CN108686216A - Include the medical composition and its use of chemical ablation agent and bioactive polysaccharide - Google Patents

Include the medical composition and its use of chemical ablation agent and bioactive polysaccharide Download PDF

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Publication number
CN108686216A
CN108686216A CN201710223913.3A CN201710223913A CN108686216A CN 108686216 A CN108686216 A CN 108686216A CN 201710223913 A CN201710223913 A CN 201710223913A CN 108686216 A CN108686216 A CN 108686216A
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China
Prior art keywords
pharmaceutical composition
polysaccharide
present
chemical ablation
concentration
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CN201710223913.3A
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Inventor
邹方霖
卢星
邹礼常
王建霞
王艺羲
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Chengdu Kuachang Science and Technology Co Ltd
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Chengdu Kuachang Science and Technology Co Ltd
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Priority to CN201710223913.3A priority Critical patent/CN108686216A/en
Publication of CN108686216A publication Critical patent/CN108686216A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Present invention relates to a kind of pharmaceutical compositions comprising chemical ablation agent and bioactive polysaccharide and the composition in the purposes for preparing the drug for preventing and treating mammal local patholoic change relevant disease.

Description

Include the medical composition and its use of chemical ablation agent and bioactive polysaccharide
Technical field
Present invention relates to a kind of pharmaceutical composition, the compositions comprising chemical ablation agent and bioactive polysaccharide to make For the purposes of the drug of prevention and treatment mammal local patholoic change relevant disease and included in local patholoic change, administration is somebody's turn to do in situ A kind of method of prevention and treatment mammal local patholoic change relevant disease of composition.
Background technology
It is scorching for mammal local patholoic change relevant disease, especially stubborn disease, such as malignant tumour, intractable The treatment of disease, intractable microorganism infection, refractory skin etc. still depends on such as surgical operation, chemotherapy And radiotherapy.
Classical chemotherapy be typically by provide for local patholoic change pathogen specificity effectively chemicals come into Row.Classical chemotherapeutics (such as cytotoxic drug) be mainly intravascular be transported to diseased region attack pathogen (such as disease Become cell), to generate pharmacy effect.By taking oncotherapy as an example, classical antitumor drug (such as 5 FU 5 fluorouracil) can lead to It crosses a variety of administering modes (being typically Formulations for systemic administration mode) attack tumour cell and generates drug effect.However, covert for local disease Related disorders, especially stubborn disease, the prior art of this treatment are considered that curative effect is very limited, systemic side effects are very big.
There is a kind of therapy referred to as chemical ablation in nineteen fifty-five.Researcher is Ethanol Injection to brain disease Become tissue to treat Parkinson's disease, and is called " chemical knife (chemical knife) ".Different from classical chemotherapeutic, chemistry disappears Melt agent usually acted in Formulations for systemic administration it is little, and being capable of useful effect when administration in local administration, especially in tissue.Chemistry Ablation agent is directly involved pathological tissues, so that the tissue necrosis is occurred, dependency structure therein is effectively destroyed, to be pressed down System even eliminates the effect of lesion.Current clinically common chemical ablation agent is mainly protein coagulation agent, and Typical Representative is Absolute ethyl alcohol.In addition, the also higher acetic acid of focal destructive, hydrochloric acid, sulfuric acid, sodium hydroxide etc..
Clinical Treatment Test shows that chemical ablation is successfully applied to eliminate several diseases of local-pathological-changed tissues Disease, such as tumour, tumour, tubercle, abnormal veins group (such as hemorrhoid etc.), local inflammation, microorganism infection are swelled, are blocked. By taking tumour as an example, the chemical ablation method of percutaneous intratumor injection absolute ethyl alcohol (or acetic acid) have positioning is accurate, wound is small, it is painful it is light, The advantages that curative for effect, has been successfully applied to the treatment of primary carcinoma of liver, adrenal tumor and lymphnode metastatic etc..
However, there is also significant limitations for existing chemical ablation therapy.First, above-mentioned chemical ablation agent is in tumor group It is limited to knit the section that effective concentration can reach under feature (anisotropism).Secondly, the tissue destructive of chemical ablation agent does not have How many specificity, making it difficult to the drug spilling avoided may damage normal structure or/and patient is caused to have an intense pain, from And make practical applicable ablation dosage limited.These defects of the prior art so that the effect of chemical ablation therapy has Limit.For example, absolute ethyl alcohol is still very low the effect of when being more than the liver tumour of 5cm for diameter, showing.
Invention content
According to an aspect of the present invention, a kind of medicine of prevention and treatment mammal local patholoic change relevant disease is provided Compositions, it includes pharmaceutically acceptable chemical ablation agent and bioactive polysaccharides, and it is formed so that working as the medicine group It closes after object is applied in the local patholoic change and is capable of providing Feng Nongdu >1% (w/v), preferably >=1.5% (w/v), more preferably >= The bioactive polysaccharide of the chemical ablation agent of 2% (w/v) and Cmax >=0.25% (w/v), preferably >=0.5% (w/v).
An embodiment according to the present invention, the peak for the chemical ablation agent that pharmaceutical composition according to the present invention is provided A concentration of 1.5-15% (w/v), preferably 2-10% (w/v) or 3-10% (w/v).
An embodiment according to the present invention, the bioactive polysaccharide that pharmaceutical composition according to the present invention is provided Cmax is 0.25-15% (w/v), preferably 0.5-10% (w/v), more preferably 1-6% (w/v) or 1-4% (w/v).
An embodiment according to the present invention, the bioactive polysaccharide and chemical ablation agent are in the pharmaceutical composition Weight ratio be 1:8-6:1, it is preferably 1:4-4:1, it is more preferably higher than 1:4- is less than 4:1 or be more than 1:4- is less than 2:1.
Pharmaceutical composition according to the present invention can be liquid dosage form, such as solution, suspension or emulsion;Can also be Solid or semisolid dosage form, such as implant, drug releasing stent, suppository, creme, cream or gelling agent.
In pharmaceutical composition according to the present invention, the chemical ablation agent is the aromatics with chemical ablation function Object preferably includes to be selected from following one kind or a variety of:Vital stain, salicylic acid compounds and quinine class compound.
In pharmaceutical composition according to the present invention, the vital stain is methylenum careuleum or its analog, and the live body It is &gt that content of the dyestuff in the pharmaceutical composition, which can make described pharmaceutical composition provide Cmax after application,;1% (w/v), It is preferred that the vital stain of 1.5-15% (w/v).
An embodiment according to the present invention, the peak for the vital stain that pharmaceutical composition according to the present invention is provided are dense Degree is 2-10% (w/v), preferably 2-6% (w/v), more preferably 3-6% (w/v).
In pharmaceutical composition according to the present invention, the salicylic acid compounds be salicylic acid, acetylsalicylic acid or its Analog, more preferably acetylsalicylic acid or its analog, and the salicylic acid compounds containing in the pharmaceutical composition It is &gt that amount, which can make described pharmaceutical composition provide Cmax after application,;The salicylic acid of 1% (w/v), preferably 3-15% (w/v) Compound.
An embodiment according to the present invention, the salicylic acid compounds that pharmaceutical composition according to the present invention is provided Cmax be 4-12% (w/v), preferably 6-10% (w/v).
In pharmaceutical composition according to the present invention, the quinine class compound be a quinin hydrochloride, quinine dihydrochloride or Its analog, and content of the quinine class compound in the pharmaceutical composition can make described pharmaceutical composition after application Offer Cmax is >The quinine class compound of 1% (w/v), preferably 3-15% (w/v).
An embodiment according to the present invention, the quinine class compound that pharmaceutical composition according to the present invention is provided Cmax is 4-10% (w/v), more preferably 4-8% (w/v).
In pharmaceutical composition according to the present invention, the bioactive polysaccharide includes that molecular weight is more than 5000, is preferably big In 10000 bio-extract and the like.
In pharmaceutical composition according to the present invention, the bioactive polysaccharide is to be carried selected from the biology having the following properties that Take object and the like:Uniform dispersion under room temperature in water is more than 5mg/ml, is preferably greater than 10mg/ml.
In pharmaceutical composition according to the present invention, the bioactive polysaccharide includes following bio-extract and its similar Object it is one or more:Algal polysaccharide sulfate, spirulina polysaccharide, seaweed selenium poly saccharide, panaxan, Codonopsis pilosula polysaccharide, yellow Stilbene are more Sugar, lentinan, mushroom selenium polysaccharide, pachymaran, grifola polysaccharide, ganoderma lucidum polysaccharide, coriolan.
According to an embodiment, pharmaceutical composition according to the present invention is also optionally including polyvalent metal compounds, The polyvalent metal compounds include following one kind or a variety of metal salts:Molysite, mantoquita, magnesium salts, zinc salt, manganese salt, aluminium salt And calcium salt, preferably molysite and mantoquita, wherein the molysite is preferably selected from following one kind or a variety of ferrous salts:Dichloride Iron, ferrous sulfate, ferrous succinate, ferrous fumarate, ferrous gluconate, ferrous lactate, iron sucrose.
According to an embodiment, pharmaceutical composition according to the present invention also optionally help by vaccine adjuvant, the vaccine Agent includes macromolecular adjuvant of the molecular weight more than 5000, particle adjuvant and combination thereof of the size more than 1nm, wherein described micro- Grain adjuvant includes with the one or more of the following group:Aluminum hydroxide particle, calcium phosphate particles, aluminum phosphate particle, aluminum sulfate particle, MF59,AS02,MPL,QS21,W805EC,ISA-51,ISA-720。
According to an embodiment, the also optionally one or more following substances of pharmaceutical composition according to the present invention: Excipient, analgesic, targeting agent, slow-released carrier, other bioactive ingredients, other medicines.
According to another aspect of the present invention, pharmaceutical composition according to the present invention is provided to prepare for preventing and controlling Treat the application in the drug of mammal local patholoic change relevant disease.
According to a further aspect of the invention, a kind of prevention and treatment mammal local patholoic change relevant disease is provided Method comprising pharmaceutical composition according to the present invention is administered in the tissue to the local patholoic change or where it.
Pharmaceutical composition according to the present invention shows significantly lower local irritation compared with classical chemical ablation agent With higher curative effect;Agent list medicine phases ratio is melted with new chemical, showing can use the chemical ablation agent of low concentration that can obtain Obtain unusual superelevation effective active;Compared with classical cytotoxic drug, more hypotoxicity, higher curative effect are shown.
Further, composition preparation according to the present invention is convenient, cost is cheap, is particularly helpful to make to be difficult to bear height The many people of volume expense also enjoys effective treatment.
The present invention is described in more detail below with reference to attached drawing.
Description of the drawings
Fig. 1 is provided using lotus liver cancer cells nude mice as the experimental result of model, shows 4 methylenum careuleum/spirulina polysaccharide group Tumour inhibiting rate (the Y of (A1, B1 group and A2, B2 group) and 4 methylenum careuleum/5 FU 5 fluorouracil group (C1, D1 group and C2, D2 group) (X-axis) Axis).
Fig. 2 is provided using lotus thyroid carcinoma cell nude mice as the experimental result of model, shows the group containing different chemical ablation agent 1 week tumour inhibiting rate (Y-axis) after conjunction object (X-axis) medication.
Fig. 3 is provided using lotus liver cancer cells nude mice as the experimental result of model, when showing different modes of administration, each seminar (X Axis) tumour inhibiting rate (Y-axis).
Fig. 4 is provided using lotus liver cancer cells nude mice as the experimental result of model, and display is fixed as 1% when panaxan's concentration When, the tumour inhibiting rate (Y-axis) with the composition of various concentration methylenum careuleum (X-axis).
Fig. 5 is provided using lotus liver cancer cells nude mice as the experimental result of model, is shown when methylenum careuleum concentration is fixed as 1%, The tumour inhibiting rate (Y-axis) of itself and the composition of various concentration active polysaccharide (X-axis).
Specific implementation mode
The present inventor through a large number of experiments, gropes and optimizes various experimental conditions, is prepared for one kind and is used for The pharmaceutical composition of local patholoic change relevant disease, especially stubborn disease in mammal is prevented and treated, it includes pharmacy Upper acceptable chemical ablation agent and active glycosides, and the active glycosides and chemical ablation agent are included in the same Topical dosage forms In.
