CN110870860A - Pharmaceutical composition comprising amino acid nutrients and conventional ineffective compounds and use thereof - Google Patents
Pharmaceutical composition comprising amino acid nutrients and conventional ineffective compounds and use thereof Download PDFInfo
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- CN110870860A CN110870860A CN201811008758.4A CN201811008758A CN110870860A CN 110870860 A CN110870860 A CN 110870860A CN 201811008758 A CN201811008758 A CN 201811008758A CN 110870860 A CN110870860 A CN 110870860A
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- amino acid
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Abstract
The present disclosure relates to the use of amino acid based nutrients as a topical active ingredient for the preparation of a topical pharmaceutical composition for the treatment of topical pathological conditions, a topical pharmaceutical composition for the treatment of topical pathological conditions comprising the amino acid based nutrients topical active ingredient and a conventional ineffective compound, and a device comprising the composition.
Description
Technical Field
The present disclosure relates to the use of amino acid based nutrients as a topical active ingredient for the preparation of a topical pharmaceutical composition for the treatment of topical pathological conditions, a topical pharmaceutical composition for the treatment of topical pathological conditions comprising the amino acid based nutrients topical active ingredient and a conventional ineffective compound, and a device comprising the composition.
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.
One of the major problems faced in the development of antineoplastic drugs is specificity. The cytotoxic drug can target tumor cells through systemic administration based on the positive result of tumor cell inhibition experiment. However, since the target cells and normal cells cannot be sufficiently distinguished, and the difference between the effective dose and the safety limit is not large enough, there is a great risk of systemic toxicity while systemic therapeutic effects (tumor cell suppression effects in and out of tumor) are produced. Furthermore, the drug molecules need to penetrate effectively into the tumor tissue to interact with the tumor cells in between, which is not an obstacle-free event. For some tumors with a poor blood supply (e.g., pancreatic cancer), the chances of patient benefit are less.
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 drug that physically targets a localized lesion, but has a higher specificity.
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 amino acid based nutrient, a conventional ineffective compound, and a pharmaceutically acceptable liquid carrier, wherein the concentration (w/v) of the amino acid based nutrient in the topical pharmaceutical composition is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
According to another aspect of the present disclosure there is provided the use of amino acid based nutrients as a topical active ingredient in combination with conventional ineffective compounds for the preparation of a topical pharmaceutical composition for the treatment of a locally diseased condition. In this aspect, the topical pharmaceutical composition comprises the amino acid based nutrient, the conventional ineffective compound, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of the amino acid based nutrient is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25%, or 10-25%; and the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
According to yet another aspect of the present disclosure, there is provided a method for preventing and treating a localized disease condition comprising topically administering to a subject in need thereof a pharmaceutical composition according to the present disclosure.
The composition comprising amino acid based nutrients and conventional ineffective compounds as their topically active synergistic agents disclosed according to the present application has the following advantages compared to single drugs containing the corresponding ingredients: provides a synergistic effect against localized disease conditions to improve efficacy, while possibly providing an antagonistic effect against non-specific tissue destruction to improve safety.
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 specificity, namely, the chemical ablation agent has higher effectiveness on local lesions and obviously lower local irritation on non-lesion tissues, so that the chemical ablation agent has larger intervention adaptability and higher application volume. 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
The inventors of the present invention have found that the combination of amino acid based nutrients as a topically active ingredient with conventional ineffective compounds has a synergistic effect in the treatment of topically diseased states, especially when their concentrations in a topical pharmaceutical composition for the treatment of topically diseased states have the quantitative ratios as defined below. In the context of the present invention, the term "local active ingredient" is used to refer to an active ingredient in a topical medicament that provides a local effect, typically a destructive effect on local tissues.
In the context of the present invention, the term "local effect" or "local activity" is used to mean that the pharmacological effect or pharmacological activity is produced at the target area primarily by the agent itself, rather than by the blood with the agent. 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.
In the context of the present invention, the term "synergistic effect" means that the combination of active ingredients shows a more favorable pharmaceutical effect on the treatment than their individual use alone, which includes, for example, synergistic efficacy and synergistic safety. The term "synergistic efficacy" refers to the combined display of the active ingredients that exhibits a higher desired efficacy than either ingredient alone and/or the combined display that does not exhibit the desired efficacy (e.g., a novel immune effect) of either ingredient alone. The term "synergistic safety" means that the active ingredients in combination exhibit a desired safety higher than that of either ingredient alone, for example, even if the efficacy of the combination is not more than the maximum efficacy of the single ingredient, it is an effective efficacy, and the safety of the combination is significantly higher than that of the single ingredient (e.g., antagonism of side effects) of the maximum efficacy of the single ingredient.
Thus, according to one aspect of the present invention, there is provided a topical pharmaceutical composition for the treatment of a locally varying disease comprising an amino acid based nutrient, a conventional ineffective compound, and a pharmaceutically acceptable liquid carrier, wherein the concentration (w/v) of the amino acid based nutrient in the topical pharmaceutical composition is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
According to another aspect of the present disclosure there is provided the use of amino acid based nutrients as a topical active ingredient in combination with conventional ineffective compounds for the preparation of a topical pharmaceutical composition for the treatment of a locally diseased condition. In this aspect, the topical pharmaceutical composition comprises the amino acid based nutrient, the conventional ineffective compound, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of the amino acid based nutrient is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25%, or 10-25%; and the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
According to a further aspect of the present disclosure there is provided a method of preventing and treating a localized disease condition comprising topically administering to an individual in need thereof a therapeutically effective amount of a liquid carrier pharmaceutical composition comprising the amino acid based nutrient as a topically active ingredient and the conventional ineffective compound according to the present disclosure.
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/volume percent concentration% (w/v) 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 scope of the present invention, the term "amino acid nutrient" is used to refer to an amino acid compound having a nutraceutical effect, preferably selected from amino acids, amino acid polymers and amino acid derivatives having a nutraceutical effect, more preferably selected from amino acid nutraceuticals and amino acid adjuvants having a nutraceutical effect, as carried in the chinese, us or european official pharmacopoeia or guidelines. In the context of the present invention, the term "nutraceutical effect" is used to refer to an in vivo effect resulting from the action of one or more of the following organisms: providing energy, participating in the synthesis of bioactive substances (e.g., proteins), participating in part of the metabolism, maintaining the intestinal micro-ecological balance of animals, and participating in other physiological regulation beneficial to the health of the body (e.g., regulating protein synthesis, regulating immune response).
In the scope of the present invention, the amino acid polymer, and the amino acid derivative as the amino acid nutrient are preferably amino acids selected from the group consisting of: proteinogenic amino acids and nonproteinogenic amino acids.
In the context of the present invention, the term "proteinogenic amino acids" refers to the main amino acids that make up a protein; the term "non-proteinogenic amino acids" refers to amino acids other than proteinogenic amino acids that may also be used as nutraceutical functional components in nutraceuticals, traditional diets and functional diets (e.g., health diets).
Specifically, in the present disclosure, the proteinogenic amino acids include amino acids selected from the group consisting of nonpolar amino acids (e.g., alanine, valine, leucine, isoleucine, phenylalanine, proline), polar neutral amino acids (e.g., tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine), basic amino acids (e.g., lysine, arginine, histidine), acidic amino acids (e.g., aspartic acid, glutamic acid), the above are L-type α -amino acids except glycine.
The amino acid polymer may be selected from oligopeptides and polypeptides comprising amino acids as described above.
In the present disclosure, the term "oligopeptide" is used to refer to an amino acid polymer comprising 2 to 10 identical or different amino acids linked by peptide bonds, while the term "polypeptide" is used to refer to an amino acid polymer comprising 11 to 100 identical or different amino acids linked by peptide bonds, for the amino acids making up the oligopeptide or polypeptide, all of one or more of the above amino acids may be present, as well as additional amino acids.
The amino acid derivative may, for example, be selected from amino acid salts comprising the amino acids as described above. In the context of the present invention, the term "amino acid salt" is used to indicate salts of amino acids with acids or bases as described above, for example sodium, calcium, potassium, iron, magnesium, zinc, magnesium salts with bases and the like, as well as salts with acids, for example hydrochloride, hydrobromide, sulphate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulphonate, p-toluenesulphonate, amino acid salts and the like. More specifically, for example, lysine hydrochloride, histidine hydrochloride, glutamic acid hydrochloride, cysteine hydrochloride, arginine hydrochloride, glycine sulfate, lysine hydrochloride, aspartic acid hydrochloride, etc.
In the present disclosure, the amino acid nutrient includes one or more of the following amino acid compounds having a nutraceutical effect: amino acids, amino acid salts, oligopeptides, and polypeptides. In the pharmaceutical composition of the present invention, the amino acid nutrient may be one or more of amino acids, amino acid salts, oligopeptides and polypeptides, for example, 2,3, 4 or 5 or more.
In the present disclosure, the amino acids, amino acid salts, oligopeptides and polypeptides as the amino acid nutrients are preferably amino acids selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, serine, cysteine, methionine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, β -alanine, taurine, gamma-aminobutyric acid (GABA), theanine, citrulline and ornithine or salts thereof or oligopeptides and polypeptides comprising or consisting of amino acids selected from the group consisting of arginine, lysine, glycine, cysteine, alanine, serine, aspartic acid and glutamic acid.
In one embodiment, the amino acid nutrient is selected from arginine, an arginine salt, or an oligopeptide or polypeptide containing arginine.
In one embodiment, the amino acid nutrient is selected from lysine, a lysine salt, or an oligopeptide or polypeptide containing lysine.
In one embodiment, the amino acid nutrient is selected from glycine, a glycine salt, or an oligopeptide or polypeptide containing glycine.
In one embodiment, the amino acid nutrient is selected from glutamic acid, a glutamate, or an oligopeptide or polypeptide containing glutamic acid.
In one embodiment, the amino acid based nutrient is selected from the group consisting of amino acids or amino acid salts having a nutraceutical effect and the concentration (w/v) of the amino acid or amino acid salt in the topical pharmaceutical composition is ≥ 2%,. gtoreq.2.5%,. gtoreq.5%,. gtoreq.7.5%, 10-25% or 18-25%, preferably 15% -25% or 20% -25%.
In one embodiment, the amino acid based nutrients are selected from oligopeptides and polypeptides having nutraceutical effects and the concentration (w/v) of said oligopeptides and polypeptides in the topical pharmaceutical composition is greater than or equal to 5%, preferably 7.5-25%, more preferably 10-25%.
In one embodiment, the amino acid based nutrient is a combination of the amino acid and/or amino acid salt and the oligopeptide and/or polypeptide and the concentration (w/v) of the combination in the topical pharmaceutical composition is greater than or equal to 5%, preferably 7.5% -25%, more preferably 10-25%.
In the context of the present disclosure, the term "conventional ineffective compound" is used in distinction to a conventionally effective compound (e.g., an antitumor compound) and refers to a compound that may exhibit an effect on a particular cell (e.g., an antitumor cell effect) in a cell assay, but does not exhibit the effect of achieving the cell by absorption in an animal assay, thereby effectively inhibiting a locally diseased disease (e.g., a solid tumor). None of the conventional ineffective compounds are approved by the drug administration (e.g., FDA) for use as therapeutic drugs (e.g., antineoplastic drugs) against specific localized disease conditions. 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; while the term "absorption compound" refers to a therapeutic drug that exerts its pharmacological effect primarily through absorption.
In the present disclosure, the conventional ineffective compound is one or more selected from the following group: other nutrients than the amino acid nutrients, ineffective aromatic compounds, acidulants.
According to one embodiment, the additional nutrient is one or more selected from the group consisting of: carbohydrate nutrients, lipid nutrients and in the topical pharmaceutical composition the concentration (w/v) of said other nutrients is more than or equal to 4%, preferably 4-50%, 15-40% or 25-40%.
In the context of the present invention, the term "carbohydrate nutrient" is used to mean 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.
In the present disclosure, the monosaccharide, the sugar polymer, and the sugar derivative as the saccharide nutrient are preferably a monosaccharide selected from the following group, a sugar polymer containing a monosaccharide selected from the following group, or a derivative thereof: glucose, ribose, deoxyribose, xylose, fructose, galactose and fucose.
