Classifications

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  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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  • A61K9/00—Medicinal preparations characterised by special physical form
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  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

• the present application discloses the application of an acid-base neutralization combination as a topical active ingredient in the preparation of a topical medicine for treating local pathological diseases, a topical pharmaceutical composition comprising the combination, and a method for treating local pathological diseases.
• Solid tumors are often used as models for the study of localized disease, especially refractory localized disease, supported by a large amount of research work.
• Solid tumor is a tumor disease with tumor symptoms, and the tumor body is a characteristic diseased tissue containing tumor cells. Taking pancreatic cancer tumor as an example, pancreatic cancer cells only account for about 30% of the volume. It can be seen that in addition to tumor cells, there are often a larger number of other components (sometimes also referred to as tumor cell microenvironment) in tumor tissue, including various other cells, various intercellular spaces, and various channels.
• Topical administration has the advantage of physically targeting the drug. Therefore, it was once believed that local administration of cytotoxic drugs can increase their intratumoral concentration, thereby improving their efficacy.
• topical administration of cytotoxic drugs did not show a significant improvement in efficacy. Merely increasing its intratumoral concentration does not seem to significantly improve its efficiency in targeting cancer cells in intratumoral tissues.
• cytotoxic drugs are still clinically administered almost systemically.
• Chemical ablative agents high-purity ethanol, high-concentration acid-base
• they have almost no systemic efficacy targeting cancer cells, but often show local efficacy.
• the object of the present invention is to provide a topical medicine for preventing and treating local pathological diseases, especially refractory local pathological diseases. More specifically, the object of the present invention is to provide a chemical ablative agent (acidifying agent or alkalizing agent) or a pharmaceutical composition comprising the same that is superior to the prior art in terms of specificity, efficacy and safety. topical medication.
• a chemical ablative agent ascidifying agent or alkalizing agent
• a pharmaceutical composition comprising the same that is superior to the prior art in terms of specificity, efficacy and safety. topical medication.
• an acid-base neutralizing combination as a topical active ingredient in the preparation of a topical pharmaceutical composition for the treatment of local pathological diseases
• the acid-base neutralizing combination comprises an acidulant and its pH A neutralizing agent, or an alkalizing agent and a pH neutralizing agent thereof, and wherein the acidifying agent is one or more selected from a strong acid or a weak acid
• the alkalizing agent is one or more selected from a weak base or a strong base or A variety of
• the pH neutralizing agent is selected from acid-base substances that can make the acidifying agent or alkalizing agent tend to pH neutralization
• the acidifying agent, alkalizing agent, and pH neutralizing agent Preferably, it is selected from acid-base substances which can be used as pH adjusting agents rather than as conventional active ingredients for the treatment of local pathological diseases.
• a topical pharmaceutical composition for treating local pathological diseases comprising an acid-base neutralizing combination as a topical active ingredient, wherein the acid-base neutralizing combination comprises an acidulant and Its pH neutralizing agent, or alkalizing agent and its pH neutralizing agent, and wherein said acidifying agent is one or more selected from strong acid or weak acid; said alkalizing agent is selected from weak base or strong base One or more; the pH neutralizing agent is selected from acid-base substances that can make the acidifying agent or alkalizing agent tend to be pH neutralized, and wherein the acidifying agent, alkalizing agent, and pH
• the neutralizing agent is preferably selected from acid-base substances that can be used as pH adjusters rather than as conventional active ingredients for the treatment of localized disease.
• a topical pharmaceutical composition for the treatment of local pathological diseases which comprises an acid-base neutralizing combination as a topical active ingredient and a topical synergist of the neutralizing combination, wherein the The acid-base neutralization combination comprises an acidifying agent and its pH neutralizing agent, or an alkalizing agent and its pH neutralizing agent, and wherein the acidifying agent is one or more selected from a strong acid or a weak acid; the alkalizing agent The agent is one or more selected from weak bases or strong bases; the pH neutralizing agent is selected from acid-base substances that can make the acidifying agent or alkalizing agent tend to neutralize pH, and the pH neutralizing agent
• the acidifying agent, alkalizing agent, and pH neutralizing agent are preferably selected from acid-base substances that can be used as pH adjusting agents rather than conventional active ingredients for the treatment of local lesions.
• compositions of the present invention further comprise a pharmaceutically acceptable carrier, such as an aqueous carrier or an alcoholic carrier, preferably water.
• a pharmaceutically acceptable carrier such as an aqueous carrier or an alcoholic carrier, preferably water.
• the composition of the present invention can be prepared in the form of injections, including liquid injections and powders for injection.
• a method for treating a local lesion disease comprising administering to a local lesion area of an individual in need thereof a therapeutically effective amount of a pharmaceutical composition capable of causing tissue necrosis in the target area, the pharmaceutical combination
• the composition comprises as a topical active ingredient an acid-base neutralizing combination and optionally a topical synergist of the neutralizing combination, wherein the acid-base neutralizing combination comprises an acidulant and its pH neutralizer, or alkalinizer and its pH neutralizing agent, and wherein said acidifying agent is one or more selected from strong acid or weak acid; said alkalizing agent is one or more selected from weak base or strong base;
• the neutralizing agent is selected from acid-base substances which can make the acidifying agent or alkalizing agent tend to be pH neutralized, and wherein the acidifying agent, alkalizing agent, and pH neutralizing agent are preferably selected from the acid-base substances which can be used as the neutralizing agent. pH adjusters rather than acid-base substances used as conventional active ingredients in the
• Embodiments according to the present invention have the following advantages over prior art acid-base chemical ablative agents: higher specificity, efficacy, and safety.
• Embodiments according to the present invention have the following advantages over prior art pharmaceutical compositions comprising acid-base chemical ablative agents: higher specificity, efficacy and safety.
• Embodiments according to the present invention have the following advantages compared to the prior art for local disease treatment: compared with existing cytotoxic drugs, show almost non-toxic systemic safety and significantly higher local disease efficacy; Compared with molecularly targeted drugs, it shows less stringent indication screening and great potential for fast-growing tumors, large tumors and hypovascular tumors.
• the applications and compositions of the present invention are also not plagued by the drug resistance problems encountered with existing cytotoxic and molecularly targeted drugs.
• the application and composition are convenient to prepare and low cost, and are particularly helpful for making safe and effective treatment available to a large number of people who cannot afford high costs.
• alkalizing agents eg, sodium hydroxide
• the inventors of the present invention mixed sodium bicarbonate with a much lower pH as a pH neutralizing agent with sodium hydroxide to neutralize the acid-base composition (3% sodium hydroxide) /7% sodium bicarbonate) as a negative control.
• sodium bicarbonate is added to sodium hydroxide solution for neutralization, the efficacy of the drug will decrease as the pH decreases (eg, from pH12 to 10.0).
• the low pH compositions (acid-base neutralizing compositions) showed significantly improved tumor inhibition rates (eg, from 43% to 68%) than high pH sodium hydroxide.
• the inventors of the present invention have studied pharmaceutically acceptable acid-base neutralizing compositions, and further studied pharmaceutical combinations comprising the acid-base neutralizing combinations and topical synergists thereof, and their applications.
• an acid-base neutralizing combination as a topical active ingredient in the preparation of a topical pharmaceutical composition for the treatment of local pathological diseases
• the acid-base neutralizing combination comprises an acidulant and its pH neutralizing agent, or alkalizing agent and pH neutralizing agent thereof, and wherein the acidifying agent is one or more selected from strong acids or weak acids; the alkalizing agent is one or more selected from weak bases or strong bases One or more; the pH neutralizing agent is selected from the acid and alkaline substances that can make the acidifying agent or alkalizing agent tend to be pH neutralized, and wherein the acidifying agent, alkalizing agent, and pH neutralization agent Both the and the agent are preferably selected from acid-base substances which are generally not used as conventional active ingredients for the treatment of local pathological diseases but are used as pH adjusting agents.
• the topical pharmaceutical composition further comprises a topical synergist of the acid-base neutralizing combination.
• the topical activity provided by the acid-base neutralizing combination includes efficient, preferably maximized, penetration between tissues.
• the topically active components include components that have effective, preferably maximized, penetration between tissues.
• the pharmaceutical composition is prepared such that the acid-base neutralizing combination provides the topical activity: the acidifying agent and its pH neutralizing agent, or the alkalizing agent and its pH neutralizing agent
• the application amount ratio (w/w) (W alkalizing agent /W neutralizing agent , or W acidifying agent /W neutralizing agent ) is (0.5-35)/(1-35), preferably (1.5-35)/ (1-35).
• the pharmaceutical composition is prepared such that the acid-base neutralizing combination provides the topical activity: the acidifying or alkalizing agent is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 2.5%, and the administration concentration of the pH neutralizer must make the administration pH of the pharmaceutical composition closer to neutral than the pH of the acidulant or alkalizer at the same concentration of the single drug, and the two
• the absolute value of the difference between the individual pHs is ⁇ 0.25, ⁇ 0.5, or ⁇ 1.0.
• a topical pharmaceutical composition for treating local pathological diseases comprising an acid-base neutralizing combination as a topical active ingredient, wherein the acid-base neutralizing combination comprises an acidulant and Its pH neutralizing agent, or alkalizing agent and its pH neutralizing agent, and wherein said acidifying agent is one or more selected from strong acid or weak acid; said alkalizing agent is selected from weak base or strong base One or more; the pH neutralizing agent is selected from acid-base substances that can make the acidifying agent or alkalizing agent tend to be pH neutralized, and wherein the acidifying agent, alkalizing agent, and pH Both neutralizing agents are preferably selected from acid-base substances that are not generally used as conventional active ingredients for the treatment of local lesions but are used as pH adjusters.
• the pharmaceutical composition is so composed that the acid-base neutralizing combination provides the topical activity: the acidifying agent and its pH neutralizing agent, or the alkalizing agent and its pH neutralizing agent
• the application amount ratio (w/w) (W alkalizing agent /W neutralizing agent , or W acidifying agent /W neutralizing agent ) is (0.5-35)/(1-35), preferably (1.5-35)/ (1-35).
• the pharmaceutical composition is so composed that the acid-base neutralizing combination provides the topical activity: the acidifying or alkalizing agent is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 2.5%, and the administration concentration of the pH neutralizer must make the administration pH of the pharmaceutical composition closer to neutral than the pH of the acidulant or alkalizer at the same concentration of the single drug, and the two
• the absolute value of the difference between the individual pHs is ⁇ 0.25, ⁇ 0.5, or ⁇ 1.0.
• a topical pharmaceutical composition for the treatment of local pathological diseases which comprises an acid-base neutralizing combination as a topical active ingredient and a topical synergist of the neutralizing combination, wherein the The acid-base neutralization combination comprises an acidifying agent and its pH neutralizing agent, or an alkalizing agent and its pH neutralizing agent, and wherein the acidifying agent is one or more selected from a strong acid or a weak acid; the alkalizing agent The agent is one or more selected from weak bases or strong bases; the pH neutralizing agent is selected from acid-base substances that can make the acidifying agent or alkalizing agent tend to neutralize pH, and the pH neutralizing agent
• the acidifying agent, alkalizing agent, and pH neutralizing agent are all preferably selected from acid-base substances that are not generally used as conventional active ingredients for the treatment of local lesions but are used as pH adjusting agents.
• the pharmaceutical composition is so composed that the acid-base neutralizing combination provides the topical activity: the acidifying agent and its pH neutralizing agent, or the alkalizing agent and its pH neutralizing agent
• the application amount ratio (w/w) (W alkalizing agent /W neutralizing agent , or W acidifying agent /W neutralizing agent ) is (0.5-35)/(1-35), preferably (1.5-35)/ (1-35).
• the pharmaceutical composition is composed such that the acid-base neutralizing combination and the topical synergist are required as topical active components that provide local synergy: the acid-base neutralizing combination is combined with the The application amount ratio (w/w) of the topical synergist (W topical synergist /W acid-base neutralization combination ) is (0.1-45)/(1.5-45).
• the pharmaceutical composition is so composed that the acid-base neutralizing combination provides the topical activity: the acidifying or alkalizing agent is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 2.5%, and the administration concentration of the pH neutralizer must make the administration pH of the pharmaceutical composition closer to neutral than the pH of the acidulant or alkalizer at the same concentration of the single drug, and the two
• the absolute value of the difference between the individual pHs is ⁇ 0.25, ⁇ 0.5, or ⁇ 1.0.
• a method for treating a local lesion disease comprising administering to a local lesion area of an individual in need thereof a therapeutically effective amount of a pharmaceutical composition capable of causing tissue necrosis in the target area, the pharmaceutical combination
• the composition comprises as a topical active ingredient an acid-base neutralizing combination and optionally a topical synergist of the neutralizing combination, wherein the acid-base neutralizing combination comprises an acidulant and its pH neutralizer, or alkalinizer and its pH neutralizing agent, and wherein said acidifying agent is one or more selected from strong acid or weak acid; said alkalizing agent is one or more selected from weak base or strong base;
• the neutralizing agent is selected from acid-base substances that can make the acidifying agent or alkalizing agent tend to be pH neutral, and wherein the acidifying agent, alkalizing agent, and pH neutralizing agent are preferably selected from the usual An acid-base substance used as a conventional active ingredient for the treatment of local lesions and as a pH adjuster.
