thyroid, parathyroid, prostate), a cyst (e.g., a cyst of breast, thyroid, parathyroid), a nodule (e.g., a nodule of breast, thyroid, parathyroid), an abnormal venous mass (e.g., a hemorrhoid), a localized inflammatory neoplasm, a microbial infection.

Item 24, the pharmaceutical composition or the method according to item 19, wherein the local inflammation refers to a non-neoplastic inflammation at a local site, including degenerative, exudative and proliferative inflammation.

Item 25, a pharmaceutical composition, use or method according to item 19, wherein the local inflammation comprises one or more of: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, and oophoritis.

Item 26 or the pharmaceutical composition or the method according to item 25, wherein the secretory gland dysfunction includes a secretory gland hyperactivity (e.g., hyperthyroidism) and a secretory gland hypofunction (e.g., hypothyroidism, islet hypofunction).

Item 27, the pharmaceutical composition of item 26, or the method, wherein the skin disorder is a lesion native or secondary to the skin or skin appendages, comprising one or more of: skin cancer, non-malignant tumors of the skin, viral skin diseases (e.g., herpes, warts, rubella, hand-foot-and-mouth disease), bacterial skin diseases (e.g., impetigo, furuncle, leprosy), fungal skin diseases (e.g., various ringworm), sexually transmitted diseases (e.g., syphilis, gonorrhea, and condyloma acuminatum), allergic and autoimmune skin diseases (e.g., contact dermatitis, eczema, urticaria), physical skin diseases (e.g., solar skin diseases, chilblain, corns, rhagades of hands and feet, pressure sores), connective tissue diseases (e.g., lupus erythematosus), skin disorders (e.g., freckles, pigmented nevi, various plaques), skin appendages diseases (e.g., acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis, and bromidrosis).

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

1. A topical pharmaceutical composition for the treatment of a topical pathological condition comprising an alkalising agent selected from one or more of a strong base and a weak base, a synergist thereof selected from one or more of a cytotoxic drug and/or a conventional ineffective drug, and a suitable solvent, wherein in the pharmaceutical composition,

the concentration of the strong base is 0.5-5%;

the concentration of the weak base is 2-35%;

The concentration of the conventional ineffective drug is 0.35-40%.

2. The pharmaceutical composition according to claim 1, wherein the concentration of the strong base is 0.75% or more or 1% or more, or 0.5-5%, preferably 0.75-5% or 1-5%.

3. The pharmaceutical composition according to claim 1 or 2, wherein the concentration of the weak base is ≥ 2.5%, preferably ≥ 3.0% or ≥ 5%, or from 2.5-35%, preferably from 3.0-35% or from 5-35%.

4. The pharmaceutical composition according to one of claims 1 to 3, wherein the strong base comprises an alkali metal hydroxide, wherein the alkali metal hydroxide comprises for example: sodium hydroxide, potassium hydroxide, calcium hydroxide.

5. The pharmaceutical composition or method according to any one of claims 1-4, wherein the weak base comprises a weak basic inorganic salt of a polybasic acid, an inorganic salt of a weak acid of a polybasic acid, a weak base containing nitrogen.

6. The pharmaceutical composition or method according to claim 5, wherein the polybasic, weak acid basic inorganic salt comprises sodium phosphate, sodium carbonate, potassium carbonate, borax.

7. The pharmaceutical composition or method according to claim 5, wherein the polybasic weak acid inorganic salt comprises sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, sodium hydrogen sulfate.

8. The pharmaceutical composition according to claim 5, wherein the weak nitrogen-containing base is selected from the group consisting of ammonia, ammonia chloride, 2-aminoethanol, tromethamine, triethanolamine, tris, 2-aminoethanol, tromethamine, triethanolamine, meglumine, and glufosinate.

9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the cytotoxic drug is selected from one or more of the following groups: drugs that disrupt the structure and function of DNA, drugs that interfere with transcribed RNA embedded in DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis, preferably one or more selected from the group consisting of: alkylating agents such as cyclophosphamide, carmustine; metal platinum complexes such as cisplatin, carboplatin; DNA topoisomerase inhibitors such as doxorubicin, topotecan, irinotecan; anti-tumor antibiotics such as actinomycins, daunorubicin; pyrimidine antagonists such as uracil derivatives 5-fluorouracil, furfluorouracil, bifurcofurouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine; taxanes such as paclitaxel, docetaxel.

10. The pharmaceutical composition according to one of claims 1 to 9, wherein the local lesions comprise tumors, non-tumorous enlargement, local inflammation, secretory gland dysfunction and skin diseases.