The sugar polymer may be selected from disaccharides, oligosaccharides and polysaccharides comprising monosaccharides as described above. In the context of the present invention, the term "disaccharide" is used to indicate a polymer comprising 2 monosaccharides linked by glycosidic bonds; the term "oligosaccharide" is used to mean a polymer comprising 3 to 10 monosaccharides linked by glycosidic linkages; and the term "polysaccharide" is used to refer to a polymer comprising more than 10 monosaccharides linked by glycosidic linkages. The monosaccharides that constitute the disaccharide, oligosaccharide or polysaccharide may be all one or more of the monosaccharides described above, or may additionally contain other monosaccharides. In one embodiment, the disaccharide may be one or more selected from: lactulose, maltose, sucrose, lactose, trehalose. In one embodiment, the oligosaccharide may be one or more selected from: chitosan oligosaccharide, xylo-oligosaccharide, fructo-oligosaccharide, mannooligosaccharide, maltooligosaccharide and isomalto-oligosaccharide. In one embodiment, the polysaccharide may be one or more selected from the group consisting of: starch, cellulose, dextran, glycosaminoglycan.
The sugar derivative may for example be the following sugar derivatives selected from the group of monosaccharides or sugar polymers as described above: sugar acid, sugar acid salt and sugar alcohol. In the context of the present invention, the term "sugar acid" is used to indicate an acid derivative of a monosaccharide or sugar polymer; the term "sugar acid salt" refers to salt derivatives of monosaccharides or sugar polymers; the term "sugar alcohol" refers to an alcoholic derivative of a monosaccharide or sugar polymer. In one embodiment, the sugar acid may be one or more selected from the group consisting of: gluconic acid, mannonic acid, arabinonic acid. In one embodiment, the sugar acid salt may be one or more selected from the group consisting of: sodium gluconate, sodium mannonate and sodium arabinonate. In one embodiment, the sugar alcohol may be one or more selected from the group consisting of: mannitol, maltitol, lactitol, xylitol.
In the pharmaceutical composition of the present invention, the carbohydrate nutrient may be one or more of monosaccharide, oligosaccharide, polysaccharide, sugar acid salt, sugar alcohol, for example, 2,3, 4, or 5 or more.
In one embodiment, the carbohydrate nutrient is selected from glucose, a glucose-containing carbohydrate polymer, or a glucose derivative.
In one embodiment, the carbohydrate nutrient is selected from ribose, a ribose-containing sugar polymer, or a ribose derivative.
In one embodiment, the carbohydrate nutrient is selected from xylose, a carbohydrate polymer comprising xylose, or a xylose derivative.
In one embodiment, the carbohydrate nutrient is preferably 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, mannan oligosaccharide and xylitol. In one embodiment, the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is greater than 5%, preferably ≥ 10%, 10-40%, 15-50% or 25-50%.
In the pharmaceutical composition according to the present disclosure, the lipid nutrient includes any pharmaceutically acceptable lipid nutrient, preferably with lipid compounds having nutraceutical effect selected from the chinese, us or european official pharmacopoeia or guidelines, more preferably one or more selected from the group consisting of: lipids, fatty acids, fatty milks and lipids.
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 and phospholipid. In one embodiment, the concentration (w/v) of the liponutrient in the pharmaceutical composition is ≥ 4%, preferably 4-25%.
In the pharmaceutical composition according to the present disclosure, the ineffective aromatic compound is one or more selected from the group consisting of: pigment aromatic compounds, salicylic acid compounds and quinoline compounds. In one embodiment, the concentration (w/v) of said ineffective aromatic compound in the topical pharmaceutical composition is not less than 0.35%, preferably 0.35-10%.
In one embodiment, the ineffective aromatic compound is a pigment aromatic compound, and the concentration (w/v) of the pigment aromatic compound in the pharmaceutical composition is not less than 0.35%, preferably 0.5-10%.
In the context of the present invention, the term "ineffective aromatic compound" is used to refer to an aromatic compound among conventional ineffective compounds. The non-effective aromatic compound includes any non-effective aromatic compound that is pharmaceutically acceptable, preferably selected from non-effective aromatic compounds known in the art, such as pharmaceutical aromatic compounds that have been approved or will be approved by or loaded in the chinese, us or european official administrative department (e.g., FDA or chinese medical administration).
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 term "vital dye" refers to an organic substance capable of coloring structures within a target area when administered topically, but with side effects within a pharmaceutically acceptable range, which may include, for example, 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 term "photosensitizer" refers to a substance that produces a photodynamic effect under the action of light of a certain wavelength to produce a therapeutic effect, which 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 term "colored chemotherapeutic agent" refers to a colored substance that can be used as a chemotherapeutic agent, which may for example include 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 one embodiment, the pigmentary aromatic compound is selected from vital dyes, preferably from dyes of the methylene blue type and Bengal.
In one embodiment, the methylene blue type dye includes the following compounds and derivatives thereof: methylene blue, patent blue, isothio blue. In one embodiment, the concentration (w/v) of the methylene blue dye in the topical pharmaceutical composition is 0.35% or more, preferably 0.35-2%, more preferably 0.35-1.5% or 0.5-1%.
In one embodiment, the color aromatic compound is selected from bengal. In one embodiment, the concentration (w/v) of said Bengal in the topical pharmaceutical composition is ≧ 5%, preferably 5-10%.
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 one embodiment, the salicylic acid-based compound is one or more selected from salicylic acid and one or more of the following compounds and derivatives thereof: acetylsalicylic acid, difluorosalicylic acid, disalicylate, dicumarol and aspirin lysine.
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 the context of the present disclosure, the term "quinoline" refers to pharmaceutically acceptable quinoline derivatives containing a quinoline ring, and includes chloroquine (chloroquine), hydroxychloroquine, aminomethylquine, amonoquine, quinine, nitroquine, piperaquine, primaquine (primaquine), pamaquine, pentaquine and isomers and pharmaceutically acceptable salts thereof, wherein quinine, chloroquine, primaquine and isomers and pharmaceutically acceptable salts thereof are preferred, and quinine and isomers and pharmaceutically acceptable salts thereof are particularly preferred. 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 quinolines are selected from water-soluble quinolines, preferably from one or more of the following: quinine hydrochloride, quinine dihydrochloride and chloroquine, and in the topical pharmaceutical composition, the concentration (w/v) of the quinoline compound is more than or equal to 3 percent, and is preferably 3-6 percent.
In the context of the present invention, the term "acidifying agent" is used to indicate an acid which is used in the pharmaceutical preparation primarily as an adjuvant, more particularly as a pH regulator, which does not usually introduce a particular biological activity in addition to providing acidity when used. In the compositions disclosed herein, the acidulant comprises any acidulant that is pharmaceutically acceptable, preferably selected from acidulants 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., "pharmaceutic adjuvants" in the fourth part of the chinese pharmacopoeia 2015 edition, or the "pharmaceutic adjuvants manual" fourth edition by r.c. ro et al).
In the present disclosure, the acidulants include strong, medium and weak acidifiers. Acids are classified into strong, medium and weak acids according to their degree of ionization in aqueous solutions. The degree of ionization of an acid is represented by the ionization constant (Ka), and a smaller Ka is weaker, for example, a weak acid has an ionization constant (Ka) of less than 0.0001. More generally, the degree of ionization is represented by the negative logarithm of the ionization constant (called the acidity coefficient, pKa), with greater pKa being less acidic. The term "strong acid" refers to acids having a pKa of less than 1, such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, selenic acid, hydrobromic acid, hydroiodic acid, chloric acid, and the like. The term "weak acid" refers to acids having a pKa greater than 4, such as carbonic acid, boric acid, acetic acid, and the like. The term "medium-strength acid" refers to an acid having a pKa of 1 to 4, such as phosphoric acid, sulfurous acid, pyruvic acid, oxalic acid, tartaric acid, nitrous acid, and the like.
In one embodiment, the acidifying agent is one or more selected from the group consisting of: a strengthening agent, a medium strengthening agent and a weak acid agent, and the concentration (w/v) of the strengthening agent in the topical pharmaceutical composition is > 0.25%, preferably 0.75-15%.
In one embodiment, the agent comprises one or more of: hydrochloric acid, sulfuric acid, nitric acid, preferably hydrochloric acid.
In one embodiment, the medium-intensity agents include one or more of: phosphoric acid, maleic acid, oxalic acid and tartaric acid.
In one embodiment, the weak acidifying agent comprises an acidifying agent selected from water-soluble saturated fatty carboxylic acids or/and water-soluble hydroxycarboxylic acids. The weak acid acidifying agent may be a C1-10 aliphatic carboxylic acid optionally substituted with 1-3 hydroxyl groups. The aliphatic carboxylic acid may be a mono-, di-or tri-aliphatic carboxylic acid. The acidulant selected from the group consisting of water-soluble saturated fatty carboxylic acids includes one or more of: acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, among which acetic acid is preferred. The acidulant selected from the group consisting of water-soluble hydroxycarboxylic acids includes one or more of: glycolic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1, 2, 3-tricarballylic acid), malic acid (2-hydroxysuccinic acid).
In one embodiment, the acidifying agent comprises a strengthening agent, preferably hydrochloric acid, and the concentration (w/v) of the strengthening agent in the pharmaceutical composition is not less than 0.25%, 0.35-2%, preferably 0.5-1.5% or 0.75-1.2%, or preferably 0.75-2% or 1-1.5%.
In one embodiment, the acidifying agent comprises a moderately strong acidifying agent, and the concentration (w/v) of the moderately strong acidifying agent in the pharmaceutical composition is > 0.5%, preferably 1-10%, 1% -5%, or 0.8-15%, preferably 1.5% -10% or 1.5% -7.5%.
In one embodiment, the acidifying agent comprises a weakly acidifying agent, preferably acetic acid, and the concentration (w/v) of the weakly acidifying agent in the pharmaceutical composition is 0.8-20%, 1.5-20%, preferably 2-15%, 3.5-15%, more preferably 5-12.5% or 5-10%.
According to one embodiment, the acidifying agent is one or more selected from the group consisting of: acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1, 2, 3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid), and tartaric acid. In one embodiment, the concentration (w/v) of the acidifying agent in the topical pharmaceutical composition is 0.8-20%, 1.5-20%, preferably 2.5-15% or 3.5-10%, further preferably 1.5-10% or 1.5-7.5%, or 3.5-15%, preferably 5-12.5% or 5-10%.
According to one embodiment, the acidifying agent is a combination of a weak acid and a strong acid, a weak acid and a medium strong acid, or a weak acid and a medium and strong acid, and the concentration of the acidifying agent in the topical pharmaceutical composition can be 1-10% or 1-15%, wherein the weight ratio of weak acid to medium/strong acid can be in the range of 99:1-1: 99.
In one embodiment, the pharmaceutical composition comprises the amino acid based nutrient, a carbohydrate nutrient, a weak acid agent (preferably acetic acid), and a pharmaceutically acceptable liquid carrier.
In the pharmaceutical composition according to the present disclosure, it further optionally comprises one or more selected from the group consisting of: analgesics, slow release carriers, and other agents selected from the group consisting of anti-tumor chemotherapeutic agents, uncouplers, and biological extracts and analogs thereof.
The pharmaceutical composition according to the present disclosure may further optionally comprise an analgesic. The analgesic is used to reduce the pain experienced by the patient and may be any suitable one known to those skilled in the art, such as benzyl alcohol, procaine hydrochloride, chlorobutanol, lidocaine hydrochloride, and the like. The concentration of the analgesic in the pharmaceutical composition may be, for example, 0.1-4% by weight. For example, benzyl alcohol may be present in the pharmaceutical composition at a concentration of 1 to 4% by weight, and procaine hydrochloride, chlorobutanol, and lidocaine hydrochloride may be present in the pharmaceutical composition at a concentration of 1 to 3% by weight, respectively.
The pharmaceutical compositions according to the present disclosure may further optionally comprise a slow release carrier. The sustained release carrier may be any suitable one known to those skilled in the art, including, for example, a gel matrix, a microparticle carrier, a micelle matrix, and the like. The concentration (w/v) of the slow release carrier in the pharmaceutical composition may be, for example, 0.5-13%, preferably 1-12% or 1-15%.