• the pharmaceutical composition is administered such that the acid-base neutralizing combination provides the topical activity: the acidifying or alkalizing agent is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 2.5%, and the administration concentration of the pH neutralizer must make the administration pH of the pharmaceutical composition closer to neutral than the pH of the acidulant or alkalizer at the same concentration of the single drug, and the two
• the absolute value of the difference between the individual pHs is ⁇ 0.25, ⁇ 0.5, or ⁇ 1.0.
• a device for treating local pathological diseases comprising a topical pharmaceutical composition comprising an acid-base neutralizing combination as defined in the present disclosure.
• the term “pharmaceutical composition” (or drug combination) is used to refer to a mixture of one or more drugs homogeneously distributed in the same dosage form.
• the term “topical pharmaceutical composition” refers to a pharmaceutical composition of a plurality of locally administrable active components that can be sufficiently mixed into a target area at a desired concentration or concentration ratio.
• the “topical pharmaceutical composition” does not Contains additives such as sodium chloride (isotonicity modifier) commonly used in non-topical medicines.
• the term "acidifier (or alkalizer)” refers to the most basic or acidic substance in the composition.
• pH neutralizer (or neutralizer) refers to an acid-base substance that increases the pH of the acidulant (or decreases the pH of the alkalinizer), thereby making the pH of the composition more neutral (pH about 7.0).
• conventional active ingredient refers to a pharmaceutical ingredient that provides effective activity when administered systemically.
• pH adjusting agent refers to a pharmaceutical ingredient that primarily provides pH adjustment rather than pharmaceutical activity (eg, antipathogenic activity) when administered systemically.
• the pharmacological effects of the pharmaceutical compositions disclosed herein include synergistic effects and, optionally, other pharmacological effects.
• the acid-base neutralizing combination itself, or the synergy provided by it in a composition comprising it and a combination is characterized by one or more of the following: including a safety synergy (eg, allowing topical Synergy to reduce irritation, synergy to reduce required dose of acidulant (or alkalinizer), local synergy (shown as short-term synergy), effective synergistic penetration between tissues (shown as mid-term synergy) ).
• a safety synergy eg, allowing topical Synergy to reduce irritation, synergy to reduce required dose of acidulant (or alkalinizer), local synergy (shown as short-term synergy), effective synergistic penetration between tissues (shown as mid-term synergy) ).
• the concentration (or amount ratio) in the term "entering the target area at a certain concentration (or amount ratio)" (or the concentration or amount ratio entering the target area) refers to the concentration (or amount ratio) at which a specific component begins to contact the target area, and this concentration (or amount ratio) is equivalent to the administration concentration (or administration amount ratio) in the local (target area) administration of the present invention. ), while in conventional (systemic) administration is not equivalent to the dose concentration (or dose ratio).
• target volume is used to refer to the target site of administration, eg, adjacent to a localized lesion, interface, interior (preferably interior), and the like.
• local activity refers to the pharmacological activity of a drug that is preferentially displayed in local target tissue rather than in pathogens (eg, tumor cells), and includes, for example, local action of a single drug and local co-action of co-drugs.
• local action is distinguished from conventional action (or conventional co-action), which refers to a drug following conventional administration (eg, intravenous, intracavitary, subcutaneous, mucosal, etc.)
• conventional action or conventional co-action
• the local effect ( or local co-action) includes chemical action (or co-chemical action) that is preferentially directed against the target tissue.
• local chemistry refers to a chemical action (or shared chemistry) that occurs in a drug preferentially within a local tissue rather than a pathogen in that tissue.
• topical active ingredient refers to a pharmaceutical ingredient that provides pharmaceutical activity including effective topical activity when used topically alone or in combination.
• the local synergy is preferably a synergy that preferentially occurs within a local tissue rather than a pathogen in that tissue.
• the local synergy includes local chemical synergy and optionally other pharmacological effects.
• the pharmaceutical composition is a topical synergistic composition.
• the pH neutralizing agent and the acidulant or alkalizer are locally synergistic in the same solution.
• the topical synergist is topically synergized with the acid-base neutralizing combination in the same solution.
• the term “synergistic effect” means that the active components together exhibit a higher desired efficacy than either component alone (eg the actual/expected ratio as agreed in the examples of the present invention). q > 1.0 efficacy).
• the term “local synergy” refers to synergy that is primarily manifested as local activity.
• the term “topical synergist” refers to a pharmaceutical component that produces a local synergistic effect by co-administration, especially in combination with pH neutralization in the present invention. In the scope of this disclosure, systemic use of a topical synergist with a particular drug (eg, the pH neutralizing combination) either produces no synergy or produces a synergy that is not local.
• terapéuticaally effective amount refers to a dose of a drug that is used to treat a disease (eg, tumor) and achieve an effective effect (eg, reduce or/and alleviate symptoms of the disease).
• compositions disclosed herein are prepared, composed or administered such that the local synergistic effect is required to cause tissue necrosis, preferably effective necrosis, in the target area with greater efficiency.
• the local synergy is pharmacodynamic synergy, eg, the use of equal doses of acidifying or alkalizing agents provides greater efficacy.
• the local synergy is a safety synergy, eg, the use of minimal net acid or net base (or minimal disturbance of acid-base balance in vivo) produces the same therapeutic effect.
• the tissue necrosis includes direct tissue necrosis and optionally indirect tissue necrosis. In one embodiment, the direct necrosis of the tissue is so severe that it is histochemically ablated.
• the term "indirect necrosis of tissue” is used to refer to the effect of the inhibition of the proliferation of pathogens (eg cells, viruses or bacteria) in the target tissue or the stimulation of the immune system of the individual to the tissue
• pathogens eg cells, viruses or bacteria
• the former such as cytotoxic drugs
• the latter such as anti-tumor vaccines
• Necrosis can then be achieved either by systemic or local administration.
• tissue necrosis refers to tissue necrosis that is independent of indirect tissue necrosis resulting from the direct application of a tissue disrupting factor to the target volume, wherein the tissue disrupting factor includes, for example, ablation components of a physical ablation instrument (eg, warming needles) , conventional chemical ablative agents, etc.
• a tissue disrupting factor includes, for example, ablation components of a physical ablation instrument (eg, warming needles) , conventional chemical ablative agents, etc.
• the term "ablation” means that the local effect of the in situ treatment is so strong that the target tissue produces tissue necrosis that essentially loses its original physiological function (inactivation).
• Tissue necrosis includes coagulation necrosis, liquefaction necrosis, fibrinoid necrosis, and the like.
• Tumor tissue necrosis can lead to morphological changes (volume reduction) of tumor tissue, which ultimately manifests as an increased tumor inhibition rate.
• chemical ablation refers to ablation that is primarily chemical rather than immunological.
• the term “chemical ablative agent” refers to a drug that exhibits an ablative effect only when administered topically.
• concentration refers to the weight percent concentration (w/v) of the specified component in the unit volume of the topical pharmaceutical composition.
• local administration ratio refers to the weight ratio of two specified components when the drug is administered locally, which may be the specified component at the drug contact target area (such as an injection pinhole or perfusion tube outlet).
• local administration concentration refers to the concentration of the specified component at the time of local administration of the drug, which may be the concentration of the specified component at the drug contact target area (eg, injection needle hole or perfusion tube outlet). concentration.
• topical administration pH (or administration pH) refers to the pH at which a drug is administered topically, which may be the pH of the drug at the point of contact with the target area (eg, an injection needle hole or perfusion tube outlet).
• the synergistic composition is a synergistic safety composition. In one embodiment, the synergistic composition is a synergistic pharmacodynamic composition.
• the pharmaceutical composition is administered at a pH of 7.5 ⁇ 4.5, preferably 10.0 ⁇ 2.0 or 4.0 ⁇ 2.0. In one embodiment, the pharmaceutical composition is administered at a pH of 8.5-11.5, 9.5-11.5, or 10.0-11.0. In one embodiment, the pharmaceutical composition is administered at a pH of 3.0-5.0, or 3.5-4.5.
• the alkalizing agent is a strong base and the pharmaceutical composition is prepared, composed or administered such that the acid-base neutralizing combination provides the topical activity: the strong base is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, 0.5-10%, preferably 0.75-10% or 1-10%; or
• the alkalizing agent is a weak base and the pharmaceutical composition is prepared, composed or administered such that the acid-base neutralizing combination provides the topical activity: the weak base is administered at a concentration of ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, 2.5-35%, preferably 3.0-35% or 5-35%; or
• the acidulant is a strong acid and the pharmaceutical composition is prepared, composed or administered such that the acid-base neutralizing combination provides the topical activity: the strong acid is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, 0.5-10%, preferably 0.75-10% or 1-10%; or
• the acidulant is a weak acid and the pharmaceutical composition is prepared, composed or administered such that the acid-base neutralizing combination provides the topical activity: the weak acid is administered at a concentration of ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20%, preferably 3.0-20% or 5-20%.
• the pharmaceutical composition is prepared, composed or administered such that the acid-base neutralizing combination provides the topical activity:
• the pH neutralizing agent is one or more selected from the group consisting of: The application concentration of weak base, strong acid and strong base salt, organic weak acid alkali metal salt, weak acid, and the pH neutralizer is ⁇ 1%, preferably 2-35%.
• the alkalizing agent is one or more strong bases
• the pH neutralizing agent is one or more selected from the group consisting of weak bases, salts of strong acids and strong bases, organic weak acids and bases Metal salts, weak acids, and pharmaceutical compositions prepared, composed or administered such that the acid-base neutralizing combination provides the topical activity: the strong base is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, 0.5-10%, preferably 0.75-10% or 1-10%, while the pH neutralizer is applied at a concentration of ⁇ 1%, preferably 2-35%.
• the alkalizing agent is one or more weak bases
• the pH neutralizing agent is one or more selected from the group consisting of other weak bases, salts of strong acids and strong bases, organic weak acids Alkali metal salts, weak acids, and said pharmaceutical compositions are prepared, composed or administered such that said acid-base neutralizing combination provides said topical activity: said weak base is administered at a concentration of ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, 2.5-35%, preferably 3.0-35% or 5-35%, and the pH neutralizer is applied at a concentration of ⁇ 1%, preferably 2-35%.
• the acidifying agent is one or more strong acids
• the pH neutralizing agent is one or more selected from the group consisting of: weak bases, strong acids and strong base salts, organic weak acid alkali metal salts , weak acid, and said pharmaceutical composition prepared, composed or administered such that said acid-base neutralizing combination provides said topical activity: said strong acid is administered at a concentration of ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1% , is 0.5-10%, preferably 0.75-10% or 1-10%, and the pH neutralizer is applied at a concentration of ⁇ 1%, preferably 2-35%.
• the acidifying agent is one or more weak acids
• the pH neutralizing agent is one or more selected from the group consisting of weak bases, strong acids and strong base salts, organic weak acid alkali metal salts , other weak acids, and said pharmaceutical compositions prepared, composed or administered such that said acid-base neutralizing combination provides said topical activity: said weak acid is administered at a concentration of ⁇ 2.5%, preferably 2.5-20%, preferably 3.0-20% or 5-20% ⁇ 0.75%, while the pH neutralizer is applied at a concentration of ⁇ 1%, preferably 2-35%.
• the concentration of the strong base is ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, or 0.5-10%, preferably 0.75-10% or 1 -10%.
• the concentration of the weak base is > 2.5%, preferably > 3.0% or > 5%, or 2.5-35%, preferably 3.0-35% or 5% -35%.
• the concentration of the strong acid is ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, or 0.5-10%, preferably 0.75-10% or 1- 10%.
• the concentration of the weak acid is > 2.5%, preferably > 3.0% or > 5%, or 2.5-20%, preferably 3.0-20% or > 5 -20%.
• the alkalizing agent is selected from strong bases, and the pH of the pharmaceutical composition is 10.0 ⁇ 2.0 or 10.5 ⁇ 1.0.
• the alkalizing agent is selected from weak bases and the pH of the pharmaceutical composition is 8.0 ⁇ 1.0 or 8.5 ⁇ 0.5.
• the acidulant is selected from weak acids and the pH of the pharmaceutical composition is 4.0 ⁇ 1.0 or 4.0 ⁇ 0.5.
• the acidulant is selected from strong acids and the pH of the pharmaceutical composition is 3.0 ⁇ 1.0 or 3.0 ⁇ 0.5.
• the addition of the pH neutralizing agent tends to neutralize the pH of the pharmaceutical composition and increases the buffer capacity of the pharmaceutical composition.
• the buffer capacity of the pharmaceutical composition is >0.01 mol ⁇ L ⁇ 1 ⁇ pH ⁇ 1 , preferably 0.015-0.45 mol ⁇ L ⁇ 1 ⁇ pH ⁇ 1 .
• the buffer capacity of the pharmaceutical composition is preferably ⁇ 0.04 mol ⁇ L -1 ⁇ pH -1 , more preferably ⁇ 0.05 mol ⁇ L -1 ⁇ pH -1 .
• the buffer capacity of the pharmaceutical composition is 0.04-0.45 mol ⁇ L -1 ⁇ pH -1 , more preferably 0.05-0.45 mol ⁇ L -1 ⁇ pH -1 .
• buffering capacity also known as buffering index
• buffering index is used to mean the addition of a strong monobasic acid (such as hydrochloric acid) or a strong monobasic acid (such as hydrochloric acid) or a strong The amount (eg xmol) of base (eg sodium hydroxide) in mol ⁇ L ⁇ 1 ⁇ pH ⁇ 1 .