According to an aspect of the present invention, it provides a kind of for preventing and treating mammal local patholoic change relevant disease Pharmaceutical composition, it includes pharmaceutically acceptable chemical ablation agent and bioactive polysaccharides, and its form so that work as the medicine Compositions are capable of providing Feng Nongdu &gt after being applied in the local patholoic change;1% (w/v), preferably >=1.5% (w/v), more preferably The chemical ablation agent of >=2% (w/v) and Cmax >=0.25% (w/v), the bioactivity of preferably >=0.5% (w/v) are more Sugar.
An embodiment according to the present invention, the peak for the chemical ablation agent that pharmaceutical composition according to the present invention is provided A concentration of 1.5-15% (w/v), preferably 2-10% (w/v) or 3-10% (w/v).
An embodiment according to the present invention, the peak for the active polysaccharide that pharmaceutical composition according to the present invention is provided are dense Degree is 0.25-15% (w/v), preferably 0.5-10% (w/v), more preferably 1-6% (w/v) or 1-4% (w/v).
An embodiment according to the present invention, the bioactive polysaccharide and chemical ablation agent are in the pharmaceutical composition Weight ratio be 1:8-6:1, it is preferably 1:4-4:1, it is more preferably higher than 1:4- is less than 4:1 or be more than 1:4- is less than 2:1.
An embodiment according to the present invention, the chemical ablation agent and active polysaccharide are included in the same local administration In dosage form.
Within the scope of this invention, term " composition " refers to the product for including each specified ingredients comprising specified amount, with And any product (such as compound, compound) directly or indirectly generated from the combination of each specified ingredients of specified amount.According to The present invention, " composition " and " pharmaceutical composition " may be used interchangeably.The composition of the present invention, in the following description It is abbreviated as 2/ component 3 of 1/ component 2 of component or 1/ component of component.
In the present invention, weight/volume percent concentration is indicated with % (v/w), volume/volume hundred is indicated with % (v/v) Divide specific concentration.The concentration of each component in composition, can also be preced with before component.Such as the algal polysaccharide of 4% methylenum careuleum/2% Sulfuric ester refers to a composition of methylenum careuleum and arasaponin, wherein a concentration of 4% (w/v) of methylenum careuleum, algal polysaccharide A concentration of 2% (w/v) of sulfuric ester.The shorthand way of other multi-component combinations and so on.
Within the scope of this invention, term " local administration " refers to main (such as injection, implantation, filling by external source in the way of Note, spray, instill, being inserted into or other modes) deliver the medicament to close or adjacent local patholoic change, neighbouring with local patholoic change position Or direct neighbor, on local patholoic change periphery or contact with local patholoic change or local patholoic change inside body part.Term " office Portion's form of administration " refer to can local administration dosage form.
Within the scope of this invention, term " chemical ablation " refers to by local organization caused by local administration chemical substance Or local lesion necrosis, to so that local patholoic change is suppressed, cut down even disappearance the phenomenon that.Term " chemical ablation agent " refers to It can show that the chemical substance of chemical ablation function, this substance are often shown in Formulations for systemic administration same dose when local administration Much lower, even substantially invalid activity is shown.
One preferred embodiment of pharmaceutical composition according to the present invention, the chemical ablation agent and active polysaccharide include Within the organization in form of administration.Within the scope of this invention, term " tissue in administration " refer to it is main in the way of external source (such as Injection, implantation, perfusion, insertion or other modes) deliver the medicament to tissue in local-pathological-changed tissues or where local patholoic change Interior, term " form of administration in tissue " refers to the dosage form that can organize interior administration.
Form of administration in one preferred embodiment of the pharmaceutical composition of the present invention, the Topical dosage forms or tissue It (such as is injected for solid dosage forms (such as solid phase implant), semisolid dosage form (such as semi-solid phase implant) or liquid dosage form Agent).
Within the scope of the invention, term " Cmax " refers to that drug enters activearm after diseased region or its external model Divide in the maximum concentration in entire lifetime in liquid phase medium.Therefore, Cmax can also be considered medicament and be delivered to animal Active component is in action intensity sometime after target site.Although the specific mechanism of action waits further to study, according to The embodiment of the present invention, the active component in composition of the invention is by exogenous in local patholoic change area (such as knurl) Or/and endogenous liquid medium is transported and at least in a moment, its action intensity (Cmax) must be critical more than one Value can form the attack realized needed for the object of the invention to lesion in this way.The present invention provides the regulation present invention's accordingly The technical solution of the composition of composition.
Classified with the physical aspect of medicament, the dosage form of composition of the invention includes liquid dosage form, solid dosage forms, semisolid Dosage form.
In one embodiment of the invention, composition of the invention is liquid dosage form, such as solution dosage or suspension Liquor type can enter medicine-feeding part (such as in tumor) for example, by injection needle, then be pushed into composition medicine liquid Target area is administered.Thus, the Cmax of the active component (chemical ablation agent and active polysaccharide etc.) can be gone out with it positioned at needle tubing Concentration at mouthful, that is, its composition concentration (or administration concentration) in the composition liquid indicates at this time.
When the composition of the present invention is liquid dosage form, wherein composition of the chemical ablation agent in the composition liquid Nong Du >Composition concentration in the composition liquid of 1% (w/v), preferably >=2% (w/v) and the active polysaccharide >= 0.25% (w/v), preferably >=0.50% (w/v).
An embodiment according to the present invention, described pharmaceutical composition is liquid dosage form, wherein the chemical ablation agent Concentration can be 1.5-15% (w/v), preferably 2-10% (w/v) or 3-10% (w/v), and the concentration of the active polysaccharide Can be 0.25-15% (w/v), preferably 0.5-10% (w/v), more preferably 1-6% (w/v) or 1-4% (w/v).
In some embodiments of the invention, composition of the invention is solid dosage forms or semisolid dosage form, such as plants people Agent, drug releasing stent, suppository, creme and gelling agent etc..
The solid dosage forms of the present composition can be prepared by knowledge well known in the art.For example, by active component Dry powder (chemical ablation agent and active glycosides etc.) mixes with appropriate solid excipients (such as gelatinizing agent, tackifier, bulking agent etc.) It is even, discharge, enter mould, molding (such as 90 DEG C, thermoforming in 12 hours), depanning, cooling, can prepare be suitable for being conventionally implanted into rifle implantation Solid dosage forms.It, can be into the position body fluid after the composition solid enters medicine-feeding part (such as in tumor) by implantation gun barrel Discharge active component.
The semisolid dosage form (such as situ-gel dosage form) of the present composition can pass through knowledge well known in the art It prepares.For example, appropriate Cheng Jiaoji &#91 is added in agent containing chemical ablation and the liquid of active glycosides etc.;Such as poloxamer (P407/ P188)], temperature sensitive type in-situ gel can be made.After composition liquid enters medicine-feeding part (such as in tumor) by injection needle, Pharmaceutical liquid is pushed into medicine-feeding part and forms gel.Gel can discharge active component into the position body fluid.
When the composition of the present invention is solid dosage forms or semisolid dosage form, active component (chemical ablation agent and work therein Property polysaccharide etc.) release be the liquid medium (such as body fluid) that is contacted by it to carry out.Therefore, the peak of active component is dense Degree can dissolve out concentration to indicate with its peak.Within the scope of the invention, term " peak dissolution concentration " refers to that the dosage form medicament is set The active component dissolves out concentration from the highest of the dosage form medicament when being put in liquid phase medium;Term " dissolution concentration " refers to the agent Type medicament when being placed in liquid phase medium the active component dissolve out the local concentration to be formed, calculation formula is:
Dissolve out concentration=(Ws/Vs) × 100%
In formula, Ws is the weight that the active component is dissolved out from the dosage form medicament, and Vs dissolves out Ws institutes for the active component Liquid medium volume extremely.
The composition of the present invention is mainly by the local patholoic change in liquid medium contact to generate drug effect.It reaches To the purpose of the present invention, composition solid dosage form of the invention or semisolid dosage form also require that active component at least in a wink Between action intensity (Cmax) in local patholoic change area (such as knurl) be more than a critical value.In fact, from liquid is used The active component concentration condition that the embodiment of dosage form is obtained can also be the active component concentration condition of other dosage forms.
In addition, when pharmaceutical composition according to the present invention is solid dosage forms or semisolid dosage form, the chemical ablation agent With the content of active glycosides should be able to make in the pharmaceutical composition of the application solid or semisolid dosage form above-mentioned three kinds of activity at The peak dissolution concentration divided meets claimed below:>The chemical ablation agent of 1% (w/v), preferably >=2% (w/v), and >=0.25% (w/v), preferred >=0.50% active polysaccharide of (w/v).
An embodiment according to the present invention is solid dosage forms or semisolid agent in pharmaceutical composition according to the present invention When type, the peak for the chemical ablation agent that pharmaceutical composition according to the present invention is provided dissolves out a concentration of 1.5-15% (w/v), preferably For 2-10% (w/v), more preferably 3-10% (w/v).
An embodiment according to the present invention is solid dosage forms or semisolid agent in pharmaceutical composition according to the present invention When type, the peak for the active polysaccharide that pharmaceutical composition according to the present invention is provided dissolves out a concentration of 0.3-15% (w/v), preferably 0.5-10% (w/v), more preferably 1-6% (w/v) or 1-4% (w/v).
To realize above-mentioned requirements, for example, in pharmaceutical composition according to the present invention is solid dosage forms or semisolid dosage form, The composition content of composition content >=5% (w/v) of the chemical ablation agent, preferably >=10% (w/v) and the active polysaccharide >=2% (w/v), preferably >=4% (w/v), they and appropriate excipient may make the dissolution Cmax of active component to meet together The requirement of the technical solution of the present composition.
Pharmaceutical composition according to the present invention, the chemical ablation agent are preferably selected from the fragrance with chemical ablation function Compound.Within the scope of this invention, term " aromatic compound " refers to the compound containing phenyl ring or heterocycle in chemical constitution.
Pharmaceutical composition according to the present invention, the aromatic compound include with one of the following group kind or it is a variety of:Vital stain, Salicylic acid compounds, quinine class compound.
Within the scope of this invention, term " vital stain " refer to enter animal live soma after can make tissue, cell, It is contaminated in the structures such as subcellular unit but to animal entirety and without the aromatic compound dyestuff of unacceptable harmfulness.The work Body dyestuff can be known to the skilled in the art any appropriate person, for example, may include following one kind or a variety of dyestuffs and Its derivative:Methylenum careuleum (including its hydrate), patent blue, isosulfan blue, toluidine blue, trypan blue, alkali blue, Yihong, alkalinity Magenta, crystal violet, gentian violet, dimethyl diaminophenazine chloride, janus green B, sarranine, cyanine dye etc..
In pharmaceutical composition according to the present invention, the content of the vital stain can make to be applied when the pharmaceutical composition It is &gt that Cmax is capable of providing after the local patholoic change;The vital stain of 1% (w/v), preferably >=2% (w/v).At one In embodiment, the Cmax of the vital stain is 1.5-15% (w/v), preferably 2-10% (w/v), more preferably 2- 6% (w/v) or 3-6% (w/v).
In one embodiment, pharmaceutical composition according to the present invention is the Topical dosage forms of liquid form, wherein The Nong Duwei &gt of the vital stain;1% (w/v), preferably >=2% (w/v).In one embodiment, the vital stain exists A concentration of 1.5-15% (w/v), preferably 2-10%w/v (w/v), more preferably 2- in the Topical dosage forms of liquid form 6% (w/v) or 3-6% (w/v).
In pharmaceutical composition according to the present invention, the vital stain is preferably selected from alkaline vital stain.In this hair In bright range, term " alkaline vital stain " refers to positively charged vital stain after dissociation.The alkalinity vital stain can be with Be known to the skilled in the art any appropriate person, for example, can be include following one kind or a variety of organic dyestuff and its Derivative:Methylenum careuleum, patent blue, isosulfan blue, toluidine blue, trypan blue, alkali blue, gallocyanine etc..