In the pharmaceutical compositions according to the present disclosure, the anti-tumor compound may be any suitable one known to the skilled person and may be selected from one or more of the following groups carried by the chinese, us or european official pharmacopoeias or guidelines: drugs that disrupt the structure and function of DNA, drugs that interfere with the transcription of RNA that intercalate into DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis. Such agents that disrupt DNA structure and function include, for example, alkylating agents (e.g., cyclophosphamide, carmustine, etc.), metal platinum complexes (e.g., cisplatin, carboplatin, etc.), DNA topoisomerase inhibitors (e.g., doxorubicin, topotecan, irinotecan, etc.). The drugs that are inserted into the DNA to interfere with the transcription of RNA include, for example, antitumor antibiotics such as actinomycins, daunorubicin, doxorubicin, and the like. The drug which interferes with DNA synthesis includes, for example, a pyrimidine antagonist (e.g., uracil derivatives such as 5-fluorouracil, furfluorouracil, difurofluorouracil, cytosine derivatives such as cytarabine, cyclocytidine, 5-azacytidine, etc.), a purine antagonist (e.g., carcinolytic, thioguanine, etc.), a folate antagonist (e.g., methotrexate), etc. The drugs affecting protein synthesis include, for example, colchicines, vinblastines, taxanes (e.g., paclitaxel, docetaxel, etc.), and the like.
In one embodiment, the anti-tumor chemotherapeutic is one or more selected from the group consisting of: uracil derivatives, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, and taxanes; preferably one or more selected from the following drugs and their analogous derivatives: uracil, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, paclitaxel.
In one embodiment, the decoupling agent is Dinitrophenol (DNP).
In one embodiment, the biological extract and analogs thereof are one or more selected from the group consisting of: polysaccharides, such as algal polysaccharides, medicinal plant polysaccharides, fungal polysaccharides; glycosides, such as ginsenoside, Panax notoginsenosides, saponin, polydatin, and holothurian saponins; polyphenols such as flavonoids, hydrolyzed tannins, procyanidins, tea polyphenols, resveratrol, apple polyphenols; terpenes, such as artemisinin, inula grandiflorum lactone, sesquiterpene lactone; flavones, such as puerarin, luteolin, silibinin, chrysin, amino acid lignin, nobiletin, and licorice total flavone; and alkaloids such as camptothecin alkaloid, matrine alkaloid, vinca alkaloid, Amaryllidaceae alkaloid, and berberine alkaloid.
The pharmaceutical composition according to the present disclosure may further optionally comprise an excipient. The excipient may be any suitable one known to those skilled in the art and may include, for example, one or more of the following: dispersion media, preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, viscosity-increasing agents, and the like. The viscosity-increasing agent is, for example, sodium carboxymethylcellulose, polyvinylpyrrolidone or gelatin. Such as an antioxidant (e.g., ascorbic acid).
The pharmaceutical composition according to the present disclosure may be any suitable dosage form for topical administration which may comprise the active ingredient (the amino acid based nutrient, the ineffective aromatic compound, and optionally other active ingredients as described above) and a liquid carrier (e.g. water, ethanol, or a water/ethanol mixture), 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 the 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.
According to another aspect of the present disclosure there is provided a topical pharmaceutical composition for the treatment of solid tumors in lyophilized or semi-lyophilized form obtained by lyophilizing or semi-lyophilizing a portion or all of one of the pharmaceutical compositions comprising the amino acid nutrient, the ineffective aromatic compound, and a pharmaceutically acceptable carrier according to the present disclosure.
According to a further aspect of the present invention there is also provided a device for the treatment of a localized disease condition comprising a pharmaceutical composition comprising an amino acid nutrient and a conventional ineffective compound according to the present disclosure. The device may be, for example, a device known in the art capable of ejecting or atomizing an internal liquid, such as an aerosol, nebulizer, atomizer, or the like.
It will be appreciated by those skilled in the art that, according to the present invention, the 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: preparing a liquid medicament comprising the topically active ingredient, a liquid medium and optionally other substances. The liquid medicament may be a solution (e.g. a solution in a hydrophilic vehicle, preferably an aqueous solution), a suspension, or an emulsion comprising the topically active ingredient. 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 concentrations of the amino acid-based nutrients and the synergistic drug (e.g., the ineffective aromatic compound) are greater than or equal to the concentrations thereof in the 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 essential components (such as amino acid nutrients and conventional ineffective compounds) and optionally other components required according to the local administration concentration are added into the solvent to prepare a liquid; 2) mixing other necessary components (such as other nutrients) and optional additives according to the amount required by the local administration concentration to the liquid prepared in 1) uniformly 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 liquid injection of the pharmaceutical composition of the present invention can be prepared by a method comprising the steps of: 1) adding amino acid nutrients, conventional ineffective compounds and optionally other components which are required according to the local administration concentration into a solvent (or a pharmaceutically acceptable liquid carrier), uniformly mixing, and sterilizing to prepare a sterilization liquid I; 2) other optional components (such as other nutrients and the like) which are required according to the local administration concentration are added into a solvent (or a pharmaceutically acceptable liquid carrier) and are uniformly mixed, and the mixture is sterilized to prepare the sterilization liquid II. When the liquid medicine is used, the sterilization liquid I and the sterilization liquid II form a mixed liquid before or after entering a local administration instrument, and the mixed liquid can be directly used as a local administration liquid medicine or 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 the amino acid based nutrients and conventional ineffective compounds in the required amounts according to the topical administration concentration; and preparing a sterile vehicle containing the required amounts of the other components (e.g., carbohydrate nutrients, analgesics, organic acids such as acetic acid) according to the concentration to be topically administered. The sterile dry powder is preferably sterile freeze-dried powder, and the preparation method comprises the following steps: 1) preparing a solution comprising amino acid nutrients, ineffective aroma compounds 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: 1) adding amino acid nutrients, synergistic medicines (such as the conventional ineffective compound) and other optional components which are required according to the local administration concentration into a solvent to prepare a liquid; 2) the other components (e.g., water-soluble acid) and optionally other components required in accordance with the local administration concentration are added to the liquid prepared in 1) and mixed uniformly to obtain a liquid medicine. 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 amino acid nutrients, synergistic medicine (such as the conventional ineffective compound) and atomization excipient which are required according to the local administration concentration into a solvent to prepare liquid; 2) the other components (e.g., water-soluble acid) and optionally other components required in accordance with the local administration concentration are added to the liquid prepared in 1) and mixed uniformly to obtain a 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 compositions of the present invention include: contains different kinds and concentrations of the amino acid nutrients, contains different kinds and concentrations of synergistic medicines, and contains different kinds and concentrations of other additives (such as 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, testis, 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 person skilled in the art, 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-diseased conditions according to the present disclosure, the amino acid-based nutrients and conventional ineffective compounds are administered locally at their concentrations or amounts in the topical pharmaceutical composition. The concentration or amount provides a synergistic effect on the local response compared to local administration.
In the scope of the present invention, the term "super-potent synergistic effect" means not only synergistic effect but also effect which is not low in safety but higher in effectiveness than that of existing conventional therapeutic drugs. For example, in tumor-bearing animal experiments, the tumor inhibition rate of the local effect or the absorption effect of the conventional tumor treatment drugs (such as 5-fluorouracil) is 45-75%, and the composition has the super-effective synergistic drug effect, namely the composition has low safety and high drug effect or/and obvious immune effect. In the present disclosure, the amino acid based nutrients and conventional ineffective compounds in the composition according to the present invention are comprised in a super effective synergistic amount ratio. The term "super-effective synergistic amount ratio" refers to a synergistic amount ratio such that the composition exhibits super-effective synergy.
According to one technical scheme disclosed by the application, in the super-effective synergistic amount ratio, the concentration of the amino acid nutrients in the composition is more than or equal to 5%, and preferably 5% -25%. When the amino acid nutrient is selected from one or more of amino acid or/and amino acid salt, the concentration of the amino acid nutrient is 10% -25%, preferably 15% -25% or 20% -25%. When the amino acid nutrient is selected from one or more oligopeptides, the concentration of the amino acid nutrient is 5% -25%, preferably 7.5% -25%.
If present, the concentration of other nutrients in the composition is 4% or more, preferably 4% to 40%. Specifically, the concentration of the carbohydrate nutrients is more than or equal to 10 percent, preferably 10 to 40 percent or 10 to 30 percent; and the concentration of the lipid nutrient is more than or equal to 4 percent, and preferably 4 to 25 percent.
If present, the concentration of ineffective aromatic compounds in the composition is 0.35% or more, preferably 0.5% to 10%. For example, the concentration of the quinoline compound is more than or equal to 3 percent, and preferably 3 to 6 percent; the concentration of the salicylic acid compound is more than or equal to 5 percent, preferably 5 to 10 percent; and the concentration of the pigment aromatic compound is more than or equal to 0.35 percent, and preferably 0.5 to 10 percent.
If present, the concentration of methylene blue-based dye in the composition is preferably from 0.35% to 2%, more preferably from 0.35% to 1.5% or from 0.5% to 1%.
The concentration of bengal, if present, in the composition is greater than or equal to 5%, preferably between 5% and 10%.
The concentration of the organic acid acidulant in the composition, if present, is preferably from 3.5% to 15%, more preferably from 4.5% to 12.5% or from 4.5% to 10%.
Based on the studies described in more detail below, the composition of the present invention, although the specific mechanism remains to be further studied, exhibits pharmaceutical effects 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.
The present disclosure includes the following items:
item 1, a topical pharmaceutical composition for the treatment of a topical pathological condition comprising an amino acid based nutrient, a conventional ineffective compound, and a pharmaceutically acceptable liquid carrier, wherein the concentration (w/v) of the amino acid based nutrient in the topical pharmaceutical composition is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
Item 2 use of amino acid based nutrients as a topical active ingredient in combination with conventional ineffective compounds for the preparation of topical pharmaceutical compositions for the treatment of locally diseased conditions.
Item 3, the use according to item 2, wherein the topical pharmaceutical composition comprises the amino acid based nutrient, the conventional ineffective compound, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of the amino acid based nutrient is ≥ 2%, preferably 2.5-25%, 5-25%, 7.5-25%, or 10-25%; and the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
Item 4, the pharmaceutical composition or use according to one of items 1 to 3, wherein the amino acid nutrient comprises one or more of the following amino acid compounds having a nutraceutical effect, amino acid salts, oligopeptides and polypeptides, preferably amino acids or salts thereof or oligopeptides and polypeptides comprising or consisting of amino acids selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, β -alanine, taurine, gamma aminobutyric acid (GABA), tea polyphenols (theanine), pumpkin seed amino acids (3-amino-3-carboxypyranate), glutamine, citrulline, ornithine, more preferably amino acids or salts thereof selected from the group or oligopeptides and polypeptides comprising or consisting of arginine, lysine, glycine, cysteine, alanine, serine, glutamic acid.
Item 5, the pharmaceutical composition or use according to item 4, wherein the amino acid based nutrient is selected from the group consisting of amino acids or amino acid salts with nutraceutical effect and the concentration (w/v) of the amino acid or amino acid salt in the topical pharmaceutical composition is ≥ 2%, ≥ 2.5% >, ≥ 5% >, > 7.5%, 10-25% or 18-25%, preferably 15% -25% or 20% -25%.
Item 6, the pharmaceutical composition or use according to item 4, wherein the amino acid based nutrients are selected from oligopeptides and polypeptides with nutraceutical effect and the concentration (w/v) of the oligopeptides and polypeptides in the topical pharmaceutical composition is ≥ 5%, preferably 7.5-25%, more preferably 10-25%.
Item 7, the pharmaceutical composition or use according to item 4, wherein the amino acid based nutrient is a combination of the amino acid and/or amino acid salt and the oligopeptide and/or polypeptide and the concentration (w/v) of the combination in the topical pharmaceutical composition is ≥ 5%, preferably 7.5-25%, more preferably 10-25%.
Item 8, the pharmaceutical composition or use according to item 4, wherein the oligopeptide is one or more selected from the group consisting of glycyl-L-tyrosine, glycylalanine, glycylglycine, lysine-glycine dipeptide, glutamine dipeptide, carnosine (β -alanine histidine copolymer), glutathione, collagen oligopeptide, casein hydrolysate peptide, soybean oligopeptide, oligoarginine, oligoglycine, oligolysine, and the polypeptide is one or more selected from the group consisting of polyaspartic acid, polyglutamic acid, polylysine.
Item 9, the pharmaceutical composition or use according to item 1, wherein the conventionally ineffective compound is one or more selected from the group consisting of: other nutrients than the amino acid nutrients, ineffective aromatic compounds, acidulants.