• the pH neutralizing agent is one of the following groups selected from the group other than the acidifying agent or alkalizing agent, and which can make the pH of the pharmaceutical composition more neutralized Or more: strong base, weak base, strong acid and strong base salt, organic weak acid alkali metal salt, weak acid, strong acid.
• the concentration of the pH neutralizer may be ⁇ 1%, preferably 2-35%.
• the pH of the acidifying agent or the alkalizing agent tends to be neutralized means: when the acidifying agent or the alkalizing agent is selected from a strong base or a weak base, the acidifying agent or the alkalizing agent The difference between the pH of the composition and the pH of the composition is ⁇ 0.25; when the acidulant or alkalinizer is selected from a strong acid or a weak acid, the difference between the pH of the composition and the pH of the acidulant or alkalinizer is ⁇ 0.25.
• the addition of pH neutralizers can also result in an increase in the buffering capacity of the composition after changing the pH.
• the pH neutralizer is preferably selected from water-soluble pharmaceutical adjuvant compounds and/or water-soluble adjunct pharmaceutical compounds.
• concentration of the pH neutralizer may be > 2% or > 3%, preferably 3-35%.
• the weak base is selected from one or more of the following groups: a polybasic weak acid-base inorganic salt, a polybasic weak acid acid-based inorganic salt, a nitrogen-containing weak base.
• polybasic weak acid inorganic salt refers to a polybasic weak acid inorganic salt capable of ionizing hydrogen ions in water
• the polybasic weak acid inorganic salt as an acidifying agent or alkalizing agent is preferably 0.01M
• the aqueous solution is alkaline, preferably a polybasic weak acid inorganic salt with pH>8.0 (eg disodium hydrogen phosphate, sodium hydrogen carbonate, potassium hydrogen carbonate).
• polybasic weak acid-base inorganic salt refers to polybasic weak acid inorganic salts that cannot ionize hydrogen ions in water, including normal salts of polybasic weak acid and strong base inorganic salts.
• nitrogen-containing weak base refers to a weakly basic compound containing nitrogen, wherein the weakly basic compound is preferably selected from weakly basic compounds whose solubility in water (w/w) is ⁇ 2%.
• the composition includes, for example, a composition listed in Table 1 below.
• the acidifying agent or alkalizing agent is selected from strong bases
• the pH neutralizing agent is one or more selected from one or more of the following groups: polybasic weak acid-base inorganic salts, Nitrogen-containing weak base, strong acid and strong base salt, polybasic weak acid acid inorganic salt, organic weak acid alkali metal salt, weak acid, strong acid, and wherein the concentration of the strong base is ⁇ 0.5%, preferably 0.75-10%; The concentration of pH neutralizer is > 1%, preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from one or more strong bases
• the pH neutralizing agent is selected from one or more polybasic weak acid-base inorganic salts
• the concentration of the strong base is ⁇ 0.75%, preferably 1-10%, more preferably 2-7%
• the concentration of the polybasic weak acid-base inorganic salt is ⁇ 2%, preferably 2-20%.
• the acidifying or alkalizing agent is selected from one or more strong bases
• the pH neutralizing agent is selected from one or more nitrogen-containing weak bases
• the strong base The concentration of the nitrogen-containing weak base is ⁇ 0.75%, preferably 1-10%, more preferably 2-7%; the concentration of the nitrogen-containing weak base is ⁇ 2%, preferably 2-35%.
• the acidulant or alkalinizer is selected from one or more strong bases
• the pH neutralizer is selected from one or more polybasic weak acid inorganic salts
• the concentration of the strong base is ⁇ 0.75%, preferably 1-10%, more preferably 2-7%
• the concentration of the polybasic weak acid inorganic salt is ⁇ 2%, preferably 2-20%.
• the acidulant or alkalinizer is selected from one or more strong bases
• the pH neutralizer is selected from one or more organic weak acid-alkali metal salts
• the concentration of the strong base is ⁇ 0.75%, preferably 1-10%, more preferably 2-7%
• the concentration of the organic weak acid alkali metal salt is ⁇ 2%, preferably 2-35%.
• the acidulant or alkalinizer is selected from one or more strong bases
• the pH neutralizer is selected from one or more salts of strong acids and strong bases, and wherein the strong base
• the concentration of the salt is ⁇ 0.75%, preferably 1-10%, more preferably 2-5%; the concentration of the strong acid and strong base salt is ⁇ 1%, preferably 1.5-10%.
• the acidifying agent or alkalizing agent is selected from one or more strong bases
• the pH neutralizer is one or more selected from one or more of the following groups: Acid-base inorganic salt, nitrogen-containing weak base, polybasic weak acid acid inorganic salt, and wherein the concentration of the strong base is ⁇ 0.75%, preferably 1-10%, more preferably 2-7%; The concentration of the neutralizing agent is ⁇ 1%, preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from weak bases
• the pH neutralizing agent is one or more selected from one or more of the following groups: other weak bases, weak organic acids Alkali metal salts, weak acids, strong acids, and wherein the concentration of the weak base is ⁇ 3.0% or ⁇ 5%, or 2.5-35%, preferably 3.0-35% or 5-35%, the pH neutralizer The concentration is ⁇ 2%, preferably 2-35%, wherein the weak base is selected from polybasic weak acid-base inorganic salts, polybasic weak acid-acid inorganic salts, or nitrogen-containing weak bases.
• the acidifying agent or alkalizing agent is selected from the group consisting of polybasic weak acid and base inorganic salts, and wherein the concentration of the polybasic weak acid base inorganic salt is ⁇ 2.5%, preferably 2.5-15%.
• the acidifying agent or alkalizing agent is selected from nitrogen-containing weak bases, and wherein the concentration of the nitrogen-containing weak base is ⁇ 2.5%, preferably 2.5-35%.
• the acidifying agent or alkalizing agent is selected from the group consisting of polybasic weak acid acid inorganic salts, and wherein the concentration of the polybasic weak acid acid inorganic salt is ⁇ 2.5%, preferably 2.5-15%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid-base inorganic salts
• the pH neutralizing agent is one or more selected from the following group or groups: Various: nitrogen-containing weak bases, polybasic weak acid inorganic salts, organic weak acid alkali metal salts, weak acids, strong acids, and wherein the concentration of the polybasic weak acid inorganic salts is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20%, preferably 3.0-20% or 5-20%, and the concentration of the pH neutralizer is ⁇ 2%, preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid inorganic salts
• the pH neutralizing agent is selected from one or more polybasic weak acid inorganic salts
• the concentration of the polybasic weak acid-base inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0%, or 2.5-10%, preferably 3.0-10%
• the concentration of the polybasic weak acid-base inorganic salt is ⁇ 2.5%, preferably 2.5-10%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid-base inorganic salts
• the pH neutralizing agent is selected from one or more nitrogen-containing weak bases
• concentration of the polybasic weak acid-base inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the nitrogen-containing weak base is ⁇ 2%, It is preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid-base inorganic salts
• the pH neutralizing agent is selected from one or more organic weak acid-base metal salts
• the concentration of the polybasic weak acid-base inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0%, or 2.5-10%, preferably 3.0-10%
• the concentration of the organic weak acid-alkali metal salt is ⁇ 5%, preferably 5-35%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid-base inorganic salts
• the pH neutralizer is one or more selected from weak acid or/and strong acid
• the concentration of the polybasic weak acid-base inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0%, or 2.5-10%, preferably 3.0-10%
• the concentration of the weak acid or/and the strong acid is ⁇ 0.5%, preferably 1-15%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid inorganic salts
• the pH neutralizing agent is one or more selected from one or more of the following groups Type: nitrogen-containing weak base, organic weak acid alkali metal salt, weak acid, strong acid, and wherein the concentration of the polybasic weak acid acid inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20 %, preferably 3.0-20% or 5-20%, the concentration of the pH neutralizer is 2%, preferably 2-35%.
• the acidulant or alkalinizer is selected from one or more polybasic weak acid acidic inorganic salts
• the pH neutralizer is selected from one or more nitrogen-containing weak bases
• concentration of the polybasic weak acid-base inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the nitrogen-containing weak base is ⁇ 2%, preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid inorganic salts
• the pH neutralizing agent is selected from one or more organic weak acid alkali metal salts
• the concentration of the polybasic weak acid-base inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0%, or 2.5-10%, preferably 3.0-10%
• the concentration of the organic weak acid-alkali metal salt is ⁇ 5%, preferably 5-35%.
• the acidifying agent or alkalizing agent is selected from one or more polybasic weak acid-base inorganic salts
• the pH neutralizer is one or more selected from weak acid or/and strong acid
• the concentration of the polybasic weak acid acid inorganic salt is ⁇ 2.5%, preferably ⁇ 3.0%, or 2.5-10%, preferably 3.0-10%
• the concentration of the weak acid or/and the strong acid is ⁇ 0.5 %, preferably 1-15%.
• the acidifying agent or alkalizing agent is selected from nitrogen-containing weak bases
• the pH neutralizing agent is one or more selected from one or more of the following groups: polybasic weak acid-base formula Inorganic salt, polybasic weak acid acid inorganic salt, organic weak acid alkali metal salt, weak acid, strong acid, and wherein the concentration of nitrogen-containing weak base is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5- 35%, preferably 3.0-35% or 5-35%, the concentration of the pH neutralizer is ⁇ 2%, preferably 2-35%
• the acidulant or alkalinizer is selected from one or more nitrogen-containing weak bases
• the pH neutralizer is selected from one or more polybasic weak acid inorganic salts
• the concentration of the nitrogen-containing weak base is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-35%, preferably 3.0-35% or 5-35%; the polybasic weak acid acid inorganic salt The concentration is ⁇ 2%, preferably 2-10%.
• the acidifying agent or alkalizing agent is selected from one or more nitrogen-containing weak bases
• the pH neutralizing agent is selected from one or more polybasic weak acid-base inorganic salts
• the concentration of the nitrogen-containing weak base is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-35%, preferably 3.0-35% or 5-35%
• the concentration of inorganic salts is ⁇ 2%, preferably 2-10%.
• the acidulant or alkalinizer is selected from one or more nitrogen-containing weak bases
• the pH neutralizer is selected from one or more organic weak acid alkali metal salts
• the concentration of the nitrogen-containing weak base is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-35%, preferably 3.0-35% or 5-35%; the organic weak acid alkali metal salt The concentration is ⁇ 2%, preferably 2-35%.
• the acidulant or alkalinizer is selected from one or more nitrogen-containing weak bases
• the pH neutralizer is one or more selected from weak acids or/and strong acids
• the concentration of the nitrogen-containing weak base is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-35%, preferably 3.0-35% or 5-35%;
• the concentration is ⁇ 0.5%, preferably 1-15%.
• the acidifying or alkalizing agent is selected from acids, wherein the acid is selected from one or more of weak or strong acids, and wherein the concentration of the strong acid is ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, or 0.5-10%, preferably 0.75-10% or 1-10%; or the concentration of the weak acid is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5 -20%, preferably 3.0-20% or 5-20%.
• the acidifying agent or alkalizing agent is selected from weak acids
• the pH neutralizing agent is one or more selected from one or more of the following groups: strong bases, polybasic weak acid bases Inorganic salts, nitrogen-containing weak bases, polybasic weak acid acid inorganic salts, organic weak acid alkali metal salts, and wherein the concentration of the weak acid is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20% , preferably 3.0-20% or 5-20%; the concentration of the pH neutralizer is ⁇ 1%, preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from one or more weak acids
• the pH neutralizer is selected from one or more polybasic weak acids and base inorganic salts and/or polybasic weak acids Acid inorganic salts, and wherein the concentration of the weak acid is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20%, preferably 3.0-20% or 5-20%; in the pH
• the concentration of the neutralizing agent is ⁇ 1%, preferably 2-25%.
• the acidulant or alkalinizer is selected from one or more weak acids
• the pH neutralizer is selected from one or more nitrogen-containing weak bases
• the concentration of the weak acid ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20%, preferably 3.0-20% or 5-20%
• the concentration of the nitrogen-containing weak base is ⁇ 1%, preferably 2 -35%.
• the acidulant or alkalinizer is selected from one or more weak acids
• the pH neutralizer is selected from one or more organic weak acid alkali metal salts
• the weak acid The concentration of the organic weak acid alkali metal salt is ⁇ 2%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20%, preferably 3.0-20% or 5-20%; , preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from strong acids
• the pH neutralizing agent is one or more selected from one or more of the following groups: polybasic weak acid-base inorganic salts, Nitrogen-containing weak bases, polybasic weak acid acid inorganic salts, organic weak acid alkali metal salts, weak acids, and wherein the concentration of the strong acid is ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, or 0.5-10%, Preferably, it is 0.75-10% or 1-10%; the concentration of the pH neutralizer is ⁇ 1%, preferably 2-35%.
• the acidifying agent or alkalizing agent is selected from one or more strong acids
• the pH neutralizer is selected from one or more polybasic weak acids and base inorganic salts and/or polybasic weak acids Acid inorganic salts, and wherein the concentration of the strong acid is ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, or 0.5-10%, preferably 0.75-10% or 1-10%; in the pH
• the concentration of the neutralizing agent is ⁇ 1%, preferably 2-25%.
• the acidulant or alkalinizer is selected from one or more strong acids
• the pH neutralizer is selected from one or more nitrogen-containing weak bases
• the concentration of the strong acid ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, or 0.5-10%, preferably 0.75-10% or 1-10%
• the concentration of the nitrogen-containing weak base is ⁇ 1%, preferably 2 -35%.