Pharmaceutical composition according to the present invention, the vital stain are preferably selected from methylenum careuleum and the like.In this hair In bright range, for term " analog " though referring to differing structure or/and in nature similar substance, these substances can be with It is natural products, derivative, semisynthetic or synthetic.Methylenum careuleum analog includes the methylene for for example having chemical ablation function Blue derivative.Methylene blue derivatives include for example design or synthesize using methylenum careuleum as primer phenothiazine compound (such as New methylene blue, 1,9-Dimethylmethylene Blue, 1- methyl methylenum careuleum etc.).
Pharmaceutical composition according to the present invention, the aromatic compound include salicylic acid compounds.
Within the scope of this invention, term " salicylic acid " refers to the compound of the entitled 2 hydroxybenzoic acid of chemistry, term " water Poplar acid compounds " refer to salicylic acid and its derivative with chemical ablation function.Salicylic acid compounds can be ability Any appropriate person known to field technique personnel, such as can be following one kind or a variety of:Salicylic acid, acetylsalicylic acid (Aspirin, aspirin), diflunisal, aminosalicylic acid, PAS, N- phenylanthranilic acids, water Poplar anilide, O-ethoxyl amide, phenyl salicylate, gaultherolin, methyl p-hydroxybenzoate, P-hydroxybenzoic acid second Ester, sasapyrin, bicoumarin are preferably selected from following one kind or a variety of:Salicylic acid, acetylsalicylic acid, difluorobenzene water Poplar acid, aminosalicylic acid, salicylanilide, ethyl-para-hydroxybenzoate, sasapyrin.
In pharmaceutical composition according to the present invention, the content of the salicylic acid compounds can make to work as the pharmaceutical composition Object is capable of providing Cmax as &gt after being applied in the local patholoic change;The salicylic acid of 1% (w/v), preferably >=2% (w/v) Close object.In one embodiment, the Cmax of the salicylic acid compounds is 3-15% (w/v), preferably 4-12% (w/ V), it is more preferably 6-10%'s (w/v).
In one embodiment, pharmaceutical composition according to the present invention is the Topical dosage forms of liquid form, wherein The Nong Duwei &gt of the salicylic acid compounds;1% (w/v), preferably >=2% (w/v).In one embodiment, the bigcatkin willow Concentration of the acid compounds in the Topical dosage forms of liquid form can be 3-15% (w/v), preferably 4-12% (w/ V), it is more preferably 6-10% (w/v).
Pharmaceutical composition according to the present invention, the salicylic acid compounds are preferably selected from salicylic acid, acetylsalicylic acid And the like, more preferably it is selected from acetylsalicylic acid and the like.Wherein, acetyl salicylic acid-like substance includes such as having Learn the acetyl-salicylic derivate of ablation functionality, including such as its single derivative (such as low-density lipoprotein, hydrogen sulfide Aspirin etc.), (such as low-density lipoprotein and hydrogen sulfide aspirin are formed the derivative that is formed of two kinds of derivatives Nitric oxide hydrogen sulfide (NOSH) aspirin), etc..
Pharmaceutical composition according to the present invention, the aromatic compound include quinine class compound.
Within the scope of this invention, term " quinine class compound " includes quinine, its isomers and derivative, derivative Include acid-addition salts including pharmaceutically acceptable salt, such as inorganic acid addition salt and organic acid addition salt.Inorganic acid addition salt Example include but not limited to:Halogen acid salt (such as hydrochloride, such as quinin hydrochloride), hydrobromate, hydriodate, dihydrochloride (such as quinine dihydrochloride), dihydrobromide, two hydriodates), disulfate, sulfate, phosphate etc..Organic acid addition salt Example include but not limited to:Bicarbonate or carbonate, ethyl carbonate salt, formates, acetate, Chinese holly edge hydrochlorate or tannic acid Salt.
In pharmaceutical composition according to the present invention, the content of the quinine class compound can make to work as the pharmaceutical composition Cmax is capable of providing as &gt after being applied in the local patholoic change;The quinine class compound of 1% (w/v), preferably >=2% (w/v). In one embodiment, the Cmax of the quinine class compound is 3-15%w/v, preferably 4-10%w/v, is more preferably 4-8%.
In one embodiment, pharmaceutical composition according to the present invention is the Topical dosage forms of liquid form, wherein The Nong Duwei &gt of the quinine class compound;1% (w/v), preferably >=2% (w/v).In one embodiment, the salicylic acid Concentration of the class compound in the Topical dosage forms of liquid form can be 3-15% (w/v), preferably 4-10% (w/v), More preferably 4-8% (w/v).
Pharmaceutical composition according to the present invention, the quinine class compound are preferably selected from quinine, a quinin hydrochloride and two Quinin hydrochloride is more preferably selected from quinine dihydrochloride and the like.Quinine dihydrochloride analog includes for example having chemical ablation The quinine dihydrochloride derivative of function, including such as the polymer of quinine dihydrochloride, complex compound.
Within the scope of this invention, term " bioactive polysaccharide (also abbreviation active polysaccharide in the present invention) " refers to having Bio-extract polysaccharide of pharmaceutical active and the like, term " activity " refers to can for the local patholoic change relevant disease Generate the pharmacological property of therapeutic effect, term " bio-extract " refer to using biomaterial as raw material, by separation process and The specific components that other process obtain, term " biology " include animal, plant, microorganism etc., term " polysaccharide " refer to by The polymer that 10 or more monosaccharide is formed by glucosides key connection.
Within the scope of this invention, term " bio-extract polysaccharide analogs " though refer to and bio-extract polysaccharide non-phase Same but structure or/and in nature similar natural products, derivative, semisynthetic or synthetic.For example, polysaccharide derivates are protected The required biological activity of corresponding natural polysaccharide has been stayed, but has been had again relative to natural polysaccharide active certain needed for enhancing Biochemical modification, including such as introduce functional group (such as sulfated polysaccharides), metal-chelating, processing polyoses extract.
It is reported that bioactive polysaccharide only has in biological polyoses less than 2%.Generally, it is considered that the activity of active polysaccharide is wide General but for disease specific activity specific is not high.For example, it is different from the anticancer drugs such as 5 FU 5 fluorouracil, cyclophosphamide, it is living Property polysaccharide is not considered the active drug for tumour cell clinically.Actually, polysaccharide medicine " belongs to non-specific to control Treat " (Sun Yushu, with one's all strength husband, Su Xiulan, polysaccharide and polyose medicament research overview;J]Medical Colleges of the Inner Mongol's journal, 2006,28 (1):75-78), health products are normally used as or immunomodulator uses.
In pharmaceutical composition according to the present invention, the active polysaccharide can be known to the skilled in the art arbitrarily Appropriate ones, such as can be selected from alga-derived, plant origin, animal origin, microbe-derived active polysaccharide.
In pharmaceutical composition according to the present invention, the active polysaccharide includes alga-derived active polysaccharide and its similar Object (abbreviation algae active polysaccharide in the present invention).The algae active polysaccharide can be known to the skilled in the art arbitrary conjunction Suitable person, such as it includes following one kind or a variety of and the like that can be:It is Juniperus formosana polysaccharides, laver amylose, laminarin, brown Polysaccharides, algal polysaccharide sulfate, ulvan, sea grass polysaccharide, sea lettuce polysaccharide, spirulina polysaccharide, purple ball polysaccharides, chlorella Polysaccharide, haematococcus polysaccharide, Phaeodactylum tricornutum, Isochrysis galbana polysaccharide, etc., be preferably selected from one or more of:Brown alga is more Sugar sulfate, spirulina polysaccharide, seaweed selenium poly saccharide.
In pharmaceutical composition according to the present invention, the active polysaccharide includes the active polysaccharide of plant origin and its similar Object (abbreviation active polysaccharides from plants in the present invention).The active polysaccharides from plants can be known to the skilled in the art arbitrary conjunction Suitable person, such as it includes following one kind or a variety of and the like that can be:Panaxan, Codonopsis pilosula polysaccharide, yellow Stilbene polysaccharide, red stilbene Polysaccharide, Siberian solomonseal rhizome polysaccharide, Lycium barbarum polysaccharides, Banlangen Polysaccharide, fern amylose, Dendrobium officinale polysaccharide, gastrodia elata polysaccharide, curcuma zedoary polysaccharide, Radix Angelicae Sinensis polysaccharide, licorice polysaccharide, Fructus Schisandrae Polysaccharide, purple sweet potato polysaccharide, soybean polyoses, aloe polysaccharide, gynostemma pentaphylla polysaccharide, outside ginkgo Kind skin polysaccharide, artist's conk polysaccharide etc., are preferably selected from the active polysaccharide and the like extracted in medicinal plant, wherein described medicinal The active polysaccharide extracted in plant includes such as one or more of:Panaxan, yellow Stilbene polysaccharide, hedysarum polybotys saccharide.
In pharmaceutical composition according to the present invention, the active polysaccharide includes the active polysaccharide of originated from fungus and its similar Object (abbreviation fungi activity polysaccharide in the present invention).The fungi activity polysaccharide can be known to the skilled in the art arbitrary conjunction Suitable person, such as it includes following one kind or a variety of and the like that can be:Lentinan, flammulina velutipes, pholiota nameko polysaccharide, Pachymaran, grifola polysaccharide, Phellinus polysaccharide, grifolan, ganoderma lucidum polysaccharide, purple sesame polysaccharide, coriolan, cordyceps sinensis are more Sugar, tremella polysaccharides etc. are preferably selected from the active polysaccharide and the like extracted in medicinal fungi, wherein in the medicinal fungi The active polysaccharide of extraction includes such as one or more of:Lentinan, pachymaran, grifola polysaccharide, ganoderma lucidum polysaccharide, rainbow conk Polysaccharide.
In pharmaceutical composition according to the present invention, the active polysaccharide be preferably selected from molecular weight more than 5000, it is more excellent High molecular reactive polysaccharide of the choosing more than 10000.
In pharmaceutical composition according to the present invention, the active polysaccharide, which is preferably selected from, contains following one kind or a variety of The active polysaccharide of group:Sulfonic group, carboxy methylation, acetyl group are more preferably selected from and contain sulfonic high molecular reactive polysaccharide.
Pharmaceutical composition according to the present invention, the active polysaccharide are preferably selected from the active polysaccharide having the following properties that: Uniform dispersion under room temperature in water is more than 5mg/ml, is preferably greater than 10mg/ml.Within the scope of this invention, term is " equal Even dispersion " refers to following a kind of or various ways dispersion:Lysate, suspension, suspension.
Pharmaceutical composition according to the present invention is also optionally including one or more following substances:Excipient, analgesic And synergist.
The excipient can be known to the skilled in the art any appropriate person, may include such as following one kind Or it is a variety of:Decentralized medium, preservative, stabilizer, wetting agent and/or emulsifier, solubilizer, tackifier, for adjusting osmotic pressure Salt and buffer.The tackifier are, for example, that sodium carboxymethylcellulose, carboxymethyl cellulose, glucan, polyethylene adjoin and cough up alkane Ketone or gelatin.The preservative is such as antioxidant example (such as ascorbic acid) or microbicide (such as sorbic acid or benzene first Acid).
The analgesic can be known to the skilled in the art any appropriate to mitigate the feeling of pain of patient Person, such as benzyl alcohol, procaine hydrochloride, anesin, hydrochloric acid benefit card etc..
The synergist can be such as following one kind or more to enhance the drug effect of pharmaceutical composition of the present invention Kind:Polyvalent metal compounds, targeting agent, slow-released carrier, other bioactive ingredients, vaccine adjuvant and other medicines.
Pharmaceutical composition according to the present invention can optionally include also further polyvalent metal compounds.The polyvalent metal Any appropriate person can be known to the skilled in the art by closing object, such as can be in iron, copper, magnesium, zinc, manganese, aluminium and calcium One or more metals compound.
