WO2021104034A1 - 对羟基苯甲醛于治疗发炎性肠道疾病的用途 - Google Patents

对羟基苯甲醛于治疗发炎性肠道疾病的用途 Download PDF

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WO2021104034A1
WO2021104034A1 PCT/CN2020/128428 CN2020128428W WO2021104034A1 WO 2021104034 A1 WO2021104034 A1 WO 2021104034A1 CN 2020128428 W CN2020128428 W CN 2020128428W WO 2021104034 A1 WO2021104034 A1 WO 2021104034A1
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hydroxybenzaldehyde
present
inflammatory bowel
individual
disease
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PCT/CN2020/128428
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French (fr)
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许竣杰
邱锡临
王筱雯
桂豫竖
张书豪
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财团法人医药工业技术发展中心
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the novel use of 4-hydroxybenzaldehyde (4-HD), in particular to the treatment of inflammatory bowel disease (IBD), or the promotion of wound healing (Wound Healing). )the use of.
  • Inflammatory bowel disease is a group of diseases related to inflammatory symptoms of the colon and small intestine.
  • the main diseases are Crohn's disease (CD, or Crohn's disease) and ulcerative colitis (UC).
  • CD Crohn's disease
  • UC ulcerative colitis
  • Crohn's disease Two types, and a small number of colon diseases that cannot be classified into the aforementioned two types, are called indeterminate colitis, etc.
  • Crohn’s disease mainly occurs in the small intestine and large intestine.
  • the oral cavity, esophagus, stomach and anus are also common sites, while the prevalent sites of ulcerative colitis are concentrated in the colon. And the rectum.
  • Inflammatory bowel diseases are often accompanied by bloody stools (gastrointestinal bleeding), chronic diarrhea (over 3 months), abdominal pain, weight loss, fever, anemia, and inflammation of organs outside the digestive tract such as eyes, skin, and joints. These symptoms It will accompany the patient for life.
  • drugs that can relieve the inflammation.
  • aminosalicylic acid preparations for example, sulfasalazine, mesalazine, etc.
  • immunosuppressive agents for example, prednisone, thiazolidine
  • Purine azathioprine
  • methotrexate methotrexate
  • 6-mercaptopurine 6-mercaptopurine
  • the present invention is based on the inventor's unexpected discovery that p-hydroxybenzaldehyde has the effect of treating inflammatory bowel diseases or healing wounds, so the compound can be used as a therapeutic drug for inflammatory bowel diseases or wound healing.
  • one aspect of the present invention is to provide the use of p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates in the preparation of medicines, wherein the medicines are used to treat inflammatory bowel diseases.
  • the inflammatory bowel disease is Crohn's disease (CD) and ulcerative colitis (UC).
  • the effective amount of the drug for treating inflammatory bowel disease is 1 to 5 mg/kg body weight. In a specific embodiment, the effective amount of the drug for treating inflammatory bowel disease is 3 mg/kg body weight.
  • the individual is a human.
  • Another aspect of the present invention is to provide the use of p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates in the preparation of medicines, wherein the medicines are used to heal wounds.
  • the effective amount of the drug for wound healing is 1 to 5 mg/kg body weight. In a specific embodiment, the effective amount of the drug for wound healing is 3 mg/kg body weight.
  • the individual is a human.
  • Figure 1 shows the toxicity assessment of p-hydroxybenzaldehyde on cells and its anti-inflammatory effect.
  • Panel A The mouse leukemia cell line RAW 264.7 was tested with different concentrations of p-hydroxybenzaldehyde in the presence of lipopolysaccharide (LPS).
  • Panel B RAW 264.7 cells containing lipopolysaccharide (LPS) were tested for the release of nitric oxide (NO) from cells treated with different concentrations of p-hydroxybenzaldehyde.
  • LPS lipopolysaccharide
  • Figure 2 shows the effect of p-hydroxybenzaldehyde on cell repair.