• the acidulant or alkalinizer is selected from one or more strong acids
• the pH neutralizer is selected from one or more organic weak acid alkali metal salts
• the strong acid The concentration of the organic weak acid and alkali metal salt is ⁇ 1% , preferably 2-35%.
• the acidulant or alkalinizer is selected from one or more strong acids
• the pH neutralizer is selected from one or more other weak acids
• the concentration of the strong acid is ⁇ 0.5%, preferably ⁇ 0.75% or ⁇ 1%, or 0.5-10%, preferably 0.75-10% or 1-10%
• the concentration of the other weak acids is ⁇ 1%, preferably 2-25%.
• the total concentration of the acid-base neutralizing composition is > 1.5%, preferably 2.25-40%.
• the total concentration of the acid-base neutralizing composition is also the locally administered concentration of the acid-base neutralizing composition.
• the strong base includes an alkali metal hydroxide, wherein the alkali metal hydroxide includes, for example: sodium hydroxide, potassium hydroxide, calcium hydroxide.
• the strong base is sodium hydroxide or/and potassium hydroxide, preferably sodium hydroxide.
• the polybasic weak acid base inorganic salts include, for example, sodium phosphate, sodium carbonate, potassium carbonate, borax, preferably sodium carbonate and/or sodium phosphate .
• the acidifying agent or alkalizing agent is sodium hydroxide
• the pH neutralizing agent is sodium carbonate
• the concentration of the sodium hydroxide is ⁇ 0.5%, preferably 0.75-5%
• the concentration of the sodium carbonate is ⁇ 2%, preferably 2-10%.
• the acidifying agent or alkalizing agent is sodium hydroxide
• the pH neutralizing agent is sodium phosphate
• the concentration of the sodium hydroxide is ⁇ 0.5%, preferably 0.75-5%
• the concentration of the sodium phosphate is ⁇ 2%, preferably 2-10%.
• the polybasic weak acid inorganic salts include, for example, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, and sodium hydrogen sulfate.
• the polybasic weak acid acid inorganic salt is sodium bicarbonate and/or disodium hydrogen phosphate.
• the acidifying agent or alkalizing agent is sodium hydroxide
• the pH neutralizing agent is sodium bicarbonate
• the concentration of the sodium hydroxide is ⁇ 0.5%, preferably 0.75-5%
• the concentration of the sodium bicarbonate is ⁇ 2%, preferably 2-10%.
• the acidifying agent or alkalizing agent is sodium hydroxide
• the pH neutralizing agent is sodium dihydrogen phosphate
• the concentration of the sodium hydroxide is ⁇ 0.5%, preferably 0.75-5%
• the concentration of the sodium dihydrogen phosphate is ⁇ 2%, preferably 2-10%.
• the acidifying agent or alkalizing agent is sodium carbonate
• the pH neutralizing agent is sodium bicarbonate
• the concentration of the sodium carbonate is ⁇ 1.5%, preferably 3-10%
• the concentration of sodium bicarbonate is ⁇ 2.5%, preferably 4-15%.
• the acidifying or alkalizing agent is disodium hydrogen phosphate
• the pH neutralizing agent is sodium dihydrogen phosphate
• the concentration of the disodium hydrogen phosphate is ⁇ 1.5%, preferably 2- 7%
• the concentration of the sodium dihydrogen phosphate is ⁇ 2%, preferably 3-10%.
• the nitrogen-containing weak bases include, for example, ammonia water, ammonium chloride, 2-aminoethanol, tromethamine, triethanolamine, tris, 2-aminoethanol, tromethamine, Triethanolamine, meglumine, meglumine.
• organic weak acid alkali metal salts include, for example, potassium hydrogen phthalate, sodium acetate, sodium propionate, sodium butyrate, sodium malonate, sodium lactate, sodium citrate, sodium citrate, malic acid Sodium, Sodium Lauryl Sulfate.
• the organic weak acid alkali metal salt is one or more selected from the following: sodium acetate , sodium propionate , sodium butyrate, sodium malonate, sodium lactate, sodium citrate, citric acid Sodium, Sodium Malate.
• the strong acid and strong base salts include, for example, sodium chloride, potassium chloride, sodium iodide, potassium iodide.
• the acidifying or alkalizing agent is sodium hydroxide
• the pH neutralizing agent is potassium chloride
• the concentration of the sodium hydroxide is ⁇ 0.5%, preferably 0.75-5%
• the concentration of the potassium chloride is ⁇ 1%, preferably 1.5-10%.
• the weak acid is selected from one or more of inorganic weak acid or/and organic weak acid, wherein the inorganic weak acid is for example: phosphoric acid , carbonic acid, boric acid , sulfurous acid ; the organic weak acid includes 1-3 Hydroxy-substituted C1-10 aliphatic carboxylic acids, such as: acetic acid, glycolic acid, propionic acid, malonic acid, butyric acid, succinic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1, 2,3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid), tartaric acid , oxalic acid , gluconic acid.
• the inorganic weak acid is for example: phosphoric acid , carbonic acid, boric acid , sulfurous acid ;
• the organic weak acid includes 1-3 Hydroxy-substituted C1-10 aliphatic carboxylic acids, such as: acetic acid, glycolic acid, propionic acid,
• the weak acid is preferably one or more selected from the group consisting of carbonic acid, acetic acid, glycolic acid, propionic acid, malonic acid, butyric acid, succinic acid, lactic acid (2-hydroxypropionic acid) , citric acid (2-hydroxy-1,2,3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid), tartaric acid , oxalic acid , gluconic acid; preferably acetic acid.
• the weak acid comprises acetic acid, and the concentration of the acetic acid is > 3.5%, preferably 5-15%.
• the acidulant or alkalinizer is acetic acid
• the pH neutralizer is sodium bicarbonate
• the concentration of the acetic acid is ⁇ 5%, preferably 5-15%
• the bicarbonate The concentration of sodium is > 2%, preferably 2-10%.
• the acidifying agent or alkalizing agent is acetic acid
• the pH neutralizing agent is sodium acetate
• the concentration of the acetic acid is ⁇ 3.5%, preferably 5-15%;
• the concentration is ⁇ 5%, preferably 5-25%.
• the weak acid includes acetic acid and gluconic acid, preferably gluconic acid.
• the strong acid includes, for example, hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, selenic acid, hydrobromic acid, hydroiodic acid.
• the strong acid is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid, preferably hydrochloric acid.
• the acidifying or alkalizing agent is hydrochloric acid
• the pH neutralizing agent is acetic acid
• the concentration of the acetic acid is ⁇ 3.5%, preferably 5-15%
• the concentration of the hydrochloric acid is ⁇ 0.5%, preferably 1-5%.
• the topical synergist is selected from one or more of cytotoxic drugs and/or conventional ineffective drugs.
• topical synergist refers to a drug which, when administered in combination with the neutralizing combination, produces a short-term synergistic effect or/and a mid-term synergy at the administration site.
• the pharmaceutical composition comprising acidulant or alkalizer, pH neutralizer compositions and their topical synergists (exemplified only by amino acid nutrients) comprises, for example, listed in Table 2 below combination.
• cytotoxic drug refers to a drug that can effectively treat local diseased diseases (such as solid tumors) by utilizing its cytotoxicity through absorption at a safe dose, which is selected from cytotoxic drugs known in the art , preferably selected from the cytotoxic drugs that have been approved or will be approved by the official competent administrative department of China, the United States or Europe (for example, the FDA or the China Food and Drug Administration), or which have been or will be loaded in the official pharmacopoeia of China, the United States or Europe It is an anti-tumor chemotherapeutic drug.
• absorption refers to the pharmacological effect of the drug being absorbed by the blood to form drug-carrying blood into the target area; the term “absorbed drug” refers to a therapeutic drug that mainly produces drug effects through absorption.
• conventional ineffective drug is used to distinguish it from conventional effective drugs (eg, anti-tumor drugs), and refers to those that may show effects on specific cells in cell experiments (eg, anti-tumor cell effects), but Animal experiments do not show more effective inhibitory effects than conventional effective compounds through absorption, so they have not been approved by pharmaceutical authorities (such as FDA) as drugs effective in the treatment of specific local disease diseases, such as non-anti-local disease drugs, Nutritional medicines, diagnostic medicines, pharmaceutical excipients, etc.
• conventional effective drugs eg, anti-tumor drugs
• animal experiments do not show more effective inhibitory effects than conventional effective compounds through absorption, so they have not been approved by pharmaceutical authorities (such as FDA) as drugs effective in the treatment of specific local disease diseases, such as non-anti-local disease drugs, Nutritional medicines, diagnostic medicines, pharmaceutical excipients, etc.
• the concentration of the cytotoxic drug is > 50% of its solubility in the pharmaceutical composition, preferably 50-100%.
• the conventional ineffective drug is > 0.35%, preferably 0.35%-25%.
• the cytotoxic drug is selected from one or more of the following group: drugs that disrupt DNA structure and function, drugs that intercalate in DNA to interfere with transcription of RNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis , preferably selected from one or more of the following groups: alkylating agents such as cyclophosphamide, carmustine; metal platinum complexes such as cisplatin, carboplatin; DNA topoisomerase inhibitors such as doxorubicin Star class, topotecan, irinotecan; antitumor antibiotics such as actinomycins, daunorubicin; pyrimidine antagonists such as uracil derivatives 5-fluorouracil, furofluorouracil, difurofluorouracil, cytosine derivatives A Glycocytidine, cyclocytidine, 5-azacytidine; taxanes such as paclitaxel, docetaxel.
• alkylating agents such as cyclopho
• the cytotoxic drug is selected from the alkylating agents (eg, cyclophosphamide, carmustine, etc.), and wherein the alkylating agent anti-tumor chemotherapeutic drug is in the topical pharmaceutical composition
• concentration (w/v) is 0.5-6%, preferably 0.75-1.5%.
• the cytotoxic drug is selected from the metal platinum complexes (eg, cisplatin, carboplatin, etc.), and wherein the concentration of the metal platinum complex in the topical pharmaceutical composition ( w/v) is 0.03-0.15%, preferably 0.05-0.15%.
• the cytotoxic drug is selected from the DNA topoisomerase inhibitors (eg, doxorubicin, topotecan, irinotecan, etc.), and wherein the DNA topoisomerase inhibits
• concentration (w/v) of the agent in the topical pharmaceutical composition is 0.05-0.20%, preferably 0.075-0.15%.
• the cytotoxic drug is selected from the anti-tumor antibiotics (eg, actinomycins, daunorubicin, etc.), and wherein the concentration of the anti-tumor antibiotic in the topical pharmaceutical composition (w/v) is 1-4%, preferably 1-2%.
• the anti-tumor antibiotics eg, actinomycins, daunorubicin, etc.
• the cytotoxic drug is selected from the group consisting of pyrimidine antagonists (eg, uracil derivatives 5-fluorouracil, furfluorouracil, difurfluorouracil, cytosine derivatives cytarabine, cyclocytidine, 5-aza cytidine, etc.), and wherein the concentration (w/v) of the pyrimidine antagonist in the topical pharmaceutical composition is 0.5-2%, preferably 0.75-1.5%.
• pyrimidine antagonists eg, uracil derivatives 5-fluorouracil, furfluorouracil, difurfluorouracil, cytosine derivatives cytarabine, cyclocytidine, 5-aza cytidine, etc.
• the cytotoxic drug is selected from the taxanes (eg, paclitaxel, docetaxel, etc.), and wherein the concentration of the taxanes in the topical pharmaceutical composition (w /v) is 0.5-2%, preferably 0.75-1.5%.
• the conventional ineffective drug is one or more selected from one or more of the following groups: amino acid nutrients, carbohydrate nutrients, lipid nutrients, pigment and aromatic compounds, salicylic acid compounds, Quinine compounds, blood volume expanders, probiotic components.
• the blood volume expander comprises a polymeric blood volume expander.
• amino acid-based nutrients refers to amino acids and their small molecule (molecular weight ⁇ 3000) derivatives having nutraceutical effects.
• saccharide nutrient is used to refer to a saccharide compound having a nutritional health effect, preferably selected from the group consisting of monosaccharides, sugar polymers and sugar derivatives having a nutritional health effect, more preferably selected from Carbohydrate nutraceuticals and saccharide excipients with nutritional and health care functions contained in Chinese, American or European official pharmacopoeia or guidelines, which include, for example, monosaccharides or their derivatives in the following group: glucose, ribose, deoxyribose, xylose , fructose, galactose, fucose.
• liponutrients refers to lipid compounds with nutritional health effects, preferably selected from the lipid compounds with nutritional health effects contained in the official pharmacopoeia or guidelines of China, the United States or Europe, More preferably, it is one or more selected from the group consisting of lipids, fatty acids, fat emulsions and lipids.
• the term "pigment aroma compound” refers to a pharmaceutically acceptable aroma compound capable of selectively absorbing or reflecting light of a specific wavelength at a target area, which may for example include vital dyes, photosensitizers and Colored chemotherapy drugs.
• the vital dye may include, for example, one or more of the following organic dyes and derivatives thereof: methylene blue (including its hydrate), patent blue, isothiocyanate, toluidine blue, trypan blue, basic blue, eosin , Basic fuchsin, crystal violet, gentian violet, neutral red, Jenners green B, safranine, Bengal red, etc.