The polyvalent metal compounds include following one kind or a variety of metal salts:Molysite, mantoquita, magnesium salts, zinc salt, manganese Salt, aluminium salt and calcium salt, preferably molysite and mantoquita.For molysite comprising iron (III) ion salt and ferrous iron (II) Ion salt is collectively referred to as molysite.Molysite includes any pharmaceutically acceptable molysite, can be iron ion or ferrous ion The salt formed with above-mentioned inorganic acid or organic acid.For example, ferrous ion salt include ferrous chloride, ferrous sulfate, ferrous succinate, Ferrous fumarate, ferrous gluconate, ferrous lactate, iron sucrose etc..Iron (III) ion salt includes such as Ferric Ammonium Citrate, the right side The sugared acid anhydride iron of rotation, iron protein succinylate.In pharmaceutical composition according to the present invention, the metallic compound is preferably ferrous ion Salt is more preferably selected from following one kind or a variety of ferrous salts:Ferrous chloride, ferrous sulfate, ferrous succinate, fumaric acid are sub- Iron, ferrous gluconate, ferrous lactate, iron sucrose.The polyvalent metal compounds further include metallo-organic compound, such as are turned Ferritin, iron content ferroheme, iron-amino acid complex etc..
Pharmaceutical composition according to the present invention can optionally include also further targeting agent.Within the scope of this invention, " target To agent " refer to the substance that can specifically bind the medicine target in local patholoic change, wherein claiming when specifically binding substance and being compound Make target compound, the referred to as targeting antibodies when specifically binding substance and being antibody.Targeting in the pharmaceutical composition of the present invention Agent includes target compound.Target compound can be known to the skilled in the art any appropriate person, such as preferably select From the one or more of following compound and its derivative:Folic acid, hyaluronic acid, transferrins.
Pharmaceutical composition according to the present invention can optionally include also further slow-released carrier.The slow-released carrier can be this Any appropriate person known to field technology personnel, including such as gel-type vehicle, particulate carrier, micella matrix.
Within the scope of the invention, term " particulate carrier " refer to can be with drug interaction (physically trapping, chemical bond Conjunction, electrostatic interaction etc.) particle, term " particle " refer to it is all can be entered with topical modes body part (such as Pathological tissues) Inner fine particle, size is between 1nm-100 μm.Particulate carrier includes organic material by host material classification Expect carrier, Inorganic material carrier and combination thereof, classify by particle size include nano-carrier (size 1-1000nm it Between), micron vectors (size is between 1-100 μm) and combination thereof.
Organic material carrier can be known to the skilled in the art any appropriate person, for example, including following one kind or It is a variety of:Polymer matrix particle, liposome particle, nano-micelle matrix, water oil microballoon etc., wherein the polymer matrix is preferred For the particulate carrier selected from following macromolecule and its one or more preparations of derivative:Polylactic acid, polyaminoacid, poly- hydroxyl fourth Acid esters, glycolide-lactide copolymer, polyalkylcyanoacrylate, polyamide, polyvinyl alcohol, polyacrylic resin, chitosan Deng.
Inorganic material carrier can be known to the skilled in the art any appropriate person, for example, including following one kind or It is a variety of:Silicon materials carrier, iron compound carrier and carbon material carrier.Carbon material carrier be preferably selected from in the following group one kind or A variety of microns of carbon particles, nanometer carbon nanobeads, carbon nanotube, fullerene, Nano diamond, nanometer carbon dots and its derivative.
Pharmaceutical composition according to the present invention also optionally include it is pharmaceutically acceptable except the bioactive polysaccharide with for Other biological activity ingredient.Within the scope of this invention, term " other bioactive ingredients " refer to bioactive polysaccharide it Bio-extract and the like outer, with pharmaceutical active.For example, brown alga extract include pheophytin (fucoxanthine), Brown alga sulfated polysaccharide, algal polysaccharide sulfate, fucoidin etc..
Pharmaceutical composition according to the present invention, the other biological activity ingredient be preferably selected from following one kind or Bio-extract of various structures and the like:Glycosides, polyphenol, terpene, flavones and alkaloid.
Pharmaceutical composition according to the present invention, the other biological activity ingredient are preferably selected from the work having the following properties that Property ingredient:Uniform dispersion under room temperature in water is more than 5mg/ml, is preferably greater than 10mg/ml.Within the scope of this invention, Term " evenly dispersed " refers to following a kind of or various ways dispersion:Lysate, suspension, suspension.
In pharmaceutical composition according to the present invention, the other biological activity ingredient can be for example selected from molecular weight More than 5000, preferably greater than 10000 macromolecule biological activity ingredient.
In pharmaceutical composition according to the present invention, the other biological activity ingredient can be for example with following one The bioactive ingredients of kind or a variety of groups:Sulfonic group, carboxy methylation, acetyl group, it is however preferred to have sulfonic bioactivity Ingredient.
Pharmaceutical composition according to the present invention, the other biological activity ingredient include active glycosides.In the scope of the present invention In, term " polysaccharide " refers to the polymer formed by glucosides key connection by 10 or more monosaccharide.
Within the scope of this invention, term " glycosides " refer to sugar and sugared derivative such as amino sugar, uronic acid etc. with it is another non- The compound that sugar substance is linked by the terminal carbon of sugar.The activity glycosides can be known to the skilled in the art Any appropriate person, such as it includes following one kind or a variety of and the like that can be:Ginsenoside, arasaponin, gleditsia sinensis Glycosides, giant knotweed saponin(e, sea cucumber total saposins etc..
Pharmaceutical composition according to the present invention, the other biological activity ingredient includes active polyphenol.
Within the scope of this invention, term " polyphenol " refers to the compound for having multiple hydroxyl phenol groups, including such as class Flavones, Hydrolysable Tannins, procyanidine etc..The active polyphenol can be known to the skilled in the art any appropriate person, example It includes following one kind or a variety of and the like that such as can be:Tea polyphenols, resveratrol, apple polyphenol etc..
Pharmaceutical composition according to the present invention, the other biological activity ingredient include active terpene.
Within the scope of this invention, term " terpene " refers to being derived by mevalonic acid, basic carbon skeleton have 2 or The compound of 2 or more isoprene unit structure features.The activity terpene can be known to the skilled in the art arbitrarily Appropriate ones, such as it includes following one kind or a variety of and the like that can be:Qinghaosu, Britanin, sequiterpene Alkene lactone etc..
Pharmaceutical composition according to the present invention, the other biological activity ingredient include active flavones.
Within the scope of this invention, term " flavones " refers to that two phenyl ring (A- and B- rings) are mutually interconnected by central three carbochains Compound made of knot.The activity flavones can be known to the skilled in the art any appropriate person, such as can be packet Include following one kind or a variety of and the like:Puerarin, cyanidenon, silibinin, Chrysin, genistein, river dried orange peel Element, glycyrrhiza total flavonoid etc..
Pharmaceutical composition according to the present invention, the other biological activity ingredient includes active alkaloid.
Within the scope of this invention, term " alkaloid " refers to the organic compounds containing nitrogen from living nature.The work Property alkaloid can be known to the skilled in the art any appropriate person, for example, can be include following one kind or it is a variety of and Its analog:Camptothecin alkaloid, matrine alkaloid, Vinca alkaloids, amaryllidaceae alkaloid, berbine life Alkaloids etc..
Pharmaceutical composition according to the present invention, the other biological activity ingredient include two or more different structure The active constituent of classification preferably includes active polysaccharide and one or more following active constituents:Active glycosides, active polyphenol, work Property terpene, active flavones, active alkaloid.
Pharmaceutical composition according to the present invention is also optionally including pharmaceutically acceptable vaccine adjuvant.In the present invention Range in, term " vaccine adjuvant " (also abbreviation adjuvant) refer to can enhance after being mixed with target antigen body be directed to target antigen Immune response ability or change immune response type substance.According to this definition, vaccine adjuvant is exempted from on ordinary meaning Epidemic disease reinforcing agent is different, and the latter is worked and need not often be mixed with target antigen.
Pharmaceutical composition according to the present invention, the vaccine adjuvant can be known to the skilled in the art any appropriate Person, for example, can be include classified below with Adjuvanting material it is one or more:Inorganic adjuvant, synthetic adjuvant, oil/breast assistant Agent, biologic adjuvants can also be particle adjuvant or/and molecule adjuvant including being classified with adjuvant size.
Within the scope of this invention, term " inorganic adjuvant " refers to the adjuvant (such as mineral salt) based on inorganic matter;Art Language " synthetic adjuvant " refers to the adjuvant (such as double stranded polynucleotide) based on synthetic;Term " oil/newborn adjuvant " refers to being based on The adjuvant (such as not formula adjuvant, MF59) of oil or/and emulsion;Term " biologic adjuvants " refers to the adjuvant based on biological source (such as microorganism, bacterium, virus, their adjuvant component (DNA, protein, polypeptide fragments etc.) and the like);Term " particle adjuvant " refers to the adjuvant (such as liposome particle adjuvant) of particulate form;Term " molecule adjuvant " refer to particulate form with Adjuvant (such as the non-methylated cytosine guanine dinucleotides-deoxy-oligonucleotide of TLR9 agonists of outer molecular forms (CpG ODN))。
In pharmaceutical composition according to the present invention, the vaccine adjuvant is preferably selected from big point of molecular weight more than 5000 Sub- adjuvant, size are more than the particle adjuvant and combination thereof of 1nm.
In pharmaceutical composition according to the present invention, the particle adjuvant includes adjuvant particle and adjuvated particle.
Within the scope of this invention, term " particle " refer to it is all can be entered with topical modes body part (such as Pathological tissues) Inner fine particle, size is between 1nm-100 μm;Term " adjuvant particle " has referred to the object of adjuvant effect Matter itself has a kind of particle adjuvant of particulate form;Term " adjuvated particle " has referred to the main matter of adjuvant effect itself Without particulate form but it is fixed on a kind of particle adjuvant on particulate carrier.
Pharmaceutical composition according to the present invention, the adjuvant particle includes with the one or more of the following group:Adjuvant solid is micro- Grain, adjuvant semisolid particle, adjuvant lipid particles.
In pharmaceutical composition according to the present invention, the adjuvant solia particle can be include that for example inorganic adjuvant is micro- Grain, wherein the inorganic adjuvant particle can include for example with the one or more of the following group:Aluminum hydroxide particle, calcium phosphate are micro- Grain, aluminum phosphate particle, aluminum sulfate particle etc..
In pharmaceutical composition according to the present invention, the adjuvant semisolid particle can be include such as biological particle, The wherein described biological particle can include for example with the one or more of the following group:Mycobacteria, Bordetella pertussis, endotoxin, Bacterial extract, phosphatidase G (PLG), virus-like particle (VLP) etc..
In pharmaceutical composition according to the present invention, the adjuvant lipid particles for example can be include that such as emulsion is micro- Grain, wherein the emulsion particles can include for example well known by persons skilled in the art with the one or more of the following group:MF59, AS02,MPL,QS21,W805EC, ISA-51, ISA-720 etc..
Pharmaceutical composition according to the present invention, the adjuvated particle for example can be to include with one kind of the following group or more Kind:Be fixed on cell factor on particulate carrier (such as Nano diamond), antigens unique framework, polypeptide (such as CpG ODN), Heat shock protein, interleukins etc..
Pharmaceutical composition according to the present invention, the macromolecular adjuvant include large biological molecule immunostimulant, wherein institute It includes following one kind or a variety of to state biological immune irritant:Granulocyte-macrophage colony stimutaing factor (GM-CSF), heat are stopped Gram albumen.
In pharmaceutical composition according to the present invention, the vaccine adjuvant for example can be include by a variety of of more than one The combined vaccine adjuvant of vaccine adjuvant composition, wherein it includes with the following group that the combined vaccine adjuvant, which for example can be,:Aluminium hydroxide Particle and CpG ODN, aluminum hydroxide particle and MPL, AS04 (LPS derivatives, single phosphatidyl lipid A and aluminium adjuvant), AS03 (dimensions Raw element E, squalene and Tween-80) etc..