  • Panel A The colorectal cancer cell line Caco-2 was treated with 1 micromolar concentration of p-hydroxybenzaldehyde, and the wound healing assay was used to evaluate the cell repair after 48 hours of drug treatment.
  • B small picture the quantitative data of A small picture is presented as a histogram.
  • Figure 3 shows the results of using p-hydroxybenzaldehyde to treat inflammatory bowel diseases in mice.
  • Panel A After dextran sulfate sodium (DSS) is used to induce IBD in mice, specific treatments are given, and disease activity index (DAI) is evaluated at a specific time point.
  • Panel B daily record of changes in mouse body weight during the experiment.
  • Figure 4 shows the histopathological changes after using p-hydroxybenzaldehyde to treat IBD in mice.
  • Panel A The results of scoring the histopathology of the middle colon of mice after specific treatment.
  • Panel B The results of scoring each histopathological index of the middle colon of the mouse after the specific treatment is administered.
  • treatment used in the present invention can refer to a curative or alleviating measure.
  • treatment used in the present invention refers to the administration or administration of an effective amount of p-hydroxybenzaldehyde according to the present invention to an individual, and the individual is suffering from IBD (for example, clone Disease (CD) and ulcerative colitis (UC)), suffering from symptoms related to IBD, disease or disorder of IBD, or having wounds to relieve partly or completely ( alleviate, ameliorate, relieve, delay onset, inhibit progression, reduce severity, and/or reduce one or more of the symptoms or features of IBD ) Occurrence (reduce Incidence).
  • IBD for example, clone Disease (CD) and ulcerative colitis (UC)
  • administered can be used interchangeably here, and refers to oral, intracranial, intraspinal, intrathecal, intramedullary, intracerebral, intraventricular, intravenous , Intraarterial, intracardiac, intradermal, subcutaneous, transdermal, intraperitoneal, or intramuscular route to administer the para-hydroxybenzaldehyde described in the present invention to an individual in need of treatment.
  • an effective amount refers to an effective amount that enables the treatment of p-hydroxybenzaldehyde according to the present invention to achieve the desired curative effect within the necessary dose and time. (For example, to treat IBD and promote wound healing).
  • an effective dose also means that the therapeutic benefits of a component of a drug exceed the toxic or harmful effects of the component.
  • the effective amount of the agent is not necessarily able to cure the disease or condition, but can delay, hinder or prevent the occurrence of the disease or condition, or can alleviate the symptoms related to the disease or condition.
  • An effective amount can be divided into one, two or more doses and administered once, two or more times in a suitable dosage form within a specified period.
  • the specific effective amount depends on various factors, such as the condition to be treated, the individual’s physical condition (e.g., individual’s weight, age, or gender), the species being treated, the duration of treatment, and concurrent therapy (if any). The nature of the word), the specific dosage form used, and the structure of the compound or its derivative.
  • the effective amount can be expressed in any suitable way.
  • the effective amount of the drug can be expressed as the total weight of the drug (for example, grams, milligrams, or micrograms), or as the ratio of the weight of the drug to the body weight (for example, several milligrams per kilogram of body weight (mg/kg, mg/ Kg)).
  • the effective dose of the drug can be expressed in terms of concentration, for example, molar concentration, mass concentration, volume concentration, molarity, molar fraction , Mass fraction and mixing ratio.
  • concentration for example, molar concentration, mass concentration, volume concentration, molarity, molar fraction , Mass fraction and mixing ratio.
  • the appropriate dosage range is 0.01 mg to 100.0 mg per kilogram of body weight. It should be understood that it is also predictable to adjust the required dosage in a wide range, depending on the different effects caused by different compositions and different administration routes. For example, oral administration is expected to require a higher dose than intravenous injection. Those skilled in the art fully understand that the dosage can be adjusted according to a rule of thumb.
  • Those skilled in the art can convert the dose obtained based on the experimental animal model into a human equivalent dose (HED) of the drug (for example, the p-hydroxybenzaldehyde described in the present invention).