Item 10, the pharmaceutical composition or use according to item 9, wherein the additional nutrient is one or more selected from the group consisting of: carbohydrate nutrients, lipid nutrients and in the topical pharmaceutical composition the concentration (w/v) of said other nutrients is more than or equal to 4%, preferably 4-40%.
Item 11, the pharmaceutical composition or use according to item 10, wherein the carbohydrate nutrient is a carbohydrate compound selected from the group consisting of one or more of the following saccharide units: glucose, ribose, xylose, fructose, galactose, fucose, preferably selected from one or more of the following: glucose, fructose, chitosan oligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, xylooligosaccharide, fructooligosaccharide, mannooligosaccharide, gluconic acid, sodium gluconate, xylitol, mannitol, maltitol, lactitol, more preferably one or more selected from the group consisting of: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannose oligomer and xylitol; and the concentration (w/v) of the carbohydrate nutrients in the pharmaceutical composition is more than 5%, preferably more than or equal to 10%, 10-40%, 15-50% or 25-50%
Item 12, the pharmaceutical composition or use according to item 10, wherein the liponutrient is one or more selected from the group consisting of: fatty acids, fatty milks and lipids, preferably selected from one or more of the following: 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 13, the pharmaceutical composition or use according to item 9, wherein the ineffective aromatic compound is one or more selected from the group consisting of: a pigment aromatic compound, a salicylic acid compound, a quinoline compound, and in the topical pharmaceutical composition, the concentration (w/v) of the ineffective aromatic compound is not less than 0.35%, preferably 0.35-10%.
Item 14, the pharmaceutical composition or use according to item 13, wherein the ineffective aromatic compound is a pigmented aromatic compound, and the concentration (w/v) of the pigmented aromatic compound in the pharmaceutical composition is not less than 0.35%, preferably 0.5-10%.
Item 15, the pharmaceutical composition or use according to item 13, wherein the chromoaromatic compound is selected from the group consisting of vital dyes, preferably from the group consisting of methylene blue type dyes and bengal.
Item 16, the pharmaceutical composition or use according to item 15, wherein the methylene blue-based dye comprises the following compounds and derivatives thereof: methylene blue, patent blue, isothioblue, and in the topical pharmaceutical composition, the concentration (w/v) of the methylene blue dye is not less than 0.35%, preferably 0.35-2%, more preferably 0.35-1.5% or 0.5-1%.
Item 17, the pharmaceutical composition or use according to item 15, wherein the chromophoric aromatic compound is selected from the group consisting of Bengal red, and the concentration (w/v) of Bengal red is ≧ 3%, preferably 5-10%, in the topical pharmaceutical composition.
Item 18, the pharmaceutical composition or use according to item 13, wherein 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%.
Item 19, the pharmaceutical composition or use according to item 13, wherein the quinolines are selected from water-soluble quinolines, preferably from one or more of: quinine hydrochloride, quinine dihydrochloride and chloroquine, and in the topical pharmaceutical composition, the concentration (w/v) of the quinoline compound is more than or equal to 3 percent, and is preferably 3-6 percent.
Item 20, the pharmaceutical composition or use according to item 9, wherein the acidifying agent is one or more selected from the group consisting of: a strengthening agent, a medium strengthening agent and a weak acid agent, and the concentration (w/v) of the strengthening agent in the topical pharmaceutical composition is > 0.25%, preferably 0.75-15%.
Item 21, the pharmaceutical composition or use according to item 20, wherein the strengthening agent is one or more selected from the group consisting of: hydrochloric acid, sulfuric acid, nitric acid, more preferably hydrochloric acid, and the concentration (w/v) of the strong acidifying agent in the topical pharmaceutical composition is not less than 0.25%, 0.35-2%, preferably 0.5-1.5% or 0.75-1.2%, or preferably 0.75-2% or 1-1.5%.
Item 22, the pharmaceutical composition or use according to item 20, wherein the mild acidifying agent is a C1-10 aliphatic carboxylic acid optionally substituted with 1-3 hydroxyl groups, preferably selected from one or more of: acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1, 2, 3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid), preferably acetic acid, and the concentration (w/v) of the weak acidifying agent in the topical pharmaceutical composition is 0.8-20%, 1.5-20%, preferably 2-15%, 3.5-15%, more preferably 5-12.5% or 5-10%.
Item 23, the pharmaceutical composition of item 20, wherein the medium-strength acidifying agent is one or more selected from the group consisting of: phosphoric acid, oxalic acid, maleic acid and tartaric acid, wherein the concentration (w/v) of the medium-strength acidifying agent is more than 0.5%, preferably 1-10%, 1-5%, or 0.8-15%, preferably 1.5-10% or 1.5-7.5%.
Item 24, a pharmaceutical composition or use according to item 20, wherein the pharmaceutical composition comprises the amino acid based nutrient, a carbohydrate nutrient, a mild acidifying agent, and a pharmaceutically acceptable liquid carrier.
Item 25, a pharmaceutical composition or use according to one of items 1 to 24, further comprising optionally one or more selected from the group consisting of: analgesics, slow release carriers, and other agents selected from the group consisting of anti-tumor chemotherapeutic agents, uncouplers, and biological extracts and analogs thereof.
Item 26, the pharmaceutical composition or use according to item 25, wherein the analgesic is one or more selected from the group consisting of: benzyl alcohol, procaine hydrochloride, chlorobutanol and lidocaine hydrochloride, and the concentration of the analgesic in the pharmaceutical composition is 0.1-4% by weight.
Item 27, a pharmaceutical composition or use according to item 25, wherein the anti-tumor chemotherapeutic is selected from one or more of the following group: drugs that disrupt the structure and function of DNA, drugs that interfere with the transcription of RNA that intercalate into DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis.
Item 28, the pharmaceutical composition or use according to item 27, wherein the anti-tumor chemotherapeutic is one or more selected from the group consisting of: uracil derivatives, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, and taxanes; preferably one or more selected from the following drugs and their analogous derivatives: 5-fluorouracil, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complex, paclitaxel.
Item 29, the pharmaceutical composition or use according to item 27 or 28, wherein the anti-tumor chemotherapeutic is selected from a water-soluble anti-tumor chemotherapeutic or an alcohol-soluble anti-tumor chemotherapeutic.
Item 30, the pharmaceutical composition or use according to item 25, wherein the decoupling agent is Dinitrophenol (DNP).
Item 31, the pharmaceutical composition or use according to item 25, wherein the biological extract and analogs thereof are one or more selected from the group consisting of: polysaccharides, such as algal polysaccharides, medicinal plant polysaccharides, fungal polysaccharides; glycosides, such as ginsenoside, Panax notoginsenosides, saponin, polydatin, and holothurian saponins; polyphenols such as flavonoids, hydrolyzed tannins, procyanidins, tea polyphenols, resveratrol, apple polyphenols; terpenes, such as artemisinin, inula grandiflorum lactone, sesquiterpene lactone; flavones, such as puerarin, luteolin, silibinin, chrysin, amino acid lignin, nobiletin, and licorice total flavone; and alkaloids such as camptothecin alkaloid, matrine alkaloid, vinca alkaloid, Amaryllidaceae alkaloid, and berberine alkaloid.
Item 32, a pharmaceutical composition or use according to one of items 1 to 31, wherein the pharmaceutically acceptable liquid carrier is water and/or ethanol.
Item 33, the pharmaceutical composition or the application according to one of items 1 to 31, wherein the pharmaceutical composition is in the form of an injection, and the injection comprises a liquid injection and a powder injection for injection.
Item 34, the pharmaceutical composition or use of item 32, wherein the powder for injection comprises a sterile dry powder and a vehicle, and one or both of the amino acid nutrient and the conventional ineffective compound are contained in the sterile dry powder, and the liquid carrier is contained in the vehicle, and the concentrations of the amino acid nutrient and the conventional ineffective compound are their concentrations in the sterile dry powder and vehicle mixture, respectively.
Item 35, a topical pharmaceutical composition for the treatment of a disease associated with a localized pathology comprising a dry powder obtained by lyophilization or semi-lyophilization of a part or all of a pharmaceutical composition according to one of items 1 and 4 to 32.
Item 36, a method for the prevention and treatment of a locally diseased condition comprising topically administering to a subject in need thereof a pharmaceutical composition according to one of items 1 and 4-35.
Item 37, a pharmaceutical composition, use or method according to one of items 1 to 36, wherein the local pathology comprises a tumor, a non-tumorous enlargement, a local inflammation, a secretory gland dysfunction and a skin disease.
Item 38, the pharmaceutical composition, the use or the method according to item 37, wherein the neoplasm comprises a malignant neoplasm and a non-malignant neoplasm.
Item 39, the pharmaceutical composition, the use or the method of item 38, 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 40, the pharmaceutical composition, use or method according to item 38, 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 stomach tumor, a nasopharyngeal tumor, a laryngeal tumor, a testicular tumor, a vaginal tumor, a uterine tumor, a fallopian tube tumor, an ovarian tumor.
Item 41, a pharmaceutical composition, use or method according to item 37, wherein the non-neoplastic mass comprises a hyperplasia (e.g. of the breast, pancreas, thyroid, parathyroid, prostate), a cyst (e.g. of the breast, thyroid, parathyroid), a nodule (e.g. of the breast, thyroid, parathyroid), an abnormal venous mass (e.g. a hemorrhoid), a localized inflammatory neoplasm, a microbial infection.
Item 42, the pharmaceutical composition, the use or the method according to item 37, wherein the local inflammation is a non-neoplastic inflammation at a local site, including degenerative, exudative and proliferative inflammation.
Item 43, a pharmaceutical composition, use or method according to item 37, 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 44, the pharmaceutical composition, the use or the method according to item 37, wherein the secretory gland dysfunction includes a secretory gland hyperactivity (e.g., hyperthyroidism) and a secretory gland hypofunction (e.g., hypothyroidism, hypoinsulinemia).
Item 45, the pharmaceutical composition, use or method according to item 37, 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).
Item 46, a device for treating a localized disease condition comprising a pharmaceutical composition according to one of items 1 and 4-32.
Item 47, the device of item 46, comprising an aerosolizer, nebulizer, atomizer.
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. Some of the amino acid nutrients and conventional ineffective compounds used in the following examples are listed in table 1.
TABLE 1
In the present invention, L-amino acids are abbreviated as amino acids (for example, L-arginine is abbreviated as arginine), reduced glutathione is abbreviated as glutathione, and alanyl-glutamine dipeptide is abbreviated as glutamine dipeptide.
In the following examples, tests of subcutaneous transplanted tumor animals were performed according to the test guidelines issued by the drug administration, unless otherwise indicated. The test animal is Balb/c nude mouse or mouse with age of 6-8 weeks and weight of 17.5-20.5 g. The subcutaneous transplantation is carried out according to the conventional subcutaneous inoculation method of tumor cells. Unless otherwise stated, the tumor is grown to a desired volume (e.g., 75-500 mm)3) This was randomly divided into several groups of 6 animals each using PEMS 3.2 software (compiled by the national institute of public health, western Sichuan university). Items for experimental observation, measurement and analysis include general state, body weight, food intake, tumor volume, tumor weight, thymus weight, spleen weight, 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 (%) ═ (TW-CW)/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, the tests were each statistically tested for group differences in mean index using Repeated measures analysis of variance (Repeated Meas μ res ANOVA). When the group difference has statistical significance (P is less than or equal to 0.05), the difference between each group and the negative control group is compared by adopting a minimum significant difference method. Quantitative indices are described as mean ± standard error (X ± SEM). When the LEVENE homogeneity test indicates that the variance is not uniform (P is less than 0.05), the difference between the groups is compared by using Mann-Whitney M rank sum test (M-W method). All statistical analyses were performed under SPSS for Windows 13.0 software.
Example 1: preparation of the composition
A number of different compositions of the present invention can be formulated according to the above-described method of preparing the compositions of the present invention, and the compositions of some of the compositions of the present invention prepared in this example are listed in Table 2.
TABLE 2
Several examples of the preparation tests of the compositions according to the invention are listed below.