• photosensitizers may include one or more of the following: mixed porphyrin-based photosensitizers, porphyrin-based compounds (such as porphyrin, porphine, purpurin, endogenous porphyrin) and derivatives thereof, phthalocyanines Compounds, bacteriochlorin compounds, fused ring quinone compounds, benzoporphyrin derivatives, 5-aminolevulinic acid, chlorin compounds, etc.
• Colored chemotherapeutic drugs may include one or more of the following: nitrophenol compounds, flavonoids (such as anthocyanins, genistein, etc.), isohexenyl naphthoquinones (such as shikonins), etc.
• methylene blue its derivatives are usually also dyes, such as 1,9-dimethylmethylene blue, 1-methylmethylene blue and the like.
• Some pigmented aromatic compounds, such as methylene blue, are not only vital dyes, photosensitizers, but also colored chemotherapy drugs.
• salicylic acid is used to refer to salicylic acid and its derivatives.
• the chemical name of the salicylic acid is 2-hydroxybenzoic acid.
• the salicylic acid derivative may be any suitable one known to those skilled in the art, which may include, for example, a metal compound-containing salicylic acid derivative and a metal compound-free salicylic acid derivative.
• the former can include, for example, sodium salicylate, magnesium salicylate, zinc salicylate, metal element complexes (such as copper aspirin), etc., while the latter can include, for example, acetylsalicylic acid (Aspirin aspirin).
• lysine difluorobenzenesalicylic acid, aminosalicylic acid, p-aminosalicylic acid, N-phenylanthranilic acid, salicylanilide, o-ethoxybenzamide, benzene salicylate esters, methyl salicylate, methyl paraben, ethyl paraben, salalicylate, dicoumarin and their pharmaceutically acceptable derivatives.
• quinine is used to refer to pharmaceutically acceptable quinine and its structural analogs, such as quinine and its isomers and pharmaceutically acceptable salts.
• quinine its isomers can be, for example, quinidine, cinchonine and cinchonidine
• its salts can be, for example, quinine hydrochloride, quinine dihydrochloride, quinine sulfate and the like.
• the concentration (w/v) of the amino acid nutrient is > 5%, preferably 10-35%.
• the concentration (w/v) of the carbohydrate nutrients is > 5%, preferably 5-40%.
• the lipid nutrient concentration is greater than 5%, preferably 10-30%.
• the concentration (w/v) of the pigment aromatic compound is ⁇ 0.35%, preferably 0.35-10%.
• the concentration (w/v) of the salicylic acid compound is > 2%, preferably 2-30%.
• the concentration (w/v) of the quinine is > 2%, preferably 2-10%.
• the amino acid-based nutrients are selected from one or more of basic amino acids and/or non-basic amino acid-based nutrients, wherein the basic amino acid-based nutrients such as arginine, amino acid, group amino acid, preferably arginine; the non-basic amino acid nutrients such as one or more of the following groups: neutral amino acids, acidic amino acids, amino acid salts, wherein the neutral amino acids such as: glycine, tryptophan , tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, alanine, valine, leucine, isoleucine, phenylalanine, proline Acid, the acidic amino acid such as: aspartic acid, glutamic acid, the amino acid salt includes the above-mentioned amino acid and the salt formed by the acid, such as lysine hydrochloride, histidine hydrochloride, glutamic acid Amino acid hydrochloride, cysteine hydrochloride
• the amino acid-based nutrients are preferably one or more amino acids selected from the group consisting of: arginine, arginine, glycine, tryptophan, serine, cysteine, glutamate Amino amide, proline.
• the concentration of the amino acid nutrients is preferably > 5%, preferably 7.5-35%.
• the amino acid nutrient includes arginine.
• the amino acid nutrient is arginine, and wherein the concentration of arginine is > 10%, preferably 10-20%.
• the acidifying or alkalizing agent is sodium hydroxide
• the pH neutralizing agent is sodium bicarbonate
• the amino acid nutrient is arginine
• the concentration of the sodium hydroxide is ⁇ 0.5%, preferably 0.75-5%
• the concentration of the sodium bicarbonate is ⁇ 2.5%, preferably 4-15%
• the concentration of the arginine is ⁇ 10%, preferably 10-20%.
• the acidulant or alkalizer is sodium carbonate
• the pH neutralizer is sodium bicarbonate
• the amino acid nutrient is arginine
• the concentration of the sodium carbonate is ⁇ 1.5 %, preferably 2-10%
• the concentration of the sodium bicarbonate is ⁇ 1%, preferably 1-5%
• the concentration of the arginine is ⁇ 10%, preferably 10-20%.
• the amino acid nutrient includes glycine.
• the amino acid nutrient is glycine, and wherein the concentration of glycine is > 10%, preferably 10-25%.
• the amino acid nutrient comprises lysine hydrochloride.
• the amino acid nutrient is a mixture of two or more amino acid nutrients.
• the carbohydrate nutrients are one or more selected from the group consisting of glucose, fructose, chitooligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, Sucrose, lactose, trehalose, xylo-oligosaccharide, fructooligosaccharide, mannooligosaccharide, xylitol, more preferably one or more selected from the following: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, milk Fructose, ribose , mannooligosaccharide, xylitol, and the concentration (w/v) of the glyconutrient in the pharmaceutical composition is ⁇ 10%, preferably 10-40%.
• the lipid nutrient is one or more selected from the group consisting of vegetable oils, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long chain fatty emulsions, Medium-chain fat emulsion, phospholipids, and the concentration (w/v) of the lipid nutrients in the pharmaceutical composition is ⁇ 4%, preferably 4-25%.
• the pigment aromatic compound is one or more selected from the following: methylene blue, patent blue, isosulfur blue, Bengal red, and in the pharmaceutical composition, the pigment aromatic compound is Concentration (w/v) ⁇ 0.35%, preferably 0.5-10%.
• the salicylic acid compound is one or more selected from the group consisting of salicylic acid, acetylsalicylic acid, lysine, and in the topical pharmaceutical composition, the water
• the concentration (w/v) of the salicylic acid compound is ⁇ 5%, preferably 5-10%.
• the quinine compound is one or more selected from the group consisting of quinine hydrochloride, quinine dihydrochloride, and quinine sulfate, and in the topical pharmaceutical composition, the quinine compound
• concentration (w/v) of the compound is > 3%, preferably 3-6%.
• the blood volume expander includes at least one of a dextran-based blood volume expander, a starch derivative blood volume expander, a gelatin derivative blood volume expander, and a synthetic blood volume expander.
• the dextran blood volume expander is selected from at least one of dextran 10, dextran 40, and dextran 70;
• the starch derivative blood volume expander is selected from carboxyethyl starch 20, carboxyethyl starch 20, carboxyethyl starch At least one of ethyl starch 40, carboxyethyl starch 130/0.38-0.45, and carboxyethyl starch 200/0.5.
• the gelatin derivative blood volume expander can be oxidized polygelatin and/or succinyl gelatin; the synthetic blood volume expander can be fluorocarbon hematopoietic and/or polyvinylpyrrolidone.
• the pharmacological concentration of the dilating agent may be 2-30%, preferably 2-25% or 2-20%.
• the probiotic component includes at least one of inactivated probiotics, water-soluble probiotic components, probiotic water-insoluble component particles, and probiotic semi-fluid components.
• the probiotic components are selected from one or more of water-soluble components of probiotics, semi-fluid components of probiotics, water-insoluble granules of probiotic components, and inactivated probiotics, and have low bacterial immunogenicity.
• the probiotic components are selected from water-soluble components of probiotics and/or their engineering analogs (such as water-soluble derivatives of probiotic polysaccharides), and the composition is a solution composition .
• the probiotic water-soluble component is selected from one or more of the following group and derivatives thereof: crushed probiotic supernatant component, probiotic extract, probiotic intracellular water-soluble
• the component, probiotic polysaccharide, and probiotic nucleic acid are preferably one or more selected from the following water-soluble pharmaceutical groups: probiotic polysaccharide, probiotic polysaccharide derivative, and probiotic nucleic acid.
• the concentration of the probiotic component is 0.25-25%, 0.25-20%, preferably 0.5-15%, more preferably 1-15% or 5-15%.
• the probiotic is selected from one or more of natural bacteria or/and engineered bacteria comprising the following group: probiotic bacillus, probiotic lactobacillus, probiotic bifidobacteria, probiotic fungi.
• the bacillus comprises one or more selected from the group consisting of: Bacillus licheniformis, Bacillus subtilis, Bacillus pumilus, Bacillus natto;
• the lactobacillus comprises selected from One or more selected from the group consisting of: Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus pumilus, and Lactobacillus fermentum;
• the bifidobacteria include one or more selected from the group consisting of: Bifidobacterium longum, Bifidobacterium adolescentis, Bifidobacterium breve, Enterococcus faecium, Streptococcus
• compositions disclosed according to the present application may be in any dosage form suitable for topical administration that may contain the active ingredient (the pharmaceutical composition, and optionally other drugs as described above), preferably the following dosage forms: injection ( Preferred are local injections), external liquids, nebulizers, and the like.
• the term "injectable” is used to refer to a sterile preparation containing the active ingredient and a liquid carrier for in vivo administration.
• the injections are classified into local injections, intravenous injections, etc. according to the mode of administration, and the intravenous injections can be used as local injections only after a given local administration concentration.
• Injections are classified into liquid injections, powder injections, etc.
• a powder for injection contains sterile dry powder and a vehicle, the sterile dry powder contains part or all of the active ingredients, and the vehicle contains all the liquid carriers.
• the concentration of the active ingredient in the injection is the concentration of the active ingredient in the mixture with all the liquid carriers, usually the end point (such as needle hole, catheter outlet, etc.) of the local drug delivery device (syringe, trocar, perfusion catheter, etc.) ) of the active ingredient concentration in the liquid medicine.
• the concentration of the active ingredient is the concentration of the active ingredient in a mixture of sterile dry powder and a vehicle (eg, a reconstituted solution, or the pharmaceutically acceptable liquid carrier).
• the term "liquid for external use” refers to an active ingredient and a liquid carrier and a donor surface [e.g. skin, mucous membranes (e.g.
• ocular mucosa, nasal mucosa, etc. or/and cavities (e.g. oral cavity, rectum, Vaginal, urethral, nasal, ear canal, etc.)] administration of liquid medicines, which include, for example, lotions, liniments, drops, gargles, paints, and the like.
• liquid medicines which include, for example, lotions, liniments, drops, gargles, paints, and the like.
• the liquid medicine often comes from local administration devices such as lotion bottles, drip bottles, drip tubes, rinse bottles, cotton swabs, and the like.
• the concentration of the active ingredient in the external liquid preparation is the concentration of the active ingredient in the liquid medicine.
• the term "nebulizer” refers to a dosage form which contains the active ingredient and a liquid carrier and which, in use, can be administered by atomizing the aforementioned liquid drug by means of pressure, which can be applied to the skin, mucous membranes (e.g. ocular mucosa, nasal mucosa, etc.) or/and cavity (eg, oral, rectal, vaginal, urethral, nasal, ear canal, etc.) administration, including, eg, aerosols, sprays, nebulizers, and the like.
• the atomization of liquid drugs is often formed by topical drug delivery devices such as aerosols, atomizers, and nebulizers.
• the drug After the drug is atomized and sprayed to the target position, it accumulates to form a liquid drug.
• the liquid medicine is substantially the same in composition as the liquid medicine before atomization.
• the concentration of the active ingredient in the nebulizer can be represented by the concentration of the active ingredient in the liquid drug prior to nebulization.
• the pharmaceutical composition of the present invention should be made into a dosage form that can be locally administered to the target area, preferably a local pharmaceutical dosage form.
• the preparation of the pharmaceutical composition of the present invention comprises the steps of: preparing a liquid medicine containing the essential components (eg, the pharmaceutical composition) and optionally other substances.
• the liquid drug can be a solution (eg, in a hydrophilic vehicle, preferably an aqueous solution), a suspension, or an emulsion.
• the dispersion medium therein can be any suitable one known to those skilled in the art, such as micro-materials or nano-materials.
• the dispersion medium therein can be any suitable one known to those skilled in the art, such as vegetable oil, synthetic oil or semi-synthetic oil for injection.
• the vegetable oil may be, for example, cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and peanut oil.
• the concentrations of the pharmaceutical composition and other drugs are greater than or equal to their concentrations in the pharmaceutical composition of the present invention.
• it can be further diluted for use.
• the liquid injection of the pharmaceutical composition of the present invention can be prepared by a method comprising the following steps: 1) The necessary components (eg, the pharmaceutical composition) in the required amount according to the local administration concentration And other components optionally present are added into water to prepare a liquid; 2) the other drugs optionally present according to the required amount of local administration concentration are added to the liquid prepared in 1) and mixed uniformly to obtain a liquid drug; 3) will be in the The liquid medicine prepared in 2) was sterilized to make a liquid injection. In use, the sterilized liquid medicine in the liquid injection can be used as a liquid medicine for topical administration directly or after dilution.
• the injection powder of the pharmaceutical composition of the present invention can be prepared by a method comprising the following steps: preparing a sterile dry powder containing the pharmaceutical composition in the required amount according to the local administration concentration; and preparation of sterile vehicles containing the required amounts of the optional other components according to the concentration for topical administration.
• Described sterilization dry powder is preferably sterilization freeze-dried dry powder, and its preparation method comprises: 1) prepare the solution that comprises amino acid to nutrient, water-soluble weak neutralization substance and optional other components; 2) sterilization filtration and separation; 3) freeze-drying; 4) plugging and capping.