  • HED human equivalent dose
  • those skilled in the art can follow the “Estimating the Maximum Safe Starting Dose of Healthy Adult Volunteers in the Initial Clinical Treatment Test” announced by the US Food and Drug Administration (FDA). Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers) to estimate the highest safe dose for human use.
  • the terms “subject” and “patient” can be used interchangeably, and refer to an animal, including humans, that can be treated with p-hydroxybenzaldehyde according to the present invention. Unless one of the genders is specified, the terms “individual” and “patient” refer to both males and females. Accordingly, the terms “individual” and “patient” include any mammal that can benefit from the p-hydroxybenzaldehyde treatment of the present invention.
  • Examples of the use of the p-hydroxybenzaldehyde in the present invention to treat "individuals" and “patients” include, but are not limited to, humans, rats, mice, guinea pigs, monkeys, pigs, goats, cows, horses, dogs, Cats, birds and chickens.
  • the patient is a mouse.
  • the patient is a human.
  • wound refers to a wound that has been cut, torn, broken, burned, or otherwise damaged to human tissue (traumatized), or trauma caused by a disease or condition that causes such trauma.
  • wound refers to promoting or accelerating the time from wound occurrence (application of p-hydroxybenzaldehyde according to the present invention) to wound closure (wound contraction completely).
  • tissue in the present invention refers to a group of cells that gather together to form a specific function in the human body.
  • tissues include, but are not limited to, bone, skin, connective tissue, and nerves (e.g., spinal cord).
  • pharmaceutically acceptable refers to molecular entities and compositions that are "generally regarded as safe” (generally regarded as safe), for example, they are physiologically tolerable, and are administered to humans At times, allergic reactions or similar adverse reactions, such as nausea, dizziness, etc., are generally not produced.
  • pharmaceutically acceptable as used herein means that it is approved by the regulatory agency of the federal government or state government or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, especially It is used for humans.
  • the present invention is based at least in part on the inventor's unexpected discovery that p-hydroxybenzaldehyde has the property of promoting cell proliferation. Based on the properties of promoting cell proliferation, the present invention provides a pharmaceutical composition containing p-hydroxybenzaldehyde, and a method for promoting wound healing in an individual and treating inflammatory bowel diseases in an individual.
  • the first aspect of the present invention relates to the use of p-hydroxybenzaldehyde in the preparation of medicaments, wherein the medicament can be used to treat inflammatory bowel diseases in an individual or promote wound healing in an individual.
  • the p-hydroxybenzaldehyde of the present invention has a chemical structure of formula (I):
  • p-hydroxybenzaldehyde can react to form salts, esters or solvates. Accordingly, p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates are also suitable for use in the present invention.
  • the salts, esters or solvates of p-hydroxybenzaldehyde can be prepared using conventional methods for preparing salts, esters or solvates well known to those skilled in the art. Taking the preparation of salts as an example, p-hydroxybenzaldehyde can be neutralized with a suitable base to form a base addition salt.
  • Representative base addition salts include salts formed by reaction with organic bases or inorganic bases.
  • organic base examples include, but are not limited to, metal alkoxides (e.g., lithium alkoxide, sodium alkoxide, potassium alkoxide (including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide) )); quaternary ammonium hydroxide (for example, choline hydroxide); and amines (for example, aliphatic amines (ie, alkyl amines, alkenyl amines, alkynyl amines, alicyclic amines), heterocyclic amines, aromatic amines, Heteroaromatic amines, basic amino acids, amino sugars, polyamines).
  • metal alkoxides e.g., lithium alkoxide, sodium alkoxide, potassium alkoxide (including lithium methoxide, sodium methoxide, potassium methoxide, lithium eth
  • the inorganic base examples include, but are not limited to, metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide); metal amides (e.g., lithium amide, sodium amide); metal carbonates (e.g., , Lithium carbonate, sodium carbonate, potassium carbonate); and ammonium bases (e.g., ammonium hydroxide, ammonium carbonate).