1. Preparation of liquid injection (1)
Amino acid nutrients (e.g., 10g glutathione), conventional ineffective compounds (e.g., 30g glucose), optional other components and liquid carrier (e.g., water for injection) are measured at the desired concentration (as described in table 2), and brought to a total volume (e.g., 100ml), slowly mixed, sterile filtered, and dispensed into the desired volume (e.g., 10 ml/bottle) for storage. The preparation (e.g., 10% glutathione/30% glucose in water) can be administered topically as a liquid medicament.
2. Preparation of liquid injection (2)
1) Amino acid nutrients (e.g. 10g glutathione), conventional ineffective compounds (e.g. 30g glucose), optional other components and liquid carrier (e.g. water for injection) to a total volume (e.g. 85ml) are measured at the desired concentration (as described in table 2) and mixed slowly and homogenized, sterilized, filtered and then stored in aliquots (e.g. 8.5 ml/vial) as solution I.
2) The acidulant (e.g. 5g of acetic acid), optional other components and vehicle (e.g. water for injection) are measured out at the desired concentration (as described in table 2), brought to a total volume (e.g. 15ml) and mixed slowly until homogeneous, sterile filtered and stored in aliquots of the desired volume (e.g. 1.5 ml/vial) as solution II.
3) The solution I and the solution II are mixed uniformly (for example, 8.5ml of the solution I and 1.5ml of the solution II are mixed) according to the required concentration of each component to form a mixed solution (for example, 10% glutathione/30% glucose/5% acetic acid aqueous solution), and then the mixed solution can be used as a liquid medicine for local administration.
3. Preparation of powder injection for injection
1) The amino acid nutrient (such as 10g of glutathione), the conventional ineffective compound (such as 30g of glucose), other optional 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 (such as shown in the table 2), are slowly mixed uniformly, and are subpackaged into the required amount (such as 10 ml/bottle) after aseptic filtration, frozen and dried, and are subjected to tamponade and capping to prepare the sterile dry powder for standby.
2) The remaining optional other components (e.g. 5g of acetic acid, if any) and a liquid carrier (e.g. water for injection) to a total volume (e.g. 100ml) are measured at the desired concentration (as described in table 2) and mixed slowly and homogenized, sterile filtered and dispensed into the desired volume (e.g. 10 ml/bottle) to prepare a sterile liquid ready for use.
3) 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., 1 vial of the vehicle described above) to the desired reconstituted solution (e.g., 10% glutathione/30% glucose/5% acetic acid in water) at the desired concentration for each component and then topically administered as a liquid medicament.
4. Preparation of external liquid preparation
Amino acid based nutrients (10g glutathione), conventional ineffective compounds (e.g. 30g glucose), optional other components and a vehicle (e.g. water) to a total volume of 80-90% such as 80-90ml are measured at the desired concentration (as described in table 2) and mixed slowly and then the remaining conventional ineffective compounds (e.g. 5g acetic acid if present), the optional other components (if present) and vehicle (e.g. water for injection) to a total volume (e.g. 100ml) are added and mixed slowly and homogeneously. The preparation (e.g., 30% glucose/10% glutathione/5% acetic acid in water) can be directly used as a liquid drug for topical liquid application for topical administration.
5. Preparation of nebulant
Amino acid based nutrients (e.g. 10g glutamate hydrochloride), conventional ineffective compounds (e.g. 30g glucose), and the following adjuvants for nebulisers were measured at the desired concentrations (as described in table 2): glycerin (2.5g), polysorbate-80 (1.5g), benzalkonium chloride (0.02g), microcrystalline cellulose-sodium carboxymethyl cellulose (1.5g), and a vehicle (e.g., water for injection) to a total volume (e.g., 100ml), and slowly mixing them well for use. The preparation (e.g. stock solution of spray containing 30% glucose/10% glutamate) can be directly sprayed on the target area to form liquid medicine after being added into a sprayer.
Example 2: preferred synergistic technical scheme of the composition
1. Synergistic pharmacological preferences
In the study, successfully modeled test animals (S180-bearing mice, tumor body mean volume 121 mm)3) The groups were randomized into 2 negative control groups and 22 study groups. The negative control was physiological saline and 11 study drugs were administered intraperitoneally and intratumorally as shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The medicine is taken once every 3 days, 3 times in total, and the injection amount is less than or equal to 120 mu l/injection. On day 5 after the completion of the administration, the animals were euthanized, and the tumor weights were measured after dissection, and the tumor inhibition ratios were calculated from the negative control groups for each administration pattern, and the results are shown in table 3.
TABLE 3
Research medicine | Tumor inhibition rate of intraperitoneal injection | Tumor inhibition rate of intratumoral injection |
1% 5-Fluorouracil | 51% | 55% |
10% glutathione | 1% | 36% |
25% glucose | 4% | 28% |
3.5% acetic acid | 2% | 41% |
0.7% methylene blue | 3% | 8% |
5%DHA | 1% | 6% |
10% glutathione/25% glucose | 2% | 65% |
10% glutathione/3.5% acetic acid | 6% | 76% |
10% glutathione/0.7% methylene blue | 7% | 74% |
10% glutathione/5% DHA | 2% | 61% |
10% glutathione/25% glucose/3.5% acetic acid | 1% | 91% |
In table 3, the positive control (5-fluorouracil) is in line with its expectation as an anti-tumor cell drug. The results of the i.p. group showed: the anti-tumor cell medicine can target tumor cells in a blood medicine form so as to inhibit the growth of tumor bodies. Once thought, the in vivo administration of tumor can increase the local drug concentration of the antitumor cell drug, and may greatly improve the drug effect. However, as shown in Table 3, intratumoral injection did not greatly increase the tumor inhibition rate of 5-fluorouracil. The targeting property (tumor cells) and the pharmacology (tumor cell inhibition) of the medicine are not changed substantially during intratumoral injection, and the medicine also faces the same targeting barrier in tissues, so that the medicine shows consistent curative effect. Thus, conventional anti-tumor cell drugs have heretofore been administered primarily by absorption rather than topically unless placed in a sustained release system.
In table 3, the group of intraperitoneal amino acid nutrient injections meets the expectation of conventional application (absorption by blood), and the tumor inhibition rates are all less than 20%, which belongs to the ineffective range. The tumor inhibition rate of the intratumoral injection group is obviously improved, and the intratumoral injection group can be applied as a local active component.
In table 3, the group of amino acid-based nutrient/conventional ineffective compound compositions for intraperitoneal injection met their expectations in conventional applications (absorption through blood), all had tumor inhibition rates of less than 20%, and showed no synergistic efficacy. Surprisingly, the tumor volume increase of the intratumoral injection group at the 3 rd day after the first medication is lower than that of the intraperitoneal injection group, and the obvious synergistic medicinal effect is shown under the same experimental conditions, so that the targeting and pharmacology of the composition in the intraperitoneal injection group are obviously different.
In another experiment, successfully modeled test animals (S180-bearing mice, mean tumor volume 129mm3) Randomized into blank control and 5 study groups (A, B, C, D, E). The negative control was physiological saline, and the composition and injection pattern of the 5 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 medicine is taken once, and the injection amount is less than or equal to 130 mu l per unit. The following day after the end of drug administration, animals were euthanized and tumor anatomy was histologically observed, with intratumoral tissue destruction distinguished by a blank control group of 0 and a 5% acetic acid group of 5, and the results are shown in table 4.
TABLE 4
Test group | Research medicine | Injection mode | Intratumoral tissue destruction |
A | 10% glutathione/30% glucose | Abdominal injection | 0 |
B | 10% glutathione/30% glucose | Intratumoral injection | 3 |
C | 10% glutathione | Intratumoral injection | 1 |
D | 30% glucose | Intratumoral injection | 1 |
E | 5% acetic acid | Intratumoral injection | 5 |
Blank control group | - | - | 0 |
Similar results can be obtained with experiments with other compositions of the invention (e.g., the compositions in table 2).
2. The synergistic medicinal effect is preferably
In the study, successfully modeled test animals (S180 cell-bearing mice, average tumor volume 113mm3) The groups were randomized into negative control and 46 study groups. The negative control was physiological saline and the composition of the study drugs included as shown in the table below: 4 kinds of amino acid nutrient single medicine (X% amino acid nutrient) with variable types and concentrations, 18 kinds of conventional ineffective compounds (Y% conventional ineffective compounds) with variable types and concentrations, and 24 compositions (X% amino acid nutrient) respectively composed of amino acid nutrient with variable types and concentrations and conventional ineffective compounds with variable types and concentrationsY% of conventional ineffective compounds). 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 3 times in total, and the dose for each time was: glutathione is less than or equal to 1000mg/kg, arginine is less than or equal to 1500mg/kg, hydrochloric acid is less than or equal to 50mg/kg, acetic acid is less than or equal to 375mg/kg, methylene blue is less than or equal to 100mg/kg, quinine dihydrochloride is less than or equal to 250mg/kg, glucose is less than or equal to 2250mg/kg, and the injection volume is less than or equal to 150 mul. Animals were euthanized 5 days after the end of dosing, tumor weights were determined after dissection, and tumor inhibition rates were calculated from negative controls. The tumor inhibition rates of the study drug groups are shown in table 5.
TABLE 5
*: the data in parentheses in the bar is the average tumor inhibition for the X% amino acid based nutrient group, e.g., the average tumor inhibition for the 2.5% glutathione group is 8%
**: the data in parentheses in the column represent the average tumor inhibition of the Y% conventional ineffective compound group, e.g., the 20% acetic acid group represents 78%
***: the unbracketed data represent the average tumor inhibition for the X% amino acid based nutrient/Y% conventional ineffective compound group, e.g., 76% for the 2.5% glutathione/20% acetic acid group
In other tumor-bearing mouse models (e.g., at 0.1X 10 per mouse)6Each mammary tumor 4T1 cell-modeled mouse was 2X 10 cells per mouse61X 10 mice each of which was modeled by liver cancer H22 cells6Colon cancer CT26 cell-modeled mice, at 2X 10 per cell6Individual melanoma B16-f10 cell-modeled mice), similar effects can also be observed.
Similar results can be obtained with experiments with other compositions of the invention (e.g., the compositions in table 2).
3. Synergistic Security component preferences
In the above study experiments, the combination group showed the same body weight, condition and none of the deaths throughout the experiment compared to the animals of the single group. The above results show that topical application of the composition of the present invention does not show systemic safety antagonism.
In another trial, healthy New Zealand rabbits (weighing 1.9-2.5 kg) were randomly grouped into 1 negative control group, 17 study groups, with 4 animals per group. The negative control drug was normal saline, the amino acid nutrient control was 10% glutathione, and the study drugs included in the following table: 8 varying concentrations of the conventional ineffective compound were single drug (X% conventional ineffective compound) and 9 compositions (10% glutathione/X% conventional ineffective compound, including the case where X ═ 0). The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group of animals was injected with 1.0ml of drug into the quadriceps muscle of the right leg. After 24h, animals were euthanized, dissected and examined for pathological sections of the injection site, and observed for the degree of congestion, edema, degeneration, necrosis, etc. for stimulation response scoring. The scoring criteria were calculated based on the negative control group phenomenon being 0 points and the 50% acetic acid group phenomenon being 5 points, and the test results of each study group are shown in table 6.
TABLE 6
In the above table, the composition groups under certain compositional conditions unexpectedly showed strong local stimulation antagonism of tissue destruction. It is well known that strong undifferentiated tissue destruction underlies the pharmacological effects of chemical ablative agents (e.g., 50% acetic acid, 25% hydrochloric acid, or 3% methylene blue), and that this local irritancy is also a limitation.
According to the research results of the synergistic pharmacology, the synergistic efficacy and the synergistic safety, the composition has the following synergistic technical scheme:
1. local administration to diseased tissue;
2. topical administration in a synergistic composition wherein:
the concentration of the amino acid based nutrient is > 2.5%, preferably 5-25% (wherein the concentration of the amino acid or/and amino acid salt is 10-25%, or/and the concentration of the nutrient peptide is 5-25%);
the concentration of the conventional ineffective compound is > 0.25%, preferably 0.35-50%, wherein:
the concentration of the lipid nutrient is 3-25%;
the concentration of the carbohydrate nutrients is 10-40%;
the vital dye concentration is 0.35-15% (wherein the methylene blue-based dye, if present, is 0.35-2%); or/and
the concentration of the acidifying agent is > 0.25%, preferably 0.5-15% (wherein: the concentration of the weak acidifying agent is > 1%, preferably 2-15%, or/and the concentration of the strong acidifying agent is > 0.25%, preferably 0.5-1.5%).