• the freeze-drying process conditions include, for example: the pre-freezing conditions are kept at the pre-freezing temperature -45°C for 4 hours; the sublimation drying conditions are that the heating rate is 0.1°C/min, and the temperature is raised to -15°C and kept for at least 10 hours; The adsorption drying conditions were kept at 30°C for 6 hours.
• the sterile dry powder of the powder for injection is reconstituted in a sterile solvent to form a reconstituted liquid drug, which can be used directly or after dilution as a liquid drug for topical administration.
• the external use liquid of the pharmaceutical composition of the present invention is prepared by a method comprising the following steps: adding the required amount of the pharmaceutical composition according to the local administration concentration and optionally other components into a vehicle It is prepared as a liquid medicine.
• the liquid medicine in the external solution can be used directly or after being diluted as a liquid medicine for topical administration.
• the pharmaceutical composition aerosol of the present invention can be prepared by a method comprising the following steps: 1) adding the required amount of the pharmaceutical composition according to the local administration concentration and aerosol excipients into The vehicle is prepared as a liquid; 2) the other components optionally present in the required amount according to the local administration concentration are added to the liquid prepared in 1) and mixed uniformly to obtain a liquid medicine.
• excipients for nebulization include, for example: glycerin, polysorbate-80, benzalkonium chloride, microcrystalline cellulose-sodium carboxymethyl cellulose, and the like.
• the liquid drug is added to a nebulizer (such as a spray) and is locally administered to the target area in the form of droplets under its atomization, where the droplets accumulate as a liquid drug.
• compositions of the present invention include: containing different types and concentrations of the pharmaceutical composition, containing different types and concentrations of other drugs, containing different types and concentrations of other additives (eg, analgesics, activators, etc.) Wait).
• other additives eg, analgesics, activators, etc.
• the pharmaceutical composition is mainly used for the prevention and treatment of local pathological diseases, especially refractory local pathological diseases, by topical administration.
• the term “focal disease” refers to a disease showing symptoms of a local disease
• the term “focal disease” refers to a structural, morphological or functional native or secondary part of the body of an animal (preferably a human)
• the abnormality may include one or more of the following: tumor, non-tumor swelling, local inflammation, abnormal secretion of secretory glands, etc.
• the local site can be any suitable one known to those skilled in the art, for example, it can be a local part including one or more of the following organs: the secretory organ where the secretory system is located, the cardiovascular organ where the blood circulatory system is located, the skin, etc. .
• the drug composition (local active ingredient, composition ratio and component concentration) can be administered to the tissue where the local lesion is located by interventional means, and produce the desired therapeutic effect in the tissue.
• the local tissue is the tumor body where the tumor cells are located; when the lesion is non-tumor, the local tissue is an abnormality such as a mass, such as hyperplasia, cyst, nodule, etc.; when the lesion is a local
• the local tissue is the inflamed area, such as an inflamed body; when the lesion is abnormal secretion, the local tissue is the abnormal source or the secretory gland where it is located.
• the abnormal source is the pancreatic islet
• the local tissue is the pancreatic islet or the pancreas where the pancreatic islet is located
• the disease is a skin disease
• the local tissue is the diseased skin or an accessory organ of the diseased skin.
• the local lesions include tumors, non-tumor swellings, local inflammation, abnormal secretory gland function, and skin diseases.
• tumor refers to a mass formed due to abnormal proliferation of cells or mutated cells, which includes solid tumors.
• solid tumor refers to a tumor with a tumor body, which can be due to any pathology (malignant and non-malignant) and at any stage, including, for example, the following groups classified by tumor cell type: epithelial cell tumors, sarcomas, Lymphoma, germ cell tumor, blastoma; and tumors named after the organ or tissue in which the tumor cell concentration is located, including, for example, tumors named after the following organs or tissues: skin, bone, muscle, breast, kidney, Liver, Lung, Gallbladder, Pancreas, Brain, Esophagus, Bladder, Large Intestine, Small Intestine, Spleen, Stomach, Prostate, Green Pill, Ovary or Uterus.
• the malignant tumor includes, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, colon cancer, oral cancer, esophageal cancer, gastric cancer, throat cancer, testicular cancer, vaginal cancer, Uterine cancer, ovarian cancer, etc.
• the non-malignant tumors include, for example, breast tumors, pancreatic tumors, thyroid tumors, prostate tumors, liver tumors, lung tumors, intestinal tumors, oral tumors, esophageal tumors, gastric tumors, nasopharyngeal tumors, laryngeal tumors, testicular tumors, vaginal tumors, Uterine tumor, fallopian tube tumor, ovarian tumor, etc.
• the locally diseased disease comprises a non-tumorous enlargement.
• non-neoplastic refers to enlargements other than tumors, including, for example, hyperplasia (eg, hyperplasia of breast, pancreas, thyroid, parathyroid, prostate, etc.), cysts (eg, cysts of breast, thyroid, parathyroid, etc.) , Nodules (such as nodules of breast, thyroid, parathyroid, etc.), abnormal venous mass (such as hemorrhoids, etc.), local inflammation and swelling, microbial infection and swelling.
• the hemorrhoids include internal hemorrhoids, external hemorrhoids and mixed hemorrhoids.
• the locally diseased disease comprises local inflammation, especially refractory inflammation.
• localized inflammation refers to non-neoplastic inflammation of a localized site, including, for example, alterative, exudative, and proliferative inflammation, which may be in the art Any suitable known to the skilled person, for example, may 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, bronchitis, bronchitis, vaginitis, metritis, salpingitis, oophoritis, etc.
• the localized disease comprises a skin disease, especially a refractory skin disease.
• skin disease refers to a disease that is native or secondary to the skin or skin appendages, which may be any suitable known to those skilled in the art, for example may include one or more of the following Species: skin cancer, non-malignant skin tumors, viral skin diseases (e.g. herpes, warts, rubella, hand, foot and mouth disease), bacterial skin diseases (e.g. impetigo, boils, leprosy), fungal skin diseases (e.g.
• various ringworm sexually transmitted diseases (such as syphilis, gonorrhea, and condyloma acuminatum), allergic and autoimmune skin diseases (such as contact dermatitis, eczema, urticaria), physical skin diseases (such as solar dermatosis, frostbite, corns) , chapped hands and feet, pressure ulcers), connective tissue diseases (such as lupus erythematosus), dyspigmented skin diseases (such as freckles, pigmented nevi, various macules), skin adnexal diseases (such as acne, rosacea, seborrheic dermatitis) , alopecia areata, alopecia, hyperhidrosis and stinkyhidrosis).
• sexually transmitted diseases such as syphilis, gonorrhea, and condyloma acuminatum
• allergic and autoimmune skin diseases such as contact dermatitis, eczema, urtic
• the focal disease comprises secretory gland dysfunction.
• secretory gland refers to a structure composed of glandular cells or groups of glandular cells that performs a secretory function, including exocrine and endocrine glands.
• Abnormal secretion function of secretory glands includes hypersecretory gland function (eg, hyperthyroidism) and hyposecretory gland function (eg, hypothyroidism, islet dysfunction (a type of diabetes)).
• the localized disease comprises cardiovascular disease.
• Interventional therapy has become an important treatment for cardiovascular disease.
• cardiovascular diseases include, for example, hemangiomas, hypertrophic obstructive cardiomyopathy, atrial fibrillation, arrhythmias, arterial embolism, and the like.
• the topical drug in the present invention is a therapeutic drug, and when it is used for the prevention and treatment of local lesions, it can also be combined with other interventional therapy, systemic chemotherapy, immunotherapy, photodynamic therapy, sonodynamic therapy, surgical intervention or Combinations of such therapies are administered in combination to further enhance efficacy.
• the pharmaceutical composition is mainly used for the prevention and treatment of local pathological diseases through topical administration.
• said one comprises acidifying or alkalizing agents, pH neutralizing agents, and topical synergists thereof in said topical pharmaceutical combination
• the concentration or amount in the drug is higher than topical administration. This concentration or amount ratio can provide a synergistic effect of the local response when administered locally.
• the pharmaceutical compositions of the present invention have been shown to promote effective destruction of the associated structures of the localized diseased tissue (eg, diseased tissue), while having minimal effects on the patient's normal tissue Therefore, the pharmaceutical effect of safe and effective treatment of local lesions can be achieved.
• the localized diseased tissue eg, diseased tissue
• Class: 1 is strong base, 2 is strong acid, 3 is polybasic weak acid inorganic salt, 4 is other weak base, 5 is organic weak acid alkali metal salt, 6 is polybasic weak acid acid inorganic salt, 7 is weak acid, 8 Amino acid compound, 9 is strong acid and strong base salt, 10 is other drugs
• mice There are two types: BALB/c mice and nude mice. Nude mice are mutant (BALB/c-nu) mice obtained by introducing a nude gene (nu) into BALB/c mice. The mice were all healthy females aged 6-8 weeks, weighing 17.5-20.5 g.
• the animal modeling of subcutaneously transplanted cells to generate local lesions is the existing technology, and the modeling is successful when the tumor grows to the required volume (such as 50-500 mm 3 in mice bearing tumors).
• Animals were divided into several groups, 6 animals in each group, and the general state, body weight, food intake, animal graft-versus-host disease, tumor volume, tumor weight, survival time, etc. were measured regularly.
• the models of local lesions respectively contain tumor cells (representing tumors), nodules containing fibroblasts (representing tumors containing fibroblasts and other local lesions), and normal living tissues (representing tumors containing fibroblasts). local lesions of common tissues).
• the volume (V) of local lesions (such as tumors), the relative proliferation rate (R) of local lesions (such as tumors), the inhibition rate (r') of local lesions (such as tumors), and the tumor inhibition rate (r) are respectively as follows:
• Relative local lesion (such as tumor) volume V t /V 0 , where V 0 and V t represent the tumor volume on the first day of administration and the t day of administration after grouping, respectively;
• Tumor inhibition rate r (CW-TW)/CW ⁇ 100%, where TW and CW are the average tumor weights of the study group and the negative control group, respectively.
• the efficacy of drug i is denoted as Ei, which can be represented by ri' or ri.
• the type of action of a drug i.e. pharmacology, can be studied by the efficacy of the drug, especially the efficacy of the agreed drug in different regimens.
• experimental results are expressed as mean ⁇ standard deviation (x ⁇ s), and the difference between the two experimental animal groups and the group mean is expressed by statistical software SPSS13.0 or SPSS19.0 was used for significance test.
• the test was carried out with statistic t.
• Positive controls for chemotherapy include classical cytotoxic drugs (such as 0.5-1% 5-fluorouracil, whose tumor inhibition rate is ⁇ 30% under the conditions of the following examples) and classical chemical ablative agents (such as 75-99% ethanol, which The tumor inhibition rate under the conditions of the following examples is ⁇ 15%).
• Positive controls for immune enhancement include cytokines (such as interleukin-12,), bacterial components (such as attenuated bacterial vaccines, etc.), vaccine adjuvants and other immune enhancers.
• EA and EB such as tumor inhibition rate
• EA +B the actual shared efficacy of A / B
• q ⁇ 1 it means that the actual sharing effect is weaker than the theoretical expectation, showing an antagonistic effect
• q>1 it means that the actual sharing effect exceeds the theoretical expectation. , showing a synergistic effect.
• the method for judging the effect of concomitant medication in animal experiments includes Burgi's method (Burgi Y. Pharmacology; Drug actions and reactions. Cancerres. 1978, 38(2), 284-285).
• the shared efficacy of drug A and drug B combined administration is judged as follows:
• the combined administration also does not show a meaningful synergistic effect, which is considered in the present invention.
• the necessary components in the pharmaceutical composition eg, alkalinizing agent 3 g sodium hydroxide, pH neutralizing agent 7 g sodium bicarbonate), optional other components, and make up to the total volume (eg 100 ml) in the desired concentration ) liquid carrier (such as water for injection), and slowly mix them evenly, after sterilization filtration, divide into required amount (such as 10ml/bottle) and store for later use.
• the preparation eg, 7% sodium bicarbonate/3% sodium hydroxide in water
• the necessary components in the pharmaceutical composition eg, alkalinizing agent 3 g sodium hydroxide, pH neutralizing agent 7 g sodium bicarbonate), optional other components, and make up to the total volume (eg 100 ml) in the desired concentration ) liquid carrier (such as water for injection), and slowly mix them evenly, after sterilization filtration, pack into required amount (such as 10ml/bottle), freeze-dry, cork, and cap, prepare as sterilized dry powder for later use.
• liquid carrier such as water for injection
• the required amount of sterile dry powder (for example, 1 bottle of the above dry powder) is reconstituted in the required amount of sterile liquid (for example, water for injection) to obtain the required reconstituted solution (for example, 7% sodium bicarbonate/ 3% aqueous sodium hydroxide solution) can be administered locally as a liquid drug.
• sterile liquid for example, water for injection
• the necessary components in the pharmaceutical composition eg, alkalinizing agent 3 g sodium hydroxide, pH neutralizing agent 7 g sodium bicarbonate), optional other components, and make up to the total volume (eg 100 ml) in the desired concentration ) in a liquid carrier such as water for injection, and mix them slowly until uniform.