Pharmaceutical composition according to the present invention can optionally include also further other medicines.The other medicines can be this The drug arbitrarily known to field technology personnel with enhancing pharmacodynamic feature, includes one kind or more of for example following antitumor drug Kind:Alkylating agents (such as cyclophosphamide, busulfan, mustargen, Ka Mosiding, etc.), destroy DNA platinum class (such as cis-platinum, card Platinum, Nedaplatin etc.), destroy DNA antibiotics (such as bleomycin, bleomycin A5, mitomycin etc.), influence biological nucleic acid Drug (such as fluorouracil, gemcitabine, cytarabine etc.), interference transcription and the drug for preventing RNA from synthesizing of synthesis (such as Aclarubicin, Doxorubicin etc.), topoisomerase enzyme inhibitor (such as Irinotecan, Hydroxycamptothecin, etc.), influence micro-pipe Albumen synthesis drug (such as vincristine, taxol, docetaxel etc.), small molecule targeted drug (such as Gefitinib, she Imatinib, Sorafenib etc.), antibody drug (such as Rituximab, ibritumomab tiuxetan, Cetuximab etc.), etc..According to The pharmaceutical composition of the present invention can be additionally used in the tumor cell drug resistance for reversing these antitumor drugs.
Pharmaceutical composition according to the present invention can also include uncoupler, such as dinitrophenol (DNP).
If it does, the polyvalent metal compounds, targeting agent, slow-released carrier, analgesic, other biological activity ingredient, The content of vaccine adjuvant and other drugs in pharmaceutical composition of the present invention should be able to make application the pharmaceutical composition it The mentioned component of following Cmax is provided afterwards:
The Cmax of the polyvalent metal compounds is, for example, 0.02-2% (w/v), is preferably 0.05-1.5% (w/ V), more preferably 0.1-1.2% (w/v) or 0.1-1.6% (w/v);
The Cmax of the targeting agent is, for example, 0.1-3% (w/v), is preferably 0.25-2.5% (w/v), more preferably 0.5-2% (w/v) or 0.5-1.5% (w/v);
The Cmax of the slow-released carrier is, for example, 0.5-13% (w/v), preferably 1-12% (w/v) or 1-15% (w/ v);
The Cmax of the vaccine adjuvant is, for example, 0.15-15% (w/v), preferably 0.3-12% (w/v), is more preferably 0.5-6% (w/v) or 1-4% (w/v);
The Cmax of the other biological activity ingredient be 0.3-15% (w/v), preferably 0.5-10% (w/v), it is more excellent It is selected as 1-6% (w/v) or 1-4% (w/v);
The Cmax of the other medicines is, for example, 0.1-15% (w/v);With
The Cmax of the analgesic for example can be 0.1-4% (w/v).Such as the concentration of benzyl alcohol can be 1-4% (w/v), procaine hydrochloride, anesin, hydrochloric acid benefit card concentration can be respectively 1-3% (w/v).
For example, in one embodiment, composition according to the present invention is liquid Topical dosage forms, wherein:
If it does, the concentration of the polyvalent metal compounds is, for example, 0.02-2% (w/v), it is preferably 0.05- 1.5% (w/v), more preferably 0.1-1.2% (w/v) or 0.1-1.6% (w/v);
If it does, the concentration of the targeting agent is, for example, 0.1-3% (w/v), it is preferably 0.25-2.5% (w/v), More preferably 0.5-2% (w/v) or 0.5-1.5% (w/v);
If it does, the concentration of the slow-released carrier is, for example, 0.5-13% (w/v), preferably 1-12% (w/v) or 1- 15% (w/v);
If it does, the Cmax of the vaccine adjuvant is, for example, 0.15-15% (w/v), preferably 0.3-12% (w/ V), it is more preferably 0.5-6% (w/v) or 1-4% (w/v);
If it does, the Cmax of the other biological activity ingredient is 0.3-15% (w/v), preferably 0.5-10% (w/v), more preferably 1-6% (w/v) or 1-4% (w/v);
If it does, the concentration of the other medicines is, for example, 0.1-15% (w/v);With
If it does, the concentration of the analgesic for example can be 0.1-4% (w/v).Such as the concentration of benzyl alcohol can be with For 1-4% (w/v), procaine hydrochloride, anesin, hydrochloric acid benefit card concentration can be respectively 1-3% (w/v).
It will be appreciated by those skilled in the art that according to required administering mode and concentration parameter, it can be by the composition system of the present invention At such as solid pharmaceutical preparation, semisolid preparation or liquid preparation.More specifically, the solid pharmaceutical preparation packet of pharmaceutical composition of the invention Include such as sublingual tablets, adhesive sheet, solid phase implant;Semisolid preparation includes such as ointment, emplastrum, paste, patch, bolt Agent;Liquid preparation includes the mother liquor of such as injection, externally used solution agent, lotion, liniment, drops and following gaseous state preparation:Spray Mist agent, aerosol, powder spray.
An embodiment according to the present invention, local administration liquid preparation according to the present invention are emulsion.The emulsion can To be oil-in-water or water-in-oil emulsion.The decentralized medium of the emulsion can be with well known by persons skilled in the art any appropriate Person, such as it is usually used in injecting purpose vegetable oil, synthetic oil or semi synthetic base oils as oily group.Vegetable oil can be such as cottonseed oil, Apricot kernel oil, olive oil, castor oil, sesame oil, soybean oil and peanut oil.
An embodiment according to the present invention, local administration liquid preparation according to the present invention are suspension.It is described outstanding Turbid dose of decentralized medium can be with any appropriate person well known by persons skilled in the art, such as micro materials or nano material.
An embodiment according to the present invention, local administration liquid preparation according to the present invention are solution.The solution Agent can be formed in a dispersion medium by by composition component dissolving, can also be individually to dissolve said components It is formed in decentralized medium and then mixing.The decentralized medium of the solution includes solvent, preferably pharmaceutically suitable hydrophilic Solvent.Term " hydrophilic solvent " refers to having hydrophilic solvent comprising for example the miscible organic solvent of water, water or Include the vehicle system of water and the miscible organic solvent of water.
In an embodiment of pharmaceutical composition according to the present invention, one of the chemical ablation agent and active polysaccharide Can be partly or entirely in the dosage form of lyophilized preparation before administration.
By taking the liquid preparation (such as injection) of the present composition as an example, it can prepare in accordance with the following methods.
Method one:If contained chemical ablation agent, bioactive polysaccharide and other additions being optionally present in composition The required concentration of agent (such as metal salt, other medicines, other synergist, analgesic, excipient etc.) can divide in water-soluble or water When in scattered concentration range, then these raw materials is directly added into water for injection and can be obtained corresponding liquid preparation.
Method two:If contained chemical ablation agent, bioactive polysaccharide and other additions being optionally present in composition The required concentration of agent (such as metal salt, curing agent, other medicines, other synergist, analgesic, excipient etc.) has not water-soluble Or when in the dispersible concentration range of water, then these raw materials are dissolved or dispersed in all composition components can be in required concentration In the solvent (such as aqueous solution containing organic solvent) of lower dissolving or dispersion, you can obtain corresponding liquid preparation.
Method three:The liquid agent of (such as passing through the above method) containing whole components is prepared first, then prepared (such as it is logical Cross lyophilized technique) it is dry powder, using preceding by the dry powder and solvent (such as the water for injection or aqueous miscible for being free of any component The solvent of organic solvent) it is mixed to form composition liquid preparation.
Method four:The liquid of (such as passing through the above method) component containing part is prepared first, then prepared (such as pass through Lyophilized technique) it is dry powder, using preceding by the dry powder and liquid (such as the aqueous solution or aqueous miscible for containing other part component The solution of organic solvent) it is mixed to form composition liquid preparation.
By taking the mother liquor of the gaseous state preparation (such as spray) of the present composition as an example, preparation method can refer to above-mentioned group Thing liquid body preparation preparation method is closed, is made by the way that one or more of excipient is added in the preparation of aforesaid liquid preparation It is standby:Glycerine, Tween-80, benzalkonium chloride, microcrystalline cellulose-sodium carboxymethylcellulose etc..
By taking the semisolid preparation (such as suppository) of the present composition as an example, preparation method can refer to said combination thing liquid Body preparation preparation method is prepared by the way that one or more of excipient is added in the preparation of aforesaid liquid preparation:Cottonseed Oil, apricot kernel oil, olive oil, green punt-pole oil, menthol, borneol, solubility emulsifiability agent, glycerine etc..
By the principle of these above-mentioned methods, those skilled in the art may be used any appropriate specific method prepare it is a variety of Include the local administration preparation of the present composition.For example, the variation in the preparation of the present invention includes:Containing different kinds and concentrations Chemical ablation agent, the active polysaccharide containing different kinds and concentrations, the metal salt containing different kinds and concentrations, containing variety classes and Other additives (such as other active drugs, analgesic, vaccine adjuvant, activity increase agent etc.) of concentration.
According to another aspect of the present invention, pharmaceutical composition according to the present invention is also provided and is preparing prevention and treatment Application in the drug of mammal local patholoic change relevant disease.Application according to the present invention, wherein the prevention and treatment are fed The drug of newborn animal local patholoic change relevant disease has the dosage form of local administration, the dosage form of the preferably interior administration of tissue.
According to a further aspect of the invention, a kind of side of disease of the prevention and treatment comprising local patholoic change is also provided Method, this method include that pharmaceutical composition according to the present invention is administered to the individual thus needed.The method of the present invention is a kind of tool The therapy for having chemical ablation effect, may even also having immunization under certain conditions.
According to the method for the present invention, the administration includes local administration, the preferably interior administration of tissue.
Within the scope of the invention, term " local patholoic change relevant disease " refers to the disease with local patholoic change symptom.Art Language " local patholoic change " refers to primary or after raw lesion in animal bodies part.Term " part " can be this field Any appropriate person known to technical staff, such as it includes part in one or more of organ that can be:Excretory system institute Secretory, cardiovascular organ, skin etc. where blood circulation system.Term " lesion " refers to structure, form or work( It is abnormal on energy, any appropriate person can be known to the skilled in the art, such as can be include it is following a kind of or It is a variety of:Tumour, non-struma big, local inflammation, gland pathocrinia etc..
Within the scope of the invention, term " tumour ", which refers to all except hematological system tumor (such as leukaemia), has The tumour in tumour cell concentration of local area, preferably entity tumor comprising malignant tumour and non-malignant tumors.Tumour can be this Any appropriate person known to field technology personnel, including for example according to tumor cell type classify with the following group:Epithelium is thin Palpebral edema tumor, sarcoma, lymthoma, germinoma, enblastoma;And include according to the organ where tumour cell concentration zones Or tissue is the tumour named, including the tumour for example named according to following organ or tissue:Skin, bone, muscle, mammary gland, Kidney, liver, lung, gall-bladder, pancreas, brain, esophagus, wing flesh, large intestine, small intestine, spleen, stomach, prostate, emerald green ball, ovary or uterus.The present invention In the tumour tumour that also includes form of ownership and tumour in any stage.
The malignant tumour include for example breast cancer, cancer of pancreas, thyroid cancer, nasopharyngeal carcinoma, prostate cancer, liver cancer, lung cancer, Intestinal cancer, carcinoma of mouth, cancer of the esophagus, gastric cancer, laryngocarcinoma, carcinoma of testis, carcinoma of vagina, uterine cancer, oophoroma, etc..The non-malignant tumors Including such as mastadenoma, Vipoma, thyroid adenoma, prostate tumor, hepatoma, lung tumor, enteroncus, oral cancer, esophagus tumor, stomach tumor, nose Swallow tumor, laryngeal tumor, testicular tumor, elytroncus (elytrophyma), hysteroma, salpingioma, ovarioncus etc..
Within the scope of the invention, term " non-struma is big " includes the enlargement other than tumour, including for example hyperplasia (such as breast The hyperplasia of gland, pancreas, thyroid gland, parathyroid gland, prostate etc.), tumour (such as the capsule of mammary gland, thyroid gland, parathyroid gland etc. It is swollen), tubercle (such as tubercle of mammary gland, thyroid gland, parathyroid gland etc.), abnormal veins group (such as hemorrhoid etc.), local inflammation hair Swollen, microorganism infection is swelled.The hemorrhoid include internal piles, external piles, mixed hemorrhoid.