With the above-described synergistic technical scheme, the synergistic effect of the composition of the present invention is not an inhibitory effect on cancer cells nor an undifferentiated tissue destruction effect, but an effect in which the components synergistically enhance the drug effect and reduce local damage. Conversely, the compositions of the invention significantly increase the specificity of local action.
Example 4: preference of amino acid nutrients
Successfully modeled test animals (S180 cell-bearing mice, mean tumor volume 91mm3) Was randomly divided into a negative control group, a positive control group and 10 study groups. The negative control was physiological saline, the positive control was 1% 5-fluorouracil, and the study drug was a 10% amino acid nutrient/5% acetic acid composition (with variable amino acid nutrient varieties). The amino acid based nutrients in the compositions used in study groups 1-9 were: glycine, cysteine hydrochloride, lysine hydrochloride, proline, valine, alanine, glutathione, serine, glutamine dipeptide, study group 10 used study drug 10% arginine/10% glycine/5% 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 3 times in total, with an injection volume of less than or equal to 150 μ l. After the application of the medicine is finished 5Animals were euthanized daily, tumor weights were determined after dissection, and tumor inhibition rates were calculated from negative controls. The tumor inhibition rate of the positive control group is 53%, and the results of the study group are shown in Table 7.
TABLE 7
Group of | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
Y(%) | 81 | 77 | 73 | 37 | 41 | 53 | 69 | 33 | 79 | 78 |
Based on these results and more similar studies, a super-effective synergistic pharmacodynamic profile of the amino acid nutrient/acidulant composition of the invention is: the amino acid nutrient is preferably one or more selected from the group consisting of the following amino acids and amino acid derivatives comprising the following amino acids: arginine, lysine, cysteine, alanine, serine, glycine, glutamic acid.
In another experiment, successfully modeled test animals (S180 cell-bearing mice, mean tumor volume 129mm3) Was randomly divided into a negative control group, a positive control group and 14 study groups. The negative control was physiological saline, the positive control was 1% 5-fluorouracil, and the study drug was 1% methylene blue/10% amino acid nutrient composition (with variable amino acid nutrient varieties). The amino acid based nutrients in the compositions used in study groups 1-13 were: arginine, glycine, cysteine hydrochloride, valine, threonine, proline, histidine hydrochloride, phenylalanine, lysine, leucine, alanine, glutathione, serine, study group 14 used study drug 1% methylene blue/5% arginine/5% glycine). 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 3 times in total, with an injection volume of less than or equal to 150 μ l. Animals were euthanized 5 days after the end of dosing, tumor weights were determined after dissection, and tumor inhibition rates were calculated from negative controls. The tumor inhibition rate of the positive control group is 55%, and the results of the study group are shown in Table 8.
TABLE 8
Group of | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 |
Y(%) | 95 | 81 | 92 | 43 | 56 | 33 | 5 | 48 | 90 | 74 | 83 | 89 | 91 | 63 |
Based on these results and more similar studies, a super-effective synergistic efficacy technical scheme of the amino acid nutrient/methylene blue dye composition of the invention is as follows: the amino acid nutrient is preferably one or more selected from the group consisting of the following amino acids and amino acid derivatives comprising the following amino acids: arginine, glycine, cysteine, threonine, proline, lysine, leucine, alanine, serine, glutamic acid, more preferably selected from amino acid compounds comprising one or more of the following amino acid units: arginine, glycine, cysteine hydrochloride, lysine, alanine, serine and glutamic acid.
Example 5: preference of conventional ineffective Compounds
1. Preference of carbohydrate nutrients
In the study, successfully modeled test animals (S180 cell-bearing mice, tumor body average volume 135mm3) Was randomly divided into a negative control group, a positive control group and 11 study groups. The negative control was physiological saline, the positive control was 1% 5-fluorouracil, and the 11 study drugs were 10% glutathione/5% acetic acid/30% carbohydrate nutrients (with variable carbohydrate nutrient varieties). The carbohydrate nutrients in the compositions used in study groups 1-11 were: glucose, maltose, lactulose, ribose, oligomannose, dextran 40, trehalose, sodium gluconate, chitosan oligosaccharide, glucosamine and xylitol. 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 3 times in total, with an injection volume of less than or equal to 150 μ l. Animals were euthanized 5 days after the end of dosing, tumor weights were determined after dissection, and tumor inhibition rates were calculated from negative controls. The tumor inhibition rate of the positive control group is 51%, and the results of the study groups are shown in Table 9.
TABLE 9
Group of | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 |
Y(%) | 85 | 56 | 71 | 76 | 69 | 41 | 51 | 87 | 83 | 81 | 75 |
Based on these results and more similar studies, a super-effective synergistic efficacy solution of the composition of the present invention is: the carbohydrate nutrient is preferably selected from one or more of the following monosaccharides and sugar derivatives comprising the following monosaccharides: glucose, ribose, xylose, fructose, galactose, fucose, more preferably one or more selected from: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannose oligomer and xylitol.
2. Acidifier comparison study
In the study, successfully modeled test animals (S180 cell-bearing mice, tumor body mean volume 225mm3) Was randomly divided into a negative control group and 4 study groups (A, B, C, D groups). The negative control group was administered with physiological saline, and the study groups were administered with the following drugs: 10% reduced glutathione/1% hydrochloric acid (pH1.4), 10% reduced glutathione/5% acetic acid (pH2.8), 20% lysine hydrochloride/5% acetic acid (pH3.4), 20% lysine hydrochloride/5% acetic acid (pH 4.5). The drug was an aqueous solution prepared according to the method of example 1, wherein 20% lysine hydrochloride/5% acetic acid (ph4.5) was raised by the addition of a suitable amount of sodium acetate. Each group was administered 3 times, once every 3 days by intratumoral injection, 150. mu.l/dose. Animals were euthanized 5 days after the end of dosing, tumor weights were determined after dissection, and tumor inhibition rates were calculated from negative controls.
In this test, the inhibition rates of A, B, C, D group were 78%, 84%, 89%, and 83%, respectively. The synergistic effect of the compositions of the present invention is not significantly negatively correlated with pH. According to the results of this test, the acidifying agents of the compositions according to the invention are preferably chosen from weak acidifying agents, and not strong acidifying agents.
Example 6: the condition of ultra-effective synergistic action of the composition is preferably
A breakthrough in the technical solution is needed to make the composition of the present invention not only produce a synergistic effect, but also make the synergistic effect so strong as to be clinically competitive. This was investigated in the following test examples.
1. The amino acid nutrient is preferably administered locally
In the study, successfully modeled test animals (S180 cell-bearing mice, tumor body mean volume 102mm3) The groups were randomly divided into a negative control group, a positive control group and 24 study groups. The negative control was physiological saline, the positive control was 1% 5-fluorouracil, and the composition of 24 study drugs, containing varying concentrations (X%) of amino acid nutrients and fixed concentrations of conventional ineffective compounds, is 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 injected intratumorally, once every 3 days for 3 times in total, and the dose for each time was: glycine is less than or equal to 1500mg/kg, arginine is less than or equal to 1500mg/kg, reduced glutathione is less than or equal to 900mg/kg, glutamate salt is less than or equal to 500mg/kg, glucose is less than or equal to 1500mg/kg, 5-fluorouracil is 50mg/kg, and the injection volume is less than or equal to 150 mul. The animals were euthanized 5 days after the end of the administration, tumor weights were measured after dissection, and the tumor inhibition rates were calculated from the negative control group, and the results are shown in table 10.
Watch 10
In the above table, it is further confirmed that the amino acid-based nutrient shows synergistic effect with the composition of the conventional ineffective compound only when the local administration concentration exceeds a certain threshold value (amino acid-based nutrient > 2.5%), and when the local administration concentration exceeds a certain value, the composition shows super-effective synergistic effect (compared with the positive control group), at which time the super-effective synergistic effect becomes sensitive to the local administration concentration and then becomes less sensitive again, and even the tumor suppression rate may be decreased.
Based on these results and more similar studies, a super-effective synergistic efficacy solution of the composition of the present invention is: the composition is such that the composition can provide a topical administration concentration of the amino acid based nutrient of 3% or more, preferably 5-25% or 3-25%, wherein:
when the amino acid nutrient comprises an acidic amino acid salt, the local administration concentration of the amino acid nutrient is 3% -25%;
when the amino acid nutrient is selected from one or more of amino acid or/and amino acid salt except acidic amino acid salt, the local administration concentration of the amino acid nutrient is 10% -25%, preferably 15% -25% or 20% -25%;
when the amino acid nutrient is selected from one or more oligopeptides, the amino acid nutrient is locally administered at a concentration of 5% to 25%, preferably 7.5% to 25%;
when the amino acid based nutrient comprises one or more of oligopeptides, amino acids or/and amino acid salts other than acidic amino acid salts, the amino acid based nutrient is administered topically at a concentration of 5% to 25%, preferably 7.5-25% or 10-25%.
2. The local administration concentration of the acidifying agent is preferably
In the study, successfully modeled test animals (S180 cell-bearing mice, tumor body mean volume 98mm3) Was randomly divided into a negative control group, a positive control group and 15 study groups. The negative control was physiological saline, the positive control was 1% 5-fluorouracil, and the study drug contained 15% lysine hydrochloride and varying concentrations (X%) of acetic acid or hydrochloric acid as 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 injected intratumorally, once every 3 days for 3 times in total, and the dose for each time was: acetic acid is less than or equal to 450mg/kg, hydrochloric acid is less than or equal to 75mg/kg, 5-fluorouracil is 50mg/kg, and the injection volume is less than or equal to 150 mul. The animals were euthanized 5 days after the end of the administration, tumor weights were measured after dissection, and the tumor inhibition rates were calculated from the negative control group, and the results are shown in table 11.
TABLE 11
In the above table, it is further confirmed that the acidifying agent shows synergistic effect with the amino acid-based nutrient composition only when the local administration concentration exceeds a certain threshold value (acetic acid > 1%, hydrochloric acid > 0.25%), and the composition shows super-effective synergistic effect (compared with the positive control group) when the local administration concentration exceeds a certain value (acetic acid > 2%, hydrochloric acid > 0.5%), at which time the super-effective synergistic effect becomes sensitive to the local administration concentration and then becomes less sensitive again, and even the tumor suppression rate may decrease.
In another set of experiments, similar results were also obtained when using a composition of 10% reduced glutathione with X% acetic acid and X% hydrochloric acid, respectively.
According to the results, a super-effective synergistic efficacy technical scheme of the composition of the invention is as follows:
the composition is such that the composition can provide a topical administration concentration of the acidifying agent of 0.75% or more, preferably 0.75% to 15%, wherein:
when the acidifying agent is selected from strong acid, the local administration concentration of the strong acid is preferably 0.75-2.5%, more preferably 0.75-2% or 1-1.5%;
when the acidifying agent is selected from weak acids, the local administration concentration of the weak acid is preferably 3.5% to 15%, more preferably 5% to 12.5% or 5% to 10%;
when the acidifying agent is selected from weak acid and strong acid, the local administration concentration of the acidifying agent is preferably 1-10%.
3. Topical administration of vital dyes
In the study, successfully modeled test animals (S180 cell-bearing mice, tumor body mean volume 112mm3) The groups were randomly divided into a negative control group, a positive control group and 8 study groups. The negative control was physiological saline, the positive control was 1% 5-fluorouracil, and 8 study drugs contained 20% lysine and varying concentrations (X%) of methylene blue as 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 injected intratumorally, once every 3 days for 3 times in total, and the dose for each time was: methylene blue is less than or equal to 75mg/kg, 5-fluorouracil is 50mg/kg, and the injection volume is less than or equal to 150 mul. The animals were euthanized 5 days after the end of the administration, tumor weights were measured after dissection, and the tumor inhibition rates were calculated from the negative control group, and the results are shown in table 12.
TABLE 12
In the above table it is further confirmed that the vital dye shows a synergistic effect with the composition of amino acid based nutrients only when the local administration concentration exceeds a certain threshold (methylene blue > 0.25%) and when the local administration concentration exceeds a certain value (methylene blue > 0.35%), the composition shows a super-effective synergistic effect (compared to the positive control group), where the super-effective synergistic effect becomes sensitive to the local administration concentration and then becomes less sensitive again, and even the tumor suppression rate may decrease.