• a liquid carrier such as water for injection
• the preparation eg, 7% sodium bicarbonate/3% aqueous sodium hydroxide solution
• the necessary components such as 3g sodium hydroxide, 7g sodium bicarbonate
• the necessary components such as 3g sodium hydroxide, 7g sodium bicarbonate
• aerosol excipients such as glycerin (2.5g), polysorbate- 80 (1.5g), benzalkonium chloride (0.02g), microcrystalline cellulose-sodium carboxymethylcellulose (1.5g)
• a vehicle such as water for injection
• the preparation for example, 7% sodium bicarbonate/3% sodium hydroxide aqueous solution
• the successfully modeled experimental animals (sarcoma-bearing S180 cell mice, with an average tumor volume of 314 mm 3 ) were randomly divided into 2 negative control groups (01, 02) and 9 drug study groups (1 -9).
• the negative control is normal saline, and the research drugs are shown in the table below.
• the medicines are all aqueous solutions, prepared according to the preparation method of Example 1.
• Negative controls and research drugs were injected intraperitoneally (groups 02, 6, and 9) and intratumorally (other research groups). Each group was administered once every 3 days, a total of 3 times, the injection volume was 150ul/a. Five days after the end of administration, the animals were euthanized, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group. The results are shown in the following table.
• mice Male or female, were randomly divided into 5 groups (groups 1, 3, 4, 7, and 8 in the table below), with 6 mice in each group.
• the experimental animals in each group were injected with 100ul of the research drugs shown in the table below into the quadriceps muscle of the right leg. After 24 hours of injection, the animals were euthanized, and the degree of hyperemia, edema, degeneration, necrosis and other phenomena at the injection site was observed, and the stimulation response was scored.
• the scoring standard was calculated on the basis of 0 points for the negative control group phenomenon and 5 points for the 3% NaOH group phenomenon.
• the results of the stimulus response scores are shown in the table below.
• the tissue necrosis research test 30 New Zealand white rabbits, weighing 2.0-2.5 kg, were male or female.
• the experimental rabbits were randomly divided into 5 groups (groups 1, 3, 4, 7, and 8 in the table below), with 6 rabbits in each group.
• the experimental rabbit was anesthetized by injecting anesthesia into the ear vein, and then fixed on the rabbit frame in the supine position. Under sterile conditions, a small incision on the right side was made to open the abdomen to expose the liver, and then a 22G PTC needle was punctured into the thickest part of the liver. In the center of the right lobe of the liver, the depth of the needle tip from the liver capsule of the puncture point was 1.5 cm, and the study drug was injected slowly and uniformly.
• Each rabbit was given an intrahepatic injection of 1.0 mL of the study drug shown in the table below.
• the rabbits were fed with conventional chow and euthanized 1 week later, and the necrotic area of the liver was measured after autopsy.
• the liver was incised along the center of the necrotic area, and the range of the necrotic area was subject to the largest slice, and the largest and smallest diameters of the necrotic area were measured respectively.
• Average diameter of necrotic area of liver tissue (maximum diameter+minimum diameter)/2. The results of the mean diameter of the necrotic area of the liver tissue are shown in the table below.
• the anti-tumor efficacy of the same composition in the B technical scheme exceeds the expected limit of the pharmacodynamic improvement in the A scheme (generally ⁇ 150%, or from no effect to effective effect, or there is a statistical difference in tumor weight). scientific significance), it is likely to be the drug effect of different pharmacology.
• compositions for intraperitoneal injection enters the bloodstream and then reaches the local lesion, and its administration composition is completely diluted or even digested by the blood (eg different retention of different compositions in certain organs).
• a composition for topical administration will have the same target composition (at least for a period of time) as it is administered.
• compositions administered in different ways should have different compositional characteristics to achieve synergistic efficacy.
• a certain concentration threshold eg, sodium hydroxide, sodium carbonate, sodium bicarbonate, acetic acid, hydrochloric acid
• the polarization of the pH of the chemical ablative agent (towards 0 or to 14) is considered to be a positive factor for its chemical ablative effect.
• pH choices for conventional chemical ablatives are typically ⁇ 2% (eg, 50% acetic acid, 25% hydrochloric acid), or > 11.5% (eg, 7% sodium hydroxide). Under such extreme pH conditions, the intense indiscriminate tissue destruction is believed to underlie the pharmacological action of conventional chemical ablative agents.
• composition group 4 was significantly different from the remaining tumor weights between groups 3 and 1 (both p ⁇ 0.05), so Shows obvious synergistic effect.
• composition study group 5 in the topical administration series, despite the same component ratio of each composition, the tumor inhibition rate of composition study group 5 was only 47% (32%: 68%) of that of composition study group 4, and There was a statistically significant difference in tumor weight between the two groups (p ⁇ 0.05). Between study groups 5 and 2, their tumor inhibition rates did not reach the universal standard of 40%, and the difference in residual tumor weight was not statistically significant (p>0.05), so they did not show synergistic efficacy.
• compositions administered in different ways may require completely different components.
• Compositions for systemic administration usually require component ratios (they are intended to be diluted into the blood anyway), while topical compositions only give component ratios, obviously, other characteristics (such as concentration) must also be given. .
• compositions of the present invention appear to exhibit significantly different pharmacology when administered locally than when administered systemically.
• its main pharmacology is not to distribute into the blood in the form of molecules to attack pathogens in the diseased tissue (such as tumor cells in the tumor), but to distribute into the interstitial space in the form of drug solution to attack the diseased tissue (such as the intratumoral tumor) at the site of administration. organize)
• the composition of the pharmaceutical composition of the present invention must be such that it can be administered locally, and above a certain concentration threshold, the ratio of the components of the pharmaceutical composition to produce a synergistic effect.
• the concentration of the acidifying agent or alkalizing agent should be less than its effective ablation concentration (for example, it can make the tumor-inhibiting concentration ⁇ 40% in the tumor-bearing mouse experiment), but greater than the synergistic drug effect Concentration threshold (for example: strong base or strong acid concentration ⁇ 0.5%, weak base or weak acid concentration ⁇ 2.5%).
• concentration of the pH-neutralizing agent is such a concentration that the pharmaceutical composition tends to be neutralized and the absolute value of the difference between the pH of the single drug at the same concentration of the acidifying agent or alkalizing agent is ⁇ 0.25 .
• compositions exhibiting synergistic efficacy were also determined to be buffer solutions with a buffer capacity of >0.01 mol ⁇ L ⁇ 1 ⁇ pH ⁇ 1 .
• composition of the present invention can further improve the efficacy, even synergistic efficacy, by adding topical synergists.
• the experimental animals were BALB/c mice, and the model cells were breast cancer 4T1 cells, and 1 ⁇ 10 6 cells per animal were subcutaneously transplanted into the right axilla of the animal for modeling.
• Successfully modeled experimental animals (average tumor volume 325mm 3 ) were randomly divided into 1 negative control group (0) and 11 drug study groups (1-11).
• the negative control is normal saline, and the research drugs are shown in the table below.
• the medicines are all aqueous solutions, prepared according to the preparation method of Example 1. Each group was administered once every 3 days, a total of 3 times, intratumor injection, the injection volume 150ul / only. Five days after the end of administration, the animals were euthanized, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group. The results are shown in the following table.
• the preferred conditions for the synergistic effect of the pharmacodynamics and the synergistic effect of the safety of the strong base/pH neutralizer composition of the present invention are as follows:
• the strong base includes an alkali metal hydroxide
• the pH neutralizer is preferably selected from compounds whose aqueous solution pH is lower than the pH of the strong base, but greater than 2.0, such as selected from One or more of the following: polybasic weak acid-base inorganic salt, organic weak acid-alkali metal salt, other weak bases, strong acid and strong base salt, polybasic weak acid acid inorganic salt, weak acid.
• the chemical composition characteristics of the composition (compound concentration and amount ratio): when the strong base is selected from alkali metal hydroxides, the concentration of the alkali metal hydroxides is ⁇ 0.5%, preferably 0.75%-7.5% % or 0.75%-5%; the concentration of the pH neutralizing agent is ⁇ 1%, preferably 1%-35%; the amount ratio of the alkali metal hydroxide to the pH neutralizing agent (w alkali metal hydroxide : wpH neutralizer ) is ⁇ 1, preferably 1/20-1/1.25.
• the ionic composition characteristics of the composition (H + concentration index): the difference between the pH of the single drug of the same concentration of the strong base and the pH of the composition is ⁇ 0.25, preferably 0.5-3.5 or 1.0-3.5; The pH of the aqueous solution of the composition is 10.0 ⁇ 2.0, preferably 10.0 ⁇ 1.0.
• the strong base/pH neutralizer composition of the present invention can further improve the efficacy or even synergistic efficacy by adding topical synergists.
• the experimental animals were BALB/c mice, and the model cells were breast cancer 4T1 cells, and 1 ⁇ 10 6 cells per animal were subcutaneously transplanted into the right axilla of the animal for modeling.
• Successfully modeled experimental animals (average tumor volume 307 mm 3 ) were randomly divided into 1 negative control group (0) and 13 drug study groups (1-13).
• the negative control is normal saline, and the study drugs are shown in the table below.
• the medicines are all aqueous solutions, prepared according to the preparation method of Example 1. Each group was administered once every 3 days, a total of 3 times, intratumoral injection, the injection volume 150ul / only. Five days after the end of administration, the animals were euthanized, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group. The results are shown in the following table.
• composition group 13 shows a significant synergistic effect.
• topical synergists can cause compositions to exhibit synergistic efficacy by altering the properties of the composition (perhaps, for example, by increasing buffer capacity).
• the preferred conditions of the weak base/pH neutralizer composition of the present invention are:
• the concentration of the weak base is ⁇ 2.5%, preferably ⁇ 3.0% or ⁇ 5%, or 2.5-20%, preferably ⁇ 3.0-20% or ⁇ 5-20%;
• the difference between the pH of the same concentration of the single drug of the weak base and the pH of the composition is ⁇ 0.25, preferably 0.5-2.5;
• the pH of the composition is 9.0 ⁇ 2.0, preferably 9.0 ⁇ 1.3;
• the pH neutralizer is selected from one or more of the following groups that satisfy the above conditions: other weak bases, organic weak acid alkali metal salts, weak acids, and strong acids. wherein the other weak base is a weak base different from the weak base used as the ablating agent;
• the concentration of the pH neutralizer is > 1%, preferably 1% to 35%.
• the amount ratio (w:w) of the polybasic weak acid salt and the polybasic weak acid salt is greater than 0.56 and less than 7, preferably 1-2.
• the weak base/pH neutralizer composition of the present invention can further improve the efficacy, even synergistic efficacy, by adding topical synergists.
• the experimental animals were BALB/c mice, and the model cells were breast cancer 4T1 cells, and 1 ⁇ 10 6 cells per animal were subcutaneously transplanted into the right axilla of the animal for modeling.
• Successfully modeled experimental animals (average tumor volume 316 mm 3 ) were divided into 1 negative control group (0) and 12 drug study groups (1-12).
• the negative control is normal saline, and the research drugs are shown in the table below.
• the medicines are all aqueous solutions, prepared according to the preparation method of Example 1. Each group was administered once every 3 days, a total of 3 times, intratumor injection, the injection volume 150ul / only. Five days after the end of administration, the animals were euthanized, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group. The results are shown in the following table.
• composition group 7 had q ⁇ 1.00, showing no synergistic effect.
• the q of composition group 8 was > 1.00, showing a significant synergistic effect.
• composition group 9 had q < 1.00, showing no synergistic effect.
• composition group 10 had a q > 1.00, showing a clear synergistic effect.
• composition group 12 had a q > 1.00, showing a clear synergistic effect.
• topical synergists can allow the composition to exhibit synergistic efficacy by altering the properties of the composition (perhaps, for example, increasing the buffer capacity) with little change in pH.
• the preferred conditions for the efficacy and safety synergy of the weak acid/pH neutralizer composition of the present invention are as follows:
• the weak acid is preferably selected from acetic acid and its analogs, such as other C1-10 aliphatic carboxylic acids substituted with 1-3 hydroxyl groups [hydroxyacetic acid, propionic acid, malonic acid, butyric acid, Succinic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1,2,3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid), tartaric acid, oxalic acid, gluconic acid]
• the pH neutralizer is preferably a compound whose aqueous pH is higher than the pH of the weak acid, but less than 10, such as one or more selected from the following: polybasic weak acid-base inorganic salts, nitrogen-containing Weak base, polybasic weak acid acid inorganic salt, organic weak acid alkali metal salt.
• the chemical composition characteristics of the composition (concentration and amount ratio of common substances): the concentration of the weak acid is > 3%, preferably 5-25%; the concentration of the pH neutralizer is ⁇ 3%, preferably 3 %-35%; the amount ratio of the weak acid and the pH neutralizer (w weak acid :w pH neutralizer ) is (5-25)/(3-35).
• the ionic composition characteristics of the composition (H + concentration index): the difference between the pH of the composition and the pH of the same concentration of single drug of the weak acid is ⁇ 0.25, preferably 0.5-2.5; and the aqueous solution of the composition The pH is 4.0 ⁇ 1.5, preferably 4.0 ⁇ 1.0.
• the weak acid/pH neutralizer composition of the present invention can further improve the efficacy, even synergistic efficacy, by adding topical synergists.
• the experimental animals were BALB/c mice, and the model cells were breast cancer 4T1 cells, and 1 ⁇ 10 5 cells per animal were subcutaneously transplanted into the right armpit of the animal to model.
• Successfully modeled experimental animals (average tumor volume 324 mm 3 ) were divided into 1 negative control group (0) and 9 drug study groups (1-9).
• the negative control is normal saline, and the research drugs are shown in the table below.