Within the scope of the invention, term " local inflammation " refers to the non-tumor inflammation of part, including for example rotten Property scorching (alterative inflammation), exudative inflammation (exudative inflammation) and productive inflammation.Secretion The inflammation of glandular organ includes such as mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharynx Inflammation, esophagitis, gastritis, gastric ulcer, rhinitis, nasosinusitis, laryngitis, tracheitis, bronchitis, vaginitis, hysteritis, fallopian tubal Inflammation, oaritis etc..Other local inflammations include such as degenerative arthritis.
Within the scope of the invention, term " gland pathocrinia " includes gland hyperfunction disease and gland Hypofunction.Wherein, term " gland hyperfunction disease " refers to that the excessively active then hormone sensitive lipase gene of secretory cell function increases Secretion also increases, such as hyperthyroidism.Term " gland hypofunction " refer to secretory cell function reduction or Certain distinctive enzyme, which lacks, to be made hormone sensitive lipase gene reduce and secretes reduction, such as Jia shape gland Gong Neng Minus move back disease, the islands Yi Gong Neng Minus move back disease (one kind of diabetes) etc..Term " hormone " refers to the semiochemicals that endocrine cell synthesized and be directly secreted into body fluid, It include steroid hormone (such as cortex hormone of aadrenaline, sex hormone etc.), amino acid derivativges hormone (such as thyroxine, Adrenal medullary hormone, epiphysin etc.), peptide and proteohormone (such as hypothalamic hormone, pituitrin, gastrointestinal hormone, Insulin, calcitonin etc.), derivative of fatty acid hormone (such as prostaglandin).
An embodiment according to the present invention, the local patholoic change relevant disease include secretion disease.The present invention's In range, term " secretion disease " refers to primary or after the raw lesion in tissue, organ where gland or gland, term " gland " refers to structure being made of gland cell or gland cell group, executing secreting function (secretion) comprising outer point Secrete gland and incretory.
An embodiment according to the present invention, the local patholoic change relevant disease includes skin disease.In the model of the present invention In enclosing, term " skin disease " refers to primary or after raw in skin or the lesion of skin accessory organ, can be art technology Any appropriate person known to personnel, such as it includes one or more of that can be:Cutaneum carcinoma, skin non-malignant tumors, virus Dermatoses (such as bleb, wart, rubella, hand-foot-and-mouth disease), bacterial dermatosis (such as impetigo, furuncle, leprosy), fungoid skin Skin disease (such as various tinea), sexually transmitted disease (such as syphilis, gonorrhoea and condyloma acuminatum), anaphylaxis and autoimmune skin disease (such as contact dermatitis, eczema, nettle rash), physics dermatoses (such as daylight dermatoses, pernio, corn, brothers' chap Split, pressure sore), connective tissue disease (such as lupus erythematosus), dyschromicum skin disease (such as freckle, mole, various spots), Cutaneous appendages disease (such as acne, brandy nose, seborrhea, alopecia areata, baldness, ephidrosis and bromhidrosis).
Topical dosage forms require drug composition (active constituent, composition when and concentration of component) can be given by local means With generating required curative effect to the tissue where local patholoic change and in the tissue.For example, when lesion is tumour, part The knurl being organized as where tumour cell.When lesion is that non-struma is big, local organization is lump (such as hyperplasia, tumour, tubercle Etc. lesions lump).When lesion is local inflammation, local organization is inflamed area (such as inflammation enlargement body).When lesion is secretion When abnormal, local organization is anomaly source or the secretion body of gland where it.In another example when disease is insulopathic, it is different For Chang Yuan in pancreas islet, local organization is then the pancreas where pancreas islet or pancreas islet.When disease is skin disease, local organization is lesion skin The accessory organ of skin or affected skin.
The composition of the present invention and the medical preparation of the composition can also be with other interventional therapies (such as through arterial duct Perfusion/embolus), systemic chemotherapy, immunotherapy, photodynamic therapy, sound motivation therapy, heat therapy, physics ablation method (such as penetrate Frequently, the ablations such as microwave, laser, high intensity focused ultrasound (HIFU), nano-knife, argon helium knife), the group of surgical intervention or such therapy Combined application is closed, to further increase curative effect.
Based on the research being more particularly described hereinafter, although specific mechanism waits further to study, combination of the invention Object is shown promote mammal local patholoic change where the dependency structure organized (such as pathological tissues, sick cell and participate in structure At their any structure) more efficiently destruction, to reach treatment disease more preferable therapeutic effect.
Embodiment
By following specific examples, the present invention is further illustrated, but not as limitation of the present invention.With In lower embodiment, all experiments are carried out according to relevant regulations on cell or experimental animal.Unless otherwise specified, Suo Youshi It tests and carries out according to a conventional method.
Material, reagent used in following specific examples etc., are commercially available unless otherwise specified.Below Portion of reagent used in embodiment is listed in Table 1 below.
Table 1
In addition, following bio-extract is provided by Xi'an Rayleigh bio tech ltd:Cordyceps sinensis polysaccharide, grifola polysaccharide, Hedgehog hydnum eats polysaccharide, seaweed selenium poly saccharide, mushroom selenium polysaccharide, spirulina polysaccharide, composite fungi amylose, arasaponin (Chun Du > 80%) etc..
In the examples below, tested tumour cell includes:Human liver cancer cell (HepG2), human breast cancer cell (MDA- MB231), human lung carcinoma cell (A549), human thyroid cancer cell (SW579), Human Prostate Cancer Cells (LNCaP/AR), human pancreas Cancer cell (PANC-1), human colon cancer cell (COLO205), people's head & neck cancer cell (F μ da), KB cell (CNE1), people Stomach cancer cell (BGC823), oophoroma (PA1), skin cancer cell (A341) etc..The research method and knot of the embodiment of the present invention Fruit is also applied for other tumour cells.
In the examples below, unless otherwise indicated, subcutaneous transplantation tumor animal experiment is referred to by the experiment that pencil authorities issue Southing row.Animal be 6~8 week old, weight 17.5-20.5g Balb/c nude mices.Above-mentioned tested cancer cell subcutaneous is inoculated in Nude mice waits for that tumour is grown to required volume (such as 100-500mm3 or so), and using 3.2 softwares of PEMS, (Sichuan University West China is public The establishment of hygienic institute) random district's groups are negative control group, positive controls and several seminar, every group of 8 nude mices.
The grouping same day starts to be administered.Experiment sets negative control group, positive controls and several seminar, is separately added into the moon Property reference material, positive control and several research drugs.Negative control object is composition solvent, and administering mode and volume are equal It is identical as seminar.Positive control is selected from above-mentioned existing antitumor medicine, and administering mode is intraperitoneal injection, day administration The convention that dosage presses selected drug carries out (such as 5 FU 5 fluorouracil 25mg/kg).Unless otherwise indicated, seminar is tumor area note Research drug is penetrated, injection volume is determined by dosage and concentration.Experimental observation, measurement and the project of analysis, including general state, body Weight, food ration, gross tumor volume, knurl weight etc..
Gross tumor volume calculation formula is as follows:
Gross tumor volume (V)=l/2 × a × b2, wherein a expressions tumour is long, and b indicates that tumour is wide.
Relative tumour volume calculation formula is as follows:
Relative tumour volume (RTV)=Vt/Vo, (i.e. first day) measures gained tumour body on the day of wherein Vo is sub-cage administration Product, Vt are gross tumor volume when next day is administered and measuring later.
Inhibition rate of tumor growth (being abbreviated as tumour inhibiting rate in the present invention) calculation formula is as follows:
Tumour inhibiting rate Y (%)=(TW-CW)/CW × 100%, wherein TW are the average knurl weight of seminar;CW is negative control The average knurl weight of group.
In the examples below, experiment is all made of duplicate measurements variance analysis (Repeated Meas μ res ANOVA) point The other group differences to index mean carry out statistical test.When group differences are statistically significant (P≤0.05), using minimum Significant difference method is compared each group with negative control group difference.Quantitative target is retouched using mean ± standard error (X ± SEM) It states.When LEVENE homogeneitys test of variance prompt heterogeneity of variance (P≤0.05), using Mann-Whitney Μ rank sum tests (M-W Method) compare group difference.All statistical analyses are completed under 13.0 softwares of SPSS for Windows.
Embodiment 1:The preparation of composition
1, the preparation of liquid preparation
Using aforementioned preparation process, the composition of the medicinal composition solution of the part present invention manufactured in the present embodiment is listed in table 2.Excipient therein includes solvent, and unless otherwise indicated, solvent contains water for injection.Medicinal composition solution is preparing completion It stores 2 hours or more afterwards and exercises use again.
Table 2
*:Solvent is the aqueous solution containing 25% ethyl alcohol, 15%PEG300 and 15% propylene glycol.
Specifically, for example with final 100ml composition solutions stereometer, at room temperature, measured according to being measured shown in table 2 Corresponding chemical ablation agent (such as methylenum careuleum or/and quinine dihydrochloride) and active polysaccharide dry powder and other groups being optionally present The dry powder of (such as polyvalent metal compounds, other medicines) is divided to be added in 80ml solvents (such as water for injection or ethanol water) Dissolving, mixing, dispersion, add other additives (such as the agent that relieves the pain, ionic strength adjustor, pH adjusting agent) and water for injection So that total volume is reached 100ml, is packed as 2ml/ bottles of spare, obtained composition liquid agents after mixing.
2, the preparation of lyophilized preparation
Lyophilized preparation can be further made in aforesaid liquid agent (such as table 2).Specifically, for example, weigh 4g methylenum careuleum and 2g algal polysaccharide sulfate dry powder is added other additives and water for injection and the total soap of Radix Notoginseng of 4% methylenum careuleum of 100ml/2% is made Glycosides aqueous solution, the liquid is filling in 7ml capacity bottles with the liquid loading amount of every 2ml, then freeze-dried, tamponade and rolls lid, i.e., Obtain injection methylenum careuleum/notoginsen triterpenes freeze-dried powder pin preparations.
The preferred processing condition of above-mentioned freeze-drying is as follows.Pre-freeze condition:It is kept for 4 hours for -45 DEG C in pre-freezing temperature, sample Solution can freeze reality completely.Lyophilization condition:When the heating rate in lyophilization stage is 0.1 DEG C/min and rises to -15 DEG C when at least keep 10 hours, then moisture distil substantially completely, and without spray bottle phenomenon generation.Desorption drying condition:It is desorbing Attached drying stage, in 30 DEG C keep 6 hours, then sample moisture can control below 3%.
In short, the preparation of the liquid agent of the composition of the present invention includes following methods:All components are mixed one with solvent It rises and is made;All components are mixed with solvent, lyophilized preparation is made, is made again of solvent is molten before use;Constituent part is mixed Unify and lyophilized preparation is made, is made again of the solution mixing redissolution containing other components before use.
3, the preparation of solid dosage forms
Composition active component, such as 500mg methylenum careuleum and 200mg spirulina polysaccharides are measured according to the relative quantity in table 2, Be added into gelatinizing agent (such as 500mg sodium carboxymethylcelluloses), tackifier (such as 500mg polyvinyl alcohol), bulking agent (such as 5000mg glucose etc.) in, the water for injection for being settled to 10ml is then added, is uniformly mixed and plastic softwood is made, then lead to The wire rod that small-sized molding machine extrusion forming is diameter≤1mm is crossed, the solid phase of length≤5mm is weighed and then be cut into heat drying It is implanted into item.Solid phase implantation item can pass through clinically used I125Particle implanting gun is implanted into animal body.
5 solid phases implantation items are put into and (imitate tumor volume in tumor bearing nude mice experiment containing 100 μ l physiological saline containers 100mm3) in and moderately shake, sampled from the solution except remaining item after 15 minutes, (such as be divided light according to a conventional method Degree meter colorimetric method) measure methylenum careuleum concentration (averagely dissolving out concentration).Phase according to methylenum careuleum concentration and its with other active components To amount, the average dissolution concentration of other active components can be calculated.Averagely dissolution concentration dissolves out dense certainly less than or equal to peak Degree.