According to the results, a super-effective synergistic efficacy technical scheme of the composition of the invention is as follows:
the composition of the composition enables the composition to provide the local administration concentration of the vital dye to be more than or equal to 0.35%, preferably 0.35% -10%, wherein:
when the vital dye is selected from methylene blue dyes, the topical administration concentration is preferably 0.35% to 2%, more preferably 0.35% to 1.5% or 0.5% to 1%.
4. Other nutrients are preferably administered locally
In the study, successfully modeled test animals (S180 cell-bearing mice, average tumor volume 124mm3) Was randomly divided into a negative control group, a positive control group and 11 study groups. The negative control was physiological saline, the positive control was 1% 5-fluorouracil, and the study drug contained 10% glutathione and varying concentrations (X%) of glucose or DHA as 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 injected intratumorally, once every 3 days for 3 times in total, and the dose for each time was: glucose is less than or equal to 2250mg/kg, DHA375mg/kg, 5-fluorouracil is 50mg/kg, and the injection volume is less than or equal to 150 mul. Administration of drugsOn day 5 after completion, the animals were euthanized, and tumor weights were measured after dissection, and the tumor inhibition ratios were calculated from the negative control groups for each administration regimen, and the results are shown in table 13.
Watch 13
In the above table it is further confirmed that other nutrients show a synergistic effect with amino acid based nutrients only when their local administered concentration exceeds a certain threshold (glucose > 5%, DHA > 2%) and when they show a super-effective synergistic effect (compared to the positive control group) when their local administered concentration exceeds a certain value (glucose > 10%, DHA > 3%), the super-effective synergistic effect becomes sensitive to their local administered concentration and then becomes less sensitive again, and even the tumor suppression rate may decrease.
According to the results, a super-effective synergistic efficacy technical scheme of the composition of the invention is as follows: the composition is such that the composition can provide a local administration concentration of the further nutrient of not less than 4%, preferably 4-45%, wherein when the further nutrient is selected from the group consisting of carbohydrate nutrients, the local administration concentration of the further nutrient is not less than 10%, preferably 10-40%.
Example 7: further study of the mechanism of the synergistic action
The following test examples further investigate the mechanism of the synergistic effect, particularly the ultra-effective synergistic effect, of the composition of the present invention, and further optimize the technical scheme of the composition of the present invention.
1. Comparative study of chemical ablation
In the study, commercially available fresh pork liver was divided into 5 groups (A, B, C, D, E groups), 3 per group. The corresponding 5 tested drugs were 50% acetic acid, normal saline, 5% acetic acid, 20% lysine hydrochloride/5% acetic acid, respectively. The drugs were all aqueous solutions and were prepared according to the method for preparing aqueous solutions of the compositions of example 1. 1ml of the test drug was slowly injected into each liver center with an insulin injection needle, and the gross pathological manifestations were examined by dissection 24 hours later. The normal tissue of the pig liver is red, and the tissue that is effectively chemically ablated turns grey-white. Chemoablation scoring was performed by comparing the gray-white area (gross appearance) of the dissected surface along the needle insertion in the pig liver. The scoring was performed with the chemical ablation of the 50% acetic acid group as 5 and the chemical ablation of the saline group as 0, and the magnitude of the scoring reflected the strength of the chemical ablation of the test drug. A. B, C, D, E groups had chemical ablations scored 5, 0, 3, 1, respectively.
High concentrations of acidifying agents (e.g., 50% acetic acid) have been used as chemical ablative agents (group a). A score of 20% lysine hydrochloride/5% acetic acid showed antagonism of chemoablation (C, D, E group comparison), although it showed synergistic efficacy against tumor tissue in previous experiments. Similar results were obtained in another experiment using methylene blue instead of acetic acid.
According to these test results, the topical administration concentration of the conventional ineffective compounds in the composition of the present invention is preferably as low as possible under the condition that the effectiveness is satisfied, for example: acetic acid is 5 to 12.5 percent, and more preferably 5 to 7.5 percent; hydrochloric acid is 0.75-2%, more preferably 0.75-1.25%; methylene blue and its analogues are 0.35% -1.5%, more preferably 0.5% -1.25%; and so on.
2. Comparative study of hardening Effect
In the study, healthy mice were randomized into 7 groups (A, B, C, D, E, F, G groups), with 6 mice per group. The corresponding 7 tested drugs were: 3% lauromacrogol, physiological saline, 5% acetic acid, 20% lysine hydrochloride/5% acetic acid, 2% methylene blue, 20% lysine hydrochloride/2% methylene blue. The drugs were all aqueous solutions and were prepared according to the method for preparing the aqueous solution of the composition of example 1. The insulin injection needle is used for slowly injecting 0.1ml of the tested medicine under the leg muscle of a healthy mouse, and the general pathological expression of an injection area after 24 hours is as follows: the normal tissue of the muscle is soft to the touch and the swelling and stiffness are felt by the effectively hardened tissue. The sclerosis scoring is carried out by comparing the gross pathological manifestations of the injection area, the scoring size reflects the sclerosis scoring of the tested medicine, the positive control (3% of lauromacrogol) is 5(A group), the negative control (physiological saline) is 0(B group), and the sclerosis scoring of C, D, E, F, G groups is respectively: 2. 1, 0.5.
The scores of 5% acetic acid and 2% methylene blue showed some antagonism of the sclerosing effect (C, F group), whereas the scores of 20% lysine hydrochloride/5% acetic acid (C, E group comparison) and 20% lysine hydrochloride/2% methylene blue (F, G group comparison) showed antagonism of the sclerosing effect despite the synergistic efficacy against tumour tissue in previous experiments.
3. Comparative study of intracellular permeation enhancers
In the study, successfully modeled test animals (S180 cell-bearing mice, average tumor volume 218mm3) The groups were randomized into negative control and 3 study groups (A, B, C). The negative control group was administered with physiological saline, and the study groups were administered with the following drugs: 10% reduced glutathione, 10% reduced glutathione/5% ethylene glycol, 10% reduced glutathione/5% acetic acid. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 2 days by intratumoral injection, 150. mu.l/each time, for a total of 3 times. The animals were euthanized the next day after the end of dosing, tumor weights were determined after dissection, and tumor inhibition rates were calculated from negative controls.
In this test, the inhibition rates of A, B, C groups were 34%, 37%, and 81%, respectively. The 10% reduced glutathione/5% ethylene glycol showed no significant synergy (A, B group comparison), while the 10% reduced glutathione/5% acetic acid showed significant synergy (A, C group comparison). Ethylene glycol is an intracellular permeation enhancer.
The results of the above studies of examples 2-7 illustrate that: the topical pharmaceutical compositions (intratumoral injection in experiments) of the present invention, in which the amino acid nutrients and the conventional ineffective compounds are used as topical active ingredients, have essential differences compared to their conventionally applied absorption pharmaceutical compositions (intraperitoneal injection in experiments):
1) the targeting is different. After the amino acid nutrients and the conventional ineffective compounds in the pharmaceutical composition are absorbed into the body, the amino acid nutrients and the conventional ineffective compounds are dispersed in the blood and run. After the medicated blood has passively entered the target area, they can only be targeted under conditions controlled by vascular wall penetration and other tissue barriers, such as targeting tumor cells. The topical pharmaceutical compositions of the present invention are directed to diseased tissues (e.g., intratumoral tissues) including, for example, blood supply vessels, matrix and/or other micro-environmental structures within tumor body tissues.
2) Different compositions of the target area drugs. After absorption of amino acid nutrients and conventional ineffective compounds in pharmaceutical compositions into the body, their composition in the blood with drug in the target area is already quite different from that in the composition due to different actions with different substances in the blood (e.g. acetic acid in the blood buffer system). Such compositions are not based on any other composition. In contrast, the amino acid based nutrients and conventional ineffective compounds in the topical pharmaceutical compositions of the present invention have a composition in the target volume in the liquid drug that substantially corresponds to the composition of the composition.
3) Different target and different composition cause different pharmacology. It has been shown in the literature that nutrients transported via the blood have a trophic effect on tumor cells and other cells, while acetate acidifiers participate in the blood buffer system. In the above tests, the absorbent pharmaceutical compositions of amino acid nutrients and conventional ineffective compounds did not show synergistic effects, even no in vivo tumor suppression. In the local medicinal composition, the amino acid nutrient and the conventional ineffective compound are used as local active components to synergistically destroy tumor body tissues so as to enable tumor cells to lose survival and proliferation. The two different pharmacologies produce distinct pharmacological effects at the same dose.
4) Different in pharmacokinetics. Absorption of drugs (e.g. cytotoxic drugs) is often based on the results of cellular experiments, with the pharmacokinetic key parameter being the blood concentration of the active ingredient (often close to the effective concentration in cellular experiments). This blood level is generally not guaranteed by the administered concentration (which is often given by dilution), but by the administered dose. Whereas the amino acid based nutrients and conventional ineffective compounds in the composition of the present invention show completely different pharmacokinetics for use as topical active ingredients. In the above test, there was a local administration concentration threshold and a local administration concentration range, and it was considered that the synergy effect was a super-effective synergy effect, which was possible only if the concentration threshold was exceeded and the concentration range was specified.
Example 8: more anti-tumor applications
In the following experiments, the successfully modeled human cancer cell-bearing nude mice were randomly divided into 1 negative control group and 5 study groups (A, B, C, D, E groups). The corresponding negative control was normal saline, and the 5 study drugs were: 20% glycine/10% acetic acid, 20% lysine/1% methylene blue, 10% glutathione/30% glucose, 20% arginine/30% glucose/5% acetic acid, 20% glycine/5% DHA/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 the following day 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 153 mm)3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 85%, 91%, 81%, 88% and 83% all meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
2) Application of the compound in lung tumor treatment
In the study, the nude mouse with human lung cancer cells (A549) successfully modeled (mean tumor volume 183 mm)3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 81%, 83%, 76%, 86%, 82%, all of which meet the generally recognized 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 this study, successfully modeled chartersThyroid cancer cell (SW579) nude mice (average tumor volume 174 mm)3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 79%, 81%, 76%, 85% and 83% of the total content of the extract 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 168 mm) were successfully modeled3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 75%, 82%, 79%, 81% and 78% of the total content of the extract meets the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
5) Application of the compound in liver tumor treatment
In the study, the nude mice (tumor mean volume 183 mm) with human hepatoma cells (HepG2) successfully modeled3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 73%, 86%, 75%, 81% and 83% 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 169 mm)3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 86%, 81%, 79%, 91% and 87% all meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
7) Application of the compound in treatment of nasopharyngeal tumors
In the present study, nude mice (average tumor volume 196 mm) with human nasopharyngeal carcinoma cells (CNE1) successfully modeled3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 91%, 81%, 79%, 86%, 82%, all of which are in accordance with the generally recognized effective antitumor markersAccurate (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 164 mm) with human gastric carcinoma cells (BGC823) successfully modeled3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 71%, 76%, 82%, 87% and 83% of the total content of the extract meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).
9) Application of the compound in ovarian tumor treatment
In the study, nude mice (mean tumor volume 191 mm) with successfully modeled human ovarian carcinoma cells (PA1)3) The groups were randomized into a negative control group and 5 study groups (A, B, C, D, E). A. The tumor inhibition rates of B, C, D, E groups were: 86%, 92%, 81%, 91% and 86% all meet the generally 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 in example 1 (e.g. the compositions in table 2) for use in the treatment of each of the tumors described above.
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 9: application in treating non-tumor (1)
In this study, 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 4 study groups (A, B, C, D groups), with 4 animals per group. The administration was started on the day of the group. The negative control is physiological saline, the positive control is a hyperplasia of mammary glands tablet, and the 4 research medicines are respectively: 20% glycine/10% acetic acid, 20% lysine/1% methylene blue, 10% glutathione/30% glucose, 20% arginine/30% glucose/5% 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 1 day, each time is 100 mu l/body, and the total dose is 5 times. The positive control group is administrated by drenching with the positive control once a day, 1g/kg each time, 27 times. Items observed, measured and analyzed in the experiment include relative nipple enlargement rate (T/C%) and pathological changes of mammary gland tissue, in addition to conventional food intake, body weight, general state.