• the medicines are all aqueous solutions, prepared according to the preparation method of Example 1. Each group was administered once every 3 days, a total of 3 times, intratumor injection, the injection volume 150ul / only. Five days after the end of administration, the animals were euthanized, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group. The results are shown in the following table.
• composition group 6 had q ⁇ 1.00, showing no synergistic effect.
• composition group 7 had a q > 1.00, showing a clear synergistic effect.
• composition group 8 had q ⁇ 1.00, showing no synergistic effect.
• the preferred conditions for the strong acid/pH neutralizer compositions of the present invention are:
• the concentration of the strong acid is >0.5%, preferably 0.75-3%;
• the amount ratio (w:w) of the strong acid and the pH neutralizer is ⁇ 1, preferably 1/20-1/1.25;
• the difference between the pH of the composition and the pH of the single agent of the same concentration of the weak acid is ⁇ 0.25, preferably 0.5-4.0;
• the pH of the composition is 4.0 ⁇ 1.5, preferably 4.0 ⁇ 1.0;
• the pH neutralizer is selected from one or more of the following groups that meet the above conditions: polybasic weak acid-base inorganic salt, nitrogen-containing weak base, polybasic weak acid-type inorganic salt, organic weak acid-base metal salts; and
• the concentration of the pH neutralizer is > 1%, preferably 1% to 35%.
• Example 7 Synergy study of the composition of the acid-base neutralizing combination of the present invention and its topical synergist
• the experimental animals were BALB/c mice, and the model cells were breast cancer 4T1 cells, and 1 ⁇ 10 6 cells per animal were subcutaneously transplanted into the right axilla of the animal for modeling.
• Successfully modeled experimental animals (average tumor volume 317 mm 3 ) were randomly divided into 2 negative control groups (01, 02) and 20 drug study groups (1-20).
• the negative control is normal saline, and the research drugs are shown in the table below.
• the medicines are all aqueous solutions, prepared according to the preparation method of Example 1. Negative controls and research drugs were injected intraperitoneally (groups 02, 11, and 15) and intratumorally (other research groups).
• Each group was administered once every 3 days, a total of 3 times, intratumor injection, the injection volume 150ul / only. Five days after the end of administration, the animals were euthanized, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group. The results are shown in the following table.
• the tumor inhibition rates of the composition study groups 11 and 15 were both lower than the conventional effective tumor inhibition standard (40%), and the tumor inhibition rates of the study group 11 and the negative control group (02 group) The difference in weight was not statistically significant (p>0.05).
• the tumor inhibition rate of study group 10 was more than 2 times higher than that of study group 11 (86%: 36%), and the tumor inhibition rate of study group 14 was more than 25 times higher than that of study group 14 (83%:3%).
• the same composition shows distinct targeting and pharmacology through completely different drug effects.
• the composition of the target area (local lesions) of the same administration composition may be completely different.
• compositions for intraperitoneal injection enters the bloodstream and then reaches the local lesion, and its administration composition is completely diluted or even digested by the blood (eg different retention of different compositions in certain organs).
• a composition for topical administration will have the same target composition (at least for a period of time) as it is administered.
• compositions administered in different ways should have different compositional characteristics to achieve synergistic efficacy.
• composition study group 12 is only 38% (33%:86%) of that of composition study group 10.
• the tumor inhibition rate of the composition study group 16 was only 27% of that of the composition study group 14 (22%:83%).
• neither composition study group 12 nor composition study group 16 showed a synergistic effect.
• composition group 10 had a q > 1.00, showing a clear synergistic effect.
• composition group 14 had a q > 1.00, showing a clear synergistic effect.
• compositions administered in different ways may require completely different components.
• Compositions for systemic administration usually require component ratios (they are intended to be diluted into the blood anyway), while topical compositions only give component ratios, obviously, other characteristics (such as concentration) must also be given. .
• composition group 18 had a q>1.00, showing a clear synergistic effect.
• composition group 14 had a q > 1.00, showing a clear synergistic effect.
• compositions of the present invention appear to exhibit significantly different pharmacology when administered locally than when administered systemically.
• its main pharmacology is not to distribute into the blood in the form of molecules to attack pathogens in the diseased tissue (such as tumor cells in the tumor), but to distribute into the interstitial space in the form of drug solution to attack the diseased tissue (such as the intratumoral tumor) at the site of administration. organize).
• composition of the acid-base neutralization combination and its local synergist is used as the necessary condition for the application technical scheme of the topical active ingredient in the preparation of the topical medicine for the treatment of local lesions:
• the composition of the pharmaceutical composition of the present invention must be such that it can be administered locally, and above a certain concentration threshold, the ratio of the components of the pharmaceutical composition to produce a synergistic effect.
• the concentration of the acidifying agent or alkalizing agent should be ⁇ its effective ablation concentration (for example, it can make the tumor-inhibiting concentration ⁇ 40% in the tumor-bearing mouse experiment) but ⁇ the synergistic pharmacodynamic concentration Threshold value (for example: the concentration of strong base or strong acid acidifying agent or alkalizing agent ⁇ 0.5%, the concentration of weak base or weak acid acidifying agent or alkalizing agent ⁇ 2.5%).
• the concentration of the acidifying agent or the alkalizing agent is as described above; the concentration of the pH neutralizing agent is such that it can be The concentration at which the synergistic effect of the acidifying agent or alkalizing agent is produced (specifically, the absolute difference between the pH of the single drug at the same concentration of the acidifying agent or alkalizing agent, which can make the pharmaceutical composition tend to be neutral and make it value ⁇ 0.25); the concentration of the topical synergist is such that it can synergize with the acidulant or alkalinizer and their respective pH neutralizers (eg, the topical synergist in 5% or more or 25% or more of the saturated solubility in the composition).
• compositions exhibiting synergistic efficacy were also determined to be buffer solutions with a buffer capacity of >0.01 mol ⁇ L ⁇ 1 ⁇ pH ⁇ 1 .
• synergistic combination of the acidifying agent with its pH neutralizer, or the alkalizing agent with its pH neutralizer appears to be the basis for the synergistic effect of the acid-base neutralizing combination/topical synergistic pharmaceutical composition of the present invention.
• Example 8 Further research on the synergistic technical scheme of the composition of the acid-base neutralization combination of the present invention and its topical synergist
• the experimental animals were BALB/c mice, and the model cells were breast cancer 4T1 cells, and 1 ⁇ 10 5 cells per animal were subcutaneously transplanted into the right armpit of the animal to model.
• Successfully modeled experimental animals (average tumor volume 336 mm 3 ) were divided into 1 negative control group (0) and 16 drug study groups (1-16).
• the negative control is normal saline, and the research drugs are shown in the table below.
• the medicines are all aqueous solutions, prepared according to the preparation method of Example 1. Each group was administered once every 3 days, a total of 3 times, intratumor injection, the injection volume 150ul / only. Five days after the end of administration, the animals were euthanized, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group. The results are shown in the following table.
• composition group 11 had a q>1.00, showing a clear synergistic effect.
• composition group 12 had a q > 1.00, showing a clear synergistic effect.
• composition group 13 had a q > 1.00, showing a clear synergistic effect.
• composition group 14 had a q>1.00, showing a clear synergistic effect.
• composition group 16 had a q > 1.00, showing a clear synergistic effect.
• Example 9 More anti-tumor applications of the pharmaceutical composition of the present invention
• the successfully modeled nude mice bearing human cancer cells were randomly divided into 1 negative control group and 6 study groups.
• the corresponding negative control is normal saline, and the 6 research drugs are: A (4% sodium bicarbonate/7% sodium carbonate), B (4% sodium bicarbonate/15% acetic acid), C (7% sodium carbonate) / 1% potassium hydroxide), D (15% arginine / 7% sodium bicarbonate / 3% sodium hydroxide), E (2% KCl / 1% NaOH / 20% arginine / 20% xylitol ), F (20% glycine/3% sodium bicarbonate/10% acetic acid).
• the medicines are all aqueous solutions, all prepared according to the preparation method of Example 1.
• All groups were injected intratumorally, once every 3 days, for a total of 3 times, each time 150 ⁇ l / only.
• the animals were euthanized on the 5th day after the end of administration, the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the respective negative control groups.
• HepG2 human hepatoma cell
• 6 study groups A, B, C, D, E, Group F.
• the tumor inhibition rates of groups A, B, C, D, E, and F were 73%, 71%, 76%, 92%, 95%, and 89%, respectively, all of which were in line with the generally considered effective antitumor standard (tumor inhibition rate). ⁇ 40%).
• CNE1 human nasopharyngeal carcinoma cells
• mice successfully modeled human gastric cancer cells (BGC823) nude mice (average tumor volume 314mm 3 ) were randomly divided into a negative control group and 6 study groups (A, B, C, D, E, Group F).
• the tumor inhibition rates of groups A, B, C, D, E, and F were 71%, 73%, 74%, 88%, 91%, and 93%, respectively, which were all in line with the generally considered effective antitumor standard (tumor inhibition rate). ⁇ 40%).
• Example 10 Further study of the composition of the acid-base neutralizing combination of the present invention and its topical synergist
• the experimental animals were divided into two series, A and B.
• a series of animals were nude mice without modeling, and were randomly divided into 4 groups.
• the drugs according to groups 1-4 in Table 11 were injected into the muscle mass of the right leg. Each group was administered once, and the injection volume was 100 ⁇ l per animal; The animals were euthanized on the 3rd day after the drug was administered, and the muscle mass specimens of the right leg of the nude mice were dissected out and subjected to gross pathological analysis.
• the area of tissue destruction (incomplete necrosis) area (T3d) and the The area of severely (completely necrotic) tissue damage (S 3d ) was shown in Table 11 below.
• the 8-month-old mouse model is used as the middle-aged and elderly patient model.
• the middle-aged and elderly patient models are inconsistent with the commonly used young patient models in terms of tumor formation, tumor tissue morphology, and body immunity.
• 1 ⁇ 10 6 mouse hepatoma Hepa1-6 cells/cell were injected subcutaneously into the right axilla to model the transplanted tumor.
• the average tumor volume of the successfully modeled mice was 136.6 mm 3 , and the model animals were randomly divided into 13 groups. Each group was administered once by intratumoral injection according to the drugs in Table 11, and the injection volume was 100 ⁇ l per animal; the tumor volume (V) was measured on the 3rd and 14th days after administration, and the negative control group was calculated according to the time.
• Tumor inhibition rate (r' 3d , r , 14d ) the results are shown in Table 11 below.
• the medicines used were all prepared according to the conventional aqueous solution preparation method or the preparation method in Example 1.
• the actual/expected ratio q 3d of short-term efficacy and the actual/expected ratio q 14d of mid-term efficacy were calculated respectively.
• the S 3d of groups 2 and 4 are 18.3 ⁇ 7.52 mm 2 and 0 mm 2 , respectively, indicating that the alkalizing agent has the maximum local action strength as expected, while the pH neutralization in the neutralization combination
• the agent desirably reduces the localized intensity of action of the alkalizing agent. It is generally believed that the area of necrosis should be positively correlated with the area of complete necrosis.
• the T 3d of groups 2 and 4 was just the opposite, being 29.6 ⁇ 8.31mm 2 and 47.6 ⁇ 15.32mm 2 , respectively, indicating that although the acid-base neutralization combination produced the antagonism of severe tissue damage, it could produce general tissue damage. Destructive synergy.
• the acid-base neutralizing composition of the present invention surpasses the acid-base acting drugs (eg high-concentration acid, high-concentration base) in the following aspects etc.) (referred to as prior art drugs) expectations:
• the characteristic pharmacology of the prior art drug is effective local action for tissues, preferably maximizing local action
• the characteristic pharmacology of the composition of the present invention is effective penetration between tissues, preferably maximizing penetration.
• the pharmacological composition of the prior art drug brings strong local irritation and acid (or alkali) excess risk
• the pharmacological composition of the composition of the present invention can greatly reduce the local Risk of irritation and acid (or base) overdose.
• the osmotic effect of the pharmacological composition of the composition of the present invention can produce a larger effective range of action.
• the efficacy and safety make the composition of the present invention more suitable for middle-aged and elderly patients at risk of local irritation and acid (or base) excess than prior art drugs.
• compositions of the present invention comprising acid-base neutralizing combinations and combinations thereof (compositions of the present invention) exceed those contemplated by the prior art comprising topical drugs (e.g. Anticipation of the composition of ethanol, high concentration acid, high concentration alkali, etc.) and their combination (referred to as prior art composition):
• topical drugs e.g. Anticipation of the composition of ethanol, high concentration acid, high concentration alkali, etc.
• the characteristic pharmacology of the prior art composition is at most local action synergy, and the characteristic pharmacology of the composition of the present invention is the synergistic effect including the effective penetration between the tissues of the acid-base neutralization combination;
• the synergistic effect including the effective inter-organization penetration effect of the acid-base neutralization combination can produce a medium-term therapeutic effect that exceeds the expectation of the prior art composition.
• compositions of the present invention prepared by the method of Example 1 (such as the synergistic composition in each embodiment), similar results can also be obtained in the application of each of the above tumor treatments.

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• 2021
  • 2021-09-30 JP JP2023519733A patent/JP2023543858A/ja active Pending
  • 2021-09-30 US US18/247,359 patent/US20230414617A1/en not_active Abandoned
  • 2021-09-30 EP EP21874572.7A patent/EP4223313A4/en not_active Withdrawn
  • 2021-09-30 WO PCT/CN2021/122041 patent/WO2022068918A1/zh not_active Ceased

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