By adjusting the amount of composition active component and gelatinizing agent dosage ratio, it can get required peak and dissolve out concentration. In the present embodiment, when solid phase is implanted into, methylenum careuleum in item forms >=5% (w/v), spirulina polysaccharide forms >=2% (w/v), carboxymethyl Sodium cellulosate forms≤5% (w/v), polyvinyl alcohol forms <8% (w/v), methylenum careuleum is averaged in the solid compositions obtained Dissolution concentration after measured >=2% (w/v), spirulina polysaccharide average dissolution concentration be computed >=0.25% (w/v).
Embodiment 2:Cooperate with Journal of Sex Research
1, activity research is shared in vitro
Human hepatoma cell strain (HepG2) is selected in this experiment first, if negative control group (negative control object is physiological saline) And medicine group, use the inhibiting tumour cells activity of CCK8 colorimetric method for determining drugs.Test solution be wait upon survey drug give it is dense The aqueous solution of degree, experiment condition and step are carried out by the specification of cck-8 kits (Japanese colleague's chemistry).Colorimetric selects 490nm wavelength measures each hole absorbance value (A on enzyme-linked immunosorbent assay instrument490), record is as a result, using the time as abscissa, extinction Value is that ordinate draws cell growth curve.Inhibiting rate of the drug to growth of tumour cell, the result row of experiment are calculated as follows In table 3.
Growth of tumour cell inhibiting rate (IR)=(1- medicine groups A490/ control group A490) X100%.
Table 3
In table 3, chemical ablation agent/bioactivity glycoside composition, which is not only shown, changes bioactive polysaccharide concentration It is insensitive, also show the anti-effect of apparent tangerine.
2, expression activitiy research is shared in vivo
One with methylenum careuleum/5 FU 5 fluorouracil be collaboration object, using methylenum careuleum/spirulina polysaccharide as antagonism reference material Zoopery in, success model experimental animal (lotus liver cancer cells nude mice, knurl average external volume 113mm3) be grouped at random Intraperitoneal injection series and intratumor injection series.Two series include respectively 1 negative control group, 4 methylenum careuleum/spirulina polysaccharide group (A1, B1 group and A2, B2 group) and 4 methylenum careuleum/5 FU 5 fluorouracil group (C1, D1 group and C2, D2 group).Negative control group injection life Brine is managed, A1, A2 group are injected intraperitoneally respectively and 1% methylenum careuleum of intratumor injection/1% spirulina polysaccharide aqueous solution, and B1, B2 group are distinguished Intraperitoneal injection and the spirulina polysaccharide aqueous solution of 1% methylenum careuleum of intratumor injection injection concentration/2%, C1, C2 group be injected intraperitoneally respectively and 1% methylenum careuleum of intratumor injection/1%5- fluorouracil aqueous solutions, D1, D2 group are injected intraperitoneally respectively and 1% methylenum careuleum of intratumor injection/ 2%5- fluorouracils.Research drug is to be configured by the preparation method of embodiment 1, and dosage is 75mg methylenum careuleum/kg. 7 days after medication, it is euthanized to animal, tumour inhibiting rate is measured after dissection.Fig. 1 provides the tumour inhibiting rate of each seminar (X-axis) (Y-axis).
In Fig. 1, when intraperitoneal injection, the tumour inhibiting rate of methylenum careuleum/spirulina polysaccharide group (A1, B1 group) is than methylenum careuleum/5- fluorine urine Low (the P&gt of pyrimidine group (C1, D1 group);0.05).And when intratumor injection, methylenum careuleum/spirulina polysaccharide group (A2, B2 group) is shown than Asia Considerably higher tumour inhibiting rate (the P&lt of first indigo plant/5 FU 5 fluorouracil group (C2, D2 group);0.05).Although 5 FU 5 fluorouracil is considered special Property, all very high antineoplastic of activity, the composition for being spirulina polysaccharide and methylenum careuleum shows high unusual association Same-action.
In further experiment, other chemical ablation agent (such as quinine dihydrochloride and acetylsalicylic acid) and active glycosides The combination of (such as ginsenoside etc.) also shows that similar unusual same use acts on.Further, of the invention other Composition (such as composition in table 2) also shows that similar effect.
3, chemical ablation agent comparative studies
One is directed to lotus thyroid carcinoma cell nude mice (69mm3) experiment, success model experimental animal be grouped at random Negative control group and seminar.100 μ l physiological saline of negative control group intratumor injection, 5 seminar's (A, B, C, D, E group) are respectively The chemical ablation agent different from 5 of 100 μ l spirulina polysaccharides of intratumor injection (methylenum careuleum, quinine dihydrochloride, acetylsalicylic acid, acetic acid, Sodium hydroxide) composition.In composition, spirulina polysaccharide and chemical ablation agent concentration are 1%.It studies drug and presses and implement Prepared by the preparation method of example one, wherein the solvent of acetylsalicylic acid/spirulina polysaccharide composition is containing 25% ethyl alcohol, 15% The solvent of the aqueous solution of PEG300 and 15% propylene glycol, other compositions is water for injection.7 days after medication, to animal into Row euthanasia, tumour inhibiting rate is measured after dissection.Fig. 2 shows 1 week after composition (X-axis) medication containing different chemical ablation agent tumor suppression Rate (Y-axis).
In Fig. 2, methylenum careuleum, quinine dihydrochloride, acetylsalicylic acid and spirulina polysaccharide composition (A, B, C group) show Tumor suppression is effective, and acetic acid, sodium hydroxide (D, E group) show that tumor suppression is invalid.
Embodiment 3:Super efficient activity research
Activity is an opposite concept in fact.Within the scope of the invention, term " activity " refers to showing for substance The property of certain therapeutic effect, term " effective active " refer to substance have with the comparable therapeutic effect of existing clinical medicine Property, term " super efficient activity " refer to substance property with significantly higher therapeutic effect compared with existing clinical medicine. By taking existing clinical antineoplastic chemotherapeutics (such as 5 FU 5 fluorouracil) as an example, they tumor bearing nude mice experiment in tumour inhibiting rate be 45-75%.The effect of here it is existing clinical medicines.The significantly higher therapeutic effect of super efficient Active pharmaceutical, such as lotus knurl are naked Yi Liushuai &gt in mouse experiment;75%.
Within the scope of the invention, term " reactive conditions ", " effective active condition " and " super efficient reactive conditions " difference Refer to researcher's offer makes substance show activity, effective active and the active condition of super efficient.
1, the further research of administering mode
Lotus liver cancer cells nude mice (knurl average external volume 118mm is directed at one3) zoopery in, animal is divided into feminine gender Control group and 6 seminar.Negative control group intratumor injection physiological saline, 4 seminar's (A, B, C, D group) are orally given respectively Medicine, intraperitoneal injection, the injection of tumor week, the algal polysaccharide sulfate aqueous solution of 1% methylenum careuleum of intratumor injection/1%.Research drug be by The preparation method of embodiment one configures.Methylenum careuleum dosage is 100mg/kg animals.Medication 1 time, after medication 7 days to animal into Row euthanasia, tumour inhibiting rate is measured after dissection.When Fig. 3 provides different modes of administration, the tumour inhibiting rate (Y-axis) of each seminar's (X-axis).
In Fig. 3, when the same methylenum careuleum/algal polysaccharide sulfate composition being administered under same dose, different dosing side Tumour inhibiting rate difference shown by formula is unusual.Tumor week injection (C groups) can be such that drug is directly contacted with knurl, show ratio Considerably higher tumour inhibiting rate (the P&lt of systemic administration group (A, B group);0.05).Intratumor injection group (D groups) then shows and is not only used than whole body Medicine group (A, B group) and the tumour inhibiting rate (P&lt more considerably higher than tumor week injection group (C groups);0.05).
In further experiment, other chemical ablation agent (such as quinine dihydrochloride, acetylsalicylic acid) and active glycosides (example Such as astragalus polyose, lentinan) combination also show that similar unusual administering mode dependence.
2, chemical ablation agent concentration is studied
At one in the experiment of lotus liver cancer cells nude mice, the pass of tumour inhibiting rate and methylenum careuleum concentration in composition is had studied System.Experimental animal (the knurl average external volume 125mm that success models3) it is random be grouped into negative control group and 5 seminar (A, B, C, D, E group).Negative control group intratumor injection physiological saline, the method system that the other intratumor injection of A, B, C, D, component E presses embodiment one Standby 5 methylenum careuleum/panaxan's aqueous solution.Wherein, arasaponin concentration is 1%, and methylenum careuleum concentration is respectively 0.25%, 0.5%, 1%, 2%, 3%.Research drug is to be configured by the preparation method of embodiment one, and injection dosage is 100mg methylenum careuleum/kg animals.7 days after medication, it is euthanized to animal, tumour inhibiting rate is measured after dissection.Fig. 4, which is provided, to be worked as When arasaponin concentration is fixed as 1%, the tumour inhibiting rate (Y-axis) with the composition of various concentration methylenum careuleum (X-axis).
In Fig. 4, methylenum careuleum Nong Du <When 1%, tumour inhibiting rate increases with the increase of methylenum careuleum concentration but still in dead space It is interior;Tumour inhibiting rate increases with methylenum careuleum concentration in the section of 1≤methylenum careuleum concentration≤2 and quickly increases;It is shown when 2%≤methylenum careuleum concentration The tumour inhibiting rate of super-active is shown.In identical methylenum careuleum dosage (100mg/kg), tumour inhibiting rate changes with methylenum careuleum concentration to be occurred Significant change and tumour inhibiting rate change reached height illustrate curative effect mainly by concentration and dose determines.
In the experiment of another composition, in quinine dihydrochloride concentration 1%-3%, 1 week Suppressive effect is with two hydrochloric acid Quinine concentration increases and increases, but bad the effect of eligible result.After quinine dihydrochloride concentration is more than 3%, especially exist 3%<The section of quinine dihydrochloride concentration≤4.5%, Suppressive effect increase with quinine dihydrochloride concentration and increase suddenly.When two hydrochloric acid When quinine concentration >=4.5%, super efficient activity is shown.
In the experiment of another composition, in acetyl salicylic acid concentration 1%-3%, 1 week and 3 weeks Suppressive effects are with second Acyl Determination of Salicylic Acid increases and increases, but bad the effect of eligible result.After acetyl salicylic acid concentration is more than 3%, especially It is in 3%<The section of acetyl salicylic acid concentration≤5%, Suppressive effect increase with acetyl salicylic acid concentration and increase suddenly.Work as acetyl When Determination of Salicylic Acid >=5%, super efficient activity is shown.
3, composition relative quantity and active polysaccharide concentration studies
One is directed to lotus liver cancer cells nude mice (knurl average external volume 103mm3) zoopery in, success model experiment Animal is grouped into negative control group and 7 seminar's (A, B, C, D, E, F, G group) at random.Negative control group intratumor injection physiology salt Water, seminar distinguish intratumor injection containing 1% methylenum careuleum and various concentration (0,0.125%, 0.25%, 0.5%, 1%, 2%, 4%) composition of astragalus polyose.Research drug is to be configured by the preparation method of embodiment one, and dosage is 50mgization Learn ablation agent/kg animals.7 days after medication, it is euthanized to animal, tumour inhibiting rate is measured after dissection.Fig. 5, which is provided, works as methylene When blue concentration is fixed as 1%, the tumour inhibiting rate (Y-axis) with the composition of various concentration astragalus polyose (X-axis).
In Fig. 5, astragalus polyose/methylenum careuleum relative quantity of B, C, D, E, F, G group is respectively 1:8,1:4,1:2,1:1,2:1, 4:1.Compared with A group tumour inhibiting rates, each group all shows the tumour inhibiting rate obviously increased.But in astragalus polyose/methylenum careuleum relative quantity It is 4:When 1 (F groups), the multiplication of astragalus polyose relative quantity but unexpectedly shows the tumour inhibiting rate being decreased obviously (with E groups).
In Fig. 5, in astragalus polyose concentration≤0.25%, 1 week Suppressive effect increases and steady with astragalus polyose concentration Increase, but distinguishes unobvious.After astragalus polyose concentration is more than 0.25%, 1 week Suppressive effect increases with concentration and quickly increases.