The relative nipple diameter calculation formula is:
RTD is Dt/D0, where D0 is the diameter of the teat measured on the first administration of the group and Dt is the diameter of the teat at each measurement.
The relative nipple enlargement rate is calculated by the formula:
and T/C (%) ═ TRTD/CRTD × 100, wherein TRTD is a positive control group or study group RTD, and CRTD is a negative control group RTD.
The relative nipple enlargement rate pharmacodynamic evaluation criteria of the study group were:
T/C (%) >50 is inactive, T/C (%) < 50 (but > 25%) and P <0.05 is active as compared to the negative control by analysis of variance, T/C (%) <25 and P <0.05 is preferably synergistic as compared to the negative control by analysis of variance.
The pathological analysis of the mammary tissue is as follows: animals were euthanized on day 4 after the last dose, a second pair of mammary glands from the rats were harvested, paraffin sections were sectioned, and changes in pathological morphology of the mammary glands were observed under light microscopy after HE staining. The mammary histopathology was integrated for each group of rats by observing the morphology of the lobules and acini, where: the lobule of the mammary gland is not hyperplastic, the number of glands is very small, acinus is not expanded, and 0 point is marked; the lobule of the mammary gland has no obvious hyperplasia, and the individual acinus has slight hyperplasia but no expansion, and the score is 1; the mammary lobules are mostly hyperplastic, and part of acini is obviously dilated, and 2 points are recorded; the lobules of the mammary gland are obviously hyperplastic, the acinus is in a extreme expansion state, the glandular epithelial cells are flat, and a large amount of secretion is recorded for 3 points in the acinus and the duct; the pathological hyperplasia of the mammary gland acinus, ducts and lobules is obvious and is recorded in 4 points. The evaluation standard of the pathological analysis drug effect is as follows: the pathological integral is more than or equal to 3 and is inactive, the pathological integral is more than 1 and less than 3, and the pathological integral is active when the variance analysis is carried out, and the P is less than 0.05 when the pathological integral is less than or equal to 1 and is obviously synergistic when the variance analysis is carried out, and the pathological integral is less than or equal to 0.05 when the pathological integral is compared with the negative control group.
From day 7 after administration, the papilla diameter was significantly reduced in A, B, C, D groups compared to the negative control group, and the difference was statistically significant (P < 0.05). On day 10 post-dose, A, B, C, D groups had a relative nipple enlargement rate (T/C) of less than 50%; the relative nipple enlargement rate of the A, B, C, D group and the positive control group was 8%, 11%, 12%, 7%, and 41%, respectively, at day 25 after the administration. At day 25 after dosing, the score for pathology was equal or less than 1 for the A, B, C, D group, which was close to the blank control group and clearly distinguishable from the negative control group (P <0.05), while the score for pathology was greater than 2 for the positive control group. The safety observations of the drugs were essentially the same.
Similar results were observed with other compositions prepared according to the invention in example 1 (e.g. the compositions in table 2).
Example 10: anti-non-tumor applications (2)
In this study, the 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 4 study groups (A, B, C, D groups), with 4 animals per group. The administration was started on the day of the group. The negative control was physiological saline, the positive control was potassium iodate (KIO3), and the 4 study drugs were: 20% glycine/10% acetic acid, 20% lysine/1% methylene blue, 10% glutathione/30% glucose, 20% arginine/30% glucose/5% acetic acid. The 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 1 day, each time is 100 mu l/body, and the total dose is 5 times. The positive control group was administered with the positive control by drenching at 27 times per day at a dose of 0.4 μ g/kg per time. Items observed, measured and analyzed in the experiment include thyroid enlargement, 24h iodine output and thyroid pathology examination, in addition to regular food intake, body weight, general state.
From the 10 th day of the test, the goiter of the study group is obviously improved compared with the negative control group, the iodine output is consistent with that of the blank control group (difference is less than 25 percent), and the effect is equivalent to that of the positive control group. In pathological examination, the negative control group can observe that the thyroid gland is obviously swollen, the follicles are dense, epithelial cells are hyperplastic and hypertrophic and are in a high column shape, hyperplastic cell mass cords can be seen, blood vessels among the follicles are obviously increased, the lumens are dilated and congested, and the fibrous tissues among the leaflets are increased.
On day 25 after administration, the study group differed from the blank control by less than 15% in thyroid size, follicular morphology size, epithelial cells, interfilament fibrous tissue, etc., and was close to the positive control. The safety observations for each group of drugs were essentially the same.
Similar results were observed with other compositions prepared according to the invention in example 1 (e.g. the compositions in table 2).
Example 11: study of anti-local inflammation
In this study, adult male rats (weighing approximately 150-180g) were randomly assigned to the placebo and building blocks. Using allergic rhinitis as a model, and using Ovalbumin (OVA) sensitizing solution (containing 0.5mgOVA and 30mgAl (OH) per milliliter)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. After the molding is successful, the PEMS 3.2 software random block is divided into a positive control group, a negative control group and a research group (A, B, C, D group), and each group comprises 4 animals. The administration was started on the day of the group. The negative control was a physiological saline spray, the positive control was a commercially available mometasone furoate nasal spray (belgium pioneer), and the 4 study drugs were sprays containing the following components: 20% glycine/10% acetic acid, 20% lysine/1% methylene blue, 10% valleyCystine/30% glucose, 20% arginine/30% glucose/5% acetic acid. The preparation method of the spray is shown in example 1. 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%).
Each group was made into a 7-time nasal spray once a day. The number of scratching and sneezing of the rats within 3 minutes after administration was observed as an index. The drug effect was judged by comparison with a blank control group. If the scratching and sneezing times of the molding set reach more than 7 times and more than 1 time of the blank control set respectively, the molding is successful. The drug was effective if the number of scratching and sneezing in the drug group reached levels similar to those in the positive control group, respectively.
The numbers of the A, B, C, D group and the positive control group differed from the blank control group by 13%, 12%, 16%, 9%, and 27% in scratching and sneezing times at day 15 after application. In the experimental process, no obvious mucosa irritation effect is seen in each group, and no anaphylactic reaction is caused.
Similar results were obtained using sprays of the same composition as the other compositions prepared in example 1 (e.g. table 2).
Example 12: studies on secretion disorders of antisecretory glands
In this study, adult male rats (weighing approximately 150-180g) were randomly assigned to the placebo and building blocks. 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). After the modeling was successfully confirmed by serological examination and pathological examination, the samples were randomly divided into a positive control group, a negative control group and 4 study groups (A, B, C, D groups) by PEMS 3.2 software, each group containing 4 mice. The administration was started on the day of the group. The negative control was physiological saline spray, the positive control was tazobactam, and the 4 study drugs were: 20% glycine/10% acetic acid, 20% lysine/1% methylene blue, 10% glutathione/30% glucose, 20% arginine/30% glucose/5% 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 swollen area every 1 day, 150 mul/body each time, and the total dose is 8 times. The positive control group was administered with the positive control by drenching at 27 times with a dose of 2mg/kg once a day.
Items observed, measured and analyzed in the experiment include serological examination and thyroid pathology examination on the day of administration and on the 16 th day after administration, in addition to the usual food intake, body weight, general state. Serological examination serum T3, T4 and Thyroid Stimulating Hormone (TSH) concentration values were determined by Radioimmunoassay (RIA). Pathological examination observed thyroid morphology, follicular morphology, epithelial cell morphology, and interlobular fibrous tissue morphology. The test results are as follows.
In the serological examination at 25 days after the administration, the increase of serum T3 and T4 was gradual in the A, B, C, D group and the decrease of TSH tended to be improved compared with the negative control group. For the serological examination results, the serum values of the A, B, C, D group and the positive control group differed from the blank control group by 9%, 11%, 13%, 8%, and 32%, respectively.
In the pathological examination, the negative control group can observe that the thyroid gland is in diffuse increase, follicular epithelial hyperplasia is in a high column shape and small follicular is formed, a plurality of epithelial cells with different sizes are formed around the follicular to absorb vacuoles, interstitial blood vessels are rich, congestion is caused, and lymphoid tissue hyperplasia is caused. Compared with the negative control group, the thyroid diffuse of the A, B, C, D group is reduced, and the follicular epithelial hyperplasia and the formation of small follicles are obviously reduced; the epithelial cells present around the follicular periphery absorb vacuoles, the number and congestion of interstitial blood vessels, and the proliferation of lymphoid tissues are reduced. A. The results of pathological examination of B, C, D group were close to those of the blank control group and were significantly better than those of the positive control group. No irreversible local damage and no apparent weight loss were observed in any of the groups.
Similar results were obtained using formulations of the same composition as the other compositions prepared in example 1 (e.g., table 2).
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 (10)
1. A topical pharmaceutical composition for the treatment of a topical pathological condition comprising an amino acid based nutrient at a concentration (w/v) > 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%, a conventional ineffective compound, and a pharmaceutically acceptable liquid carrier; the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
2. Use of amino acid based nutrients as a topical active ingredient in combination with conventional ineffective compounds for the preparation of a topical pharmaceutical composition for the treatment of locally diseased conditions.
3. Use according to claim 2, wherein the topical pharmaceutical composition comprises said amino acid based nutrient, said conventional ineffective compound, and a pharmaceutically acceptable liquid carrier, and wherein the concentration (w/v) of said amino acid based nutrient is > 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%; and the concentration (w/v) of the conventional ineffective compound is more than 0.25%, preferably 0.35-40%.
4. Pharmaceutical composition or use according to any of claims 1 to 3, wherein the amino acid nutrient comprises one or more of the amino acid compounds, amino acid salts, oligopeptides and polypeptides having a nutraceutical effect, preferably amino acids or salts thereof or oligopeptides and polypeptides comprising or consisting of amino acids alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, β -alanine, taurine, gamma-aminobutyric acid (GABA), tea polyphenols (theanine), pumpkin seed amino acids (3-amino-3-carboxypyranopyranic acid), glutamine, citrulline, ornithine, more preferably amino acids or salts thereof selected from the group or oligopeptides and polypeptides comprising or consisting of amino acids arginine, lysine, glycine, cysteine, alanine, serine, glutamic acid.
5. The pharmaceutical composition or use according to claim 4, wherein the amino acid based nutrient is selected from the group consisting of amino acids or amino acid salts having a nutraceutical effect and the concentration (w/v) of the amino acid or amino acid salt in the topical pharmaceutical composition is > 2%, preferably 2.5-25%, 5-25%, 7.5-25% or 10-25%.
6. The pharmaceutical composition or use according to claim 4, wherein the amino acid based nutrients are selected from oligopeptides and polypeptides with nutraceutical effect and the concentration (w/v) of said oligopeptides and polypeptides in the topical pharmaceutical composition is greater than or equal to 5%, preferably 7.5-25%.
7. The pharmaceutical composition or use according to claim 4, wherein the amino acid based nutrient is a combination of the amino acid and/or amino acid salt and the oligopeptide and/or polypeptide and the concentration (w/v) of the combination in the topical pharmaceutical composition is greater than or equal to 5%, preferably 10-25%.
8. The pharmaceutical composition or use according to claim 1, wherein the conventional ineffective compound is one or more selected from the group consisting of: other nutrients than the amino acid nutrients, ineffective aromatic compounds, acidulants.
9. A topical pharmaceutical composition for the treatment of a disease associated with a localized pathology, comprising a dry powder obtained by lyophilization or semi-lyophilization of a part or all of a pharmaceutical composition according to one of claims 1 and 4 to 8.
10. A device for treating a localized disease condition comprising a pharmaceutical composition according to one of claims 1 and 4-9.
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CN114736079A (en) * | 2022-04-18 | 2022-07-12 | 北京化工大学秦皇岛环渤海生物产业研究院 | Special sweet potato fertilizer containing polyglutamic acid and preparation method thereof |
WO2023131142A1 (en) * | 2022-01-04 | 2023-07-13 | 成都夸常奥普医疗科技有限公司 | Stable solution, preparation method, use, pharmaceutical composition and kit |
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CN114736079A (en) * | 2022-04-18 | 2022-07-12 | 北京化工大学秦皇岛环渤海生物产业研究院 | Special sweet potato fertilizer containing polyglutamic acid and preparation method thereof |
CN114736079B (en) * | 2022-04-18 | 2023-07-14 | 北京化工大学秦皇岛环渤海生物产业研究院 | Special fertilizer containing polyglutamic acid for sweet potato and preparation method of special fertilizer |
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