In further experiment, other chemical ablation agent (such as quinine dihydrochloride and acetylsalicylic acid) and active polysaccharide The combination of (such as algal polysaccharide sulfate) also shows that similar relative quantity and concentration relationship.
Although reason unknown, chemical ablation agent/bioactive polysaccharide composition shows unusual pharmacy behavior, i.e., Only when following three conditions are provided simultaneously with, super efficient activity can be generated:Administration in tissue;Chemical ablation agent administration is dense Degree >=1.5%, preferably >=2%;Bioactive polysaccharide Gei Yaonongdu >0.25%, preferably >=0.5%.Chemical ablation agent therein Administration concentration, for quinine class compound, this concentration is preferably greater than 4.5%;For salicylic acid compounds, this A concentration is preferably greater than 5%.
In addition, it is contemplated that bioactive polysaccharide has immunological enhancement more, composition is it is also possible to generate significant length Effect activity.
4, the safety research of super efficient reactive conditions
During above-mentioned experiment of nude mouse, during chemical ablation agent/experiment of the bioactive polysaccharide seminar after medication Have no that nude mice is dead because of administration.Compared with negative control group compared in seminar, especially with above-mentioned super efficient active technologies side There are apparent color and luster variation and myodegeneration in injection site in the seminar of case.This prompts the application conditions to cause flesh really The partial injury of cell.Such as, it is generally recognized that 1% methylthioninium chloride injection is through cannot act as local injection, otherwise to there is safety Risk.When being made local administration, should all as far as possible dilution processing (Wu Weibiao, various concentration methylenum careuleum is in the postoperative town of anal intestine Effect in pain compares, northern pharmacy the 10th phase of volume 13 in 2016, pp190-191).However, further zoopery knot Fruit is unexpected.
Weight 1.9~2.5kg new zealand rabbits are taken, are divided into negative control group, clinical medicine control group and 3 seminar, often 6 animals of group.Physiological saline is administered in negative control group, and absolute ethyl alcohol is administered in clinical medicine, and seminar's (A, B, C group) is administered respectively The mushroom selenium polysaccharide of the mushroom selenium polysaccharide of 2% methylenum careuleum/2%, 3% methylenum careuleum/2%, 4% methylenum careuleum/2% mushroom selenium polysaccharide are water-soluble Liquid.Each group animal injects 1.0ml drugs in right leg quadriceps muscle of thigh.Each group puts to death 4 rabbits after for 24 hours, carries out injection site Check pathological section, whether there is or not hyperemia, oedema, denaturation, necrosis etc. to stimulate phenomenon for observation.Stimulate the reaction standards of grading:Feminine gender note 0 Point, suspicious 1 point, slight 2 points, intensity 3 is divided, serious 4 points, 5 points extremely serious.Local stimulation test result is shown in Table 4.
Table 4
Group Stimulate the reaction scores
Negative control group 0
Clinical medicine control group 3
A groups 0
B groups 0
C groups 0
In table 4, it is surprising that in entirely experiment section, seminar's each group is not observed in nude mice tests The myodegeneration of middle appearance does not observe local stimulation (the clinical medicine control often occurred using classical chemical ablation agent yet Group), stimulate the reaction scores total score closer to negative control group and significantly lower than clinical medicine control group, and in the present invention Composition stimulate the reaction scoring total score not with chemical ablation agent concentration change and significant change.
4 animals remaining to each group continue to observe, and each group puts to death remaining rabbit, longitudinally slit injection site after 3 weeks Muscle observes injection site.Visible clinical drug control group and each seminar's mucous membrane and shallow muscle layer are diffused the fiber knot of hyperplasia Tissue substitution is formed, organizes basic regenerative healing, intensive cell is in fusiformis, is arranged in pencil.In entirely experiment section, research The regenerative healing of group does not change with concentration and significant change, generated tissue damage can repair on an equal basis.
Absolute ethyl alcohol is the chemical ablation agent being most widely used in the prior art.Compared with absolute ethyl alcohol, 4% methylene It is blue/2% mushroom selenium polysaccharide aqueous solution lower local irritation is not only shown in above-mentioned experiment, but also in another lotus liver Cancer experiment of nude mouse (knurl average external volume 58mm3, drug intratumor injection amount 35ul) in show higher tumor killing effect (anhydrous second The mushroom selenium polysaccharide aqueous solution tumour inhibiting rate 95% of alcohol tumour inhibiting rate 71%, 4% methylenum careuleum/2%).
In further experiment, other compositions of the invention (such as composition in table 2) also show that similar knot Fruit.
Embodiment 4:Further Synergistic technique project study
At one for experimental animal (the knurl average external volume that in the experiment of lotus liver cancer cells nude mice, success models 251mm3) it is grouped into negative control group, positive controls (A groups) and 4 seminar's (B, C, D, E group) at random.Negative control object For physiological saline, positive control is the astragalus polyose aqueous solution of 2% methylenum careuleum/1%, and 4 research drugs are respectively 2% methylene Blue/1% aqueous solution except astragalus polyose also containing following synergist:0.7% frerrous chloride, 0.5% folic acid, 2% nanometer of Buddha's warrior attendant Stone, 2% aluminum hydroxide particles.Drug is to be configured by the preparation method of embodiment one, and injection dosage is 80mg methylenum careuleum/kg Animal.7 days after medication, it is euthanized to animal, tumour inhibiting rate is measured after dissection.Table 5 provides result.
Table 5
In further experiment, other chemical ablation agent (such as quinine dihydrochloride and acetylsalicylic acid) and active glycosides The combination of (such as algal polysaccharide sulfuric acid ester) also shows that similar result.
Embodiment 5:The extension of animal model is studied
For a variety of lotus cancer cell nude mice (knurl 131-206mm3) zoopery in, success model experimental animal Random grouping.Negative control group and seminar's difference intratumor injection physiological saline and 2% methylenum careuleum/1% arasaponin are water-soluble Liquid.Each seminar (A, B, C, D, E, F, G, I, H, J group) nude mice institute lotus cancer cell difference is as follows:Breast cancer cell (MDA- MB231), lung carcinoma cell (A549), thyroid carcinoma cell (SW579), prostate gland cancer cell (LNCaP/AR), pancreatic cancer cell (PANC-1), colon cancer cell (COLO205), head & neck cancer cell (F μ da), nasopharyngeal carcinoma cell (CNE1), stomach cancer cell (BGC823), ovarian cancer cell (PA1).It studies drug to configure by the preparation method of embodiment one, injection dosage is the Asias 100mg First indigo plant/kg animals.7 days after medication, it is euthanized to animal, tumour inhibiting rate is measured after dissection.Table 6 provides result.
Table 6
Test serial number Nude mice institute lotus cancer cell Average tumour inhibiting rate (%)
A Breast cancer cell (MDA-MB231) 76%
B Lung carcinoma cell (A549) 73%
C Thyroid carcinoma cell (SW579) 86%
D Prostate gland cancer cell (LNCaP/AR) 82%
E Pancreatic cancer cell (PANC-1) 91%
F Colon cancer cell (COLO205) 78%
G Head & neck cancer cell (F μ da) 81%
H Nasopharyngeal carcinoma cell (CNE1) 79%
I Stomach cancer cell (BGC823) 85%
J Ovarian cancer cell (PA1) 82%
Using implement 1 prepare other compositions (such as other compositions in table 2) when, can also be observed that with it is upper It states and tests similar result.
Compared with clinical antitumor medicine (such as 5 FU 5 fluorouracil), the chemical ablation agent and activity in the present composition are more Sugar is not the specific drug of cancer cell, and the structure effect relation of their antitumor activity is unclear, is not all included into usually thin Cytotoxic drugs.In vitro in cancer cell experiment, active polysaccharide is not almost shown inhibits cancer cell multiplication to chemical ablation agent Apparent synergistic effect.However, in zoopery, when composition of the invention is administered in tumor, is also only administered in tumor But the effect of remote super 5 FU 5 fluorouracil is shown.
Although not intended to limiting the invention to any specific principle, but think under the conditions of local administration, it is of the invention Composition produces synergistic effect.In view of the inside and outside difference of body shares effect, the effect is antitumor cell association Together as it is chemical ablation cooperates with.Thus, the technical solution obtained as model using tumour, it should be also applied for other parts Lesion relevant disease, it is generally recognized that chemical ablation is suitable for these diseases.

Claims (10)

1. a kind of pharmaceutical composition of prevention and treatment mammal local patholoic change relevant disease, it includes pharmaceutically acceptable Chemical ablation agent and bioactive polysaccharide, and it is formed so that can after the pharmaceutical composition is applied in the local patholoic change Feng Nongdu &gt is provided;1% (w/v), preferably >=1.5% (w/v), more preferably >=2% the chemical ablation agent of (w/v) and Cmax The bioactive polysaccharide of >=0.25% (w/v), preferably >=0.5% (w/v).
2. pharmaceutical composition according to claim 1, wherein the Cmax of the chemical ablation agent is 1.5-15% (w/v), it is excellent It is selected as 2-10% (w/v) or 3-10% (w/v).
3. pharmaceutical composition according to claim 1, wherein the Cmax of the active polysaccharide is 0.25-15% (w/v), preferably For 0.5-10% (w/v), more preferably 1-6% (w/v) or 1-4% (w/v).
4. according to the pharmaceutical composition of one of claim 1-3, wherein the bioactive polysaccharide and chemical ablation agent are in the medicine Weight ratio in compositions is 1:8-6:1, it is preferably 1:4-4:1, it is more preferably higher than 1:4- is less than 4:1 or be more than 1:4- is small In 2:1.
It is liquid dosage form, such as solution, suspension or emulsion 5. according to the pharmaceutical composition of one of claim 1-3; Can be solid or semisolid dosage form, such as implant, drug releasing stent, suppository, creme, cream or gelling agent.
6. according to the pharmaceutical composition of one of claim 1-3, wherein the chemical ablation agent is with chemical ablation function Aromatic compound preferably includes to be selected from following one kind or a variety of:Vital stain, salicylic acid compounds and quinine class chemical combination Object.
7. according to the pharmaceutical composition of one of claim 1-3, wherein the vital stain is methylenum careuleum or its analog, and institute It is &gt to state content of the vital stain in the pharmaceutical composition described pharmaceutical composition can be made to provide Cmax after application;1% (w/v), the vital stain of preferably 1.5-15% (w/v).
8. according to the pharmaceutical composition of one of claim 1-3, wherein the salicylic acid compounds are salicylic acid, acetyl salicylic Acid or its analog, more preferably acetylsalicylic acid or its analog, and the salicylic acid compounds are in the pharmaceutical composition In content can make described pharmaceutical composition provide after application Cmax be >The water of 1% (w/v), preferably 3-15% (w/v) Poplar acid compounds.
9. according to the pharmaceutical composition of one of claim 1-3, wherein the quinine class compound is a quinin hydrochloride, two hydrochloric acid Quinine or its analog, and content of the quinine class compound in the pharmaceutical composition can make described pharmaceutical composition exist It is &gt that Cmax is provided after;The quinine class compound of 1% (w/v), preferably 3-15% (w/v).
10. according to the pharmaceutical composition of one of claim 1-3, it is more than wherein the bioactive polysaccharide includes molecular weight 5000, it is preferably greater than 10000 bio-extract and the like;The bioactive polysaccharide is selected from having the following properties that Bio-extract and the like:Uniform dispersion under room temperature in water is more than 5mg/ml, is preferably greater than 10mg/ml;Institute It states bioactive polysaccharide and preferably includes the one or more of following bio-extract and the like:Algal polysaccharide sulfate, spiral shell Revolve polysaccharides, seaweed selenium poly saccharide, panaxan, Codonopsis pilosula polysaccharide, yellow Stilbene polysaccharide, lentinan, mushroom selenium polysaccharide, pachymaran, Grifola polysaccharide, ganoderma lucidum polysaccharide, coriolan.
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WO2022068918A1 (en) * 2020-09-30 2022-04-07 成都夸常奥普医疗科技有限公司 Pharmaceutical composition comprising acid-base neutralization combination and application thereof
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