  • metal hydroxides e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide
  • metal amides e.g., lithium amide, sodium amide
  • metal carbonates e.g., Lithium carbonate, sodium carbonate, potassium carbonate
  • ammonium bases e.g., ammonium hydroxide, ammonium carbonate.
  • solvate solvate
  • solvate here represents a complex compound formed by the reaction between a compound (for example, p-hydroxybenzaldehyde) and the surrounding solvent molecules (for example, water,
  • the present invention also covers p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates as a form of a pharmaceutical composition, that is, the above-mentioned compound and a pharmaceutically acceptable carrier are formulated into said Pharmaceutical composition.
  • pharmaceutically acceptable carrier refers to a carrier that is compatible with the other ingredients of the formulation and is harmless to the recipient. It can be a diluent, a pharmaceutically acceptable carrier, an excipient, or A stabilizer, which is non-toxic to people who come into contact with it at the dose and concentration used.
  • physiologically acceptable carrier is a pH buffered aqueous solution.
  • Examples of pharmaceutically acceptable carriers include, but are not limited to, buffers (e.g., buffers containing phosphate, citrate, and other organic acids); antioxidants (e.g., ascorbic acid); hydrophilic polymers (e.g., , Polyvinylpyrrolidone); amino acids (for example, glycine, glutamine, asparagine, arginine or lysine); monosaccharides, disaccharides and other carbohydrates (for example, glucose, mannose or dextrin); Chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)); sugar alcohols (e.g., mannitol or sorbitol); salt-forming counterions (e.g., sodium); and/or nonionic surfactants (e.g., spitting Temperature (TWEEN), polyethylene glycol (PEG) and polyoxyethylene/polyoxypropylene ether block copolymer (PLURONIC).
  • buffers e.
  • the weight of the p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates accounts for about 0.1 to 99% of the total weight of the pharmaceutical composition. In some embodiments, the weight of p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates accounts for at least 1% of the total weight of the pharmaceutical composition. In certain embodiments, the weight of p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates accounts for at least 5% of the total weight of the pharmaceutical composition. In other specific embodiments, the weight of p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates accounts for about at least 10% of the total weight of the pharmaceutical composition. In other specific embodiments, the weight of p-hydroxybenzaldehyde, its pharmaceutically acceptable salts, esters or solvates accounts for about at least 25% of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition of the present invention can be formulated into a pharmaceutical preparation.
  • the pharmaceutical preparation of the present invention is suitable for oral, mucosal (for example, nose, sublingual, vagina, buccal or rectal), parenteral (for example, subcutaneous, intravenous, single bolus injection). Injection), intramuscular or intraarterial) and other routes are administered to the patient in a single unit dosage form.
  • dosage forms include, but are not limited to, tablets; caplets; capsules (for example, elastic gelatin capsules); cachet; troche; lozenge ; Dispersion; suppository; ointment; cataplasm (or poultice); paste; powder; dressing; cream; plaster; solution; patch; aerosol (for example, nasal Sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration, including suspensions (for example, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions And elixirs (elixir); liquid dosage forms suitable for parenteral administration; and sterile solids (for example, crystalline or amorphous solids) in liquid dosage forms that can be reduced to facilitate parenteral administration.
  • the scope of the present invention also encompasses these pharmaceutical preparations.
  • compositions should match the mode of administration.
  • oral administration requires enteric coating to protect the pharmaceutical composition of the present invention from degradation in the gastrointestinal tract.
  • pharmaceutical preparations may contain ingredients that help deliver the active ingredient to the site of action.
  • the pharmaceutical composition of the present invention can be administered in the form of a liposome preparation to prevent it from being damaged by degrading enzymes, thereby promoting transportation in the circulatory system, and achieving the purpose of delivery across cell membranes into cells.
  • the part of the pharmaceutical composition of the present invention that contains poorly soluble compounds can be achieved by using solubilizers, emulsifiers, and surfactants (for example, cyclodextrin (for example, ⁇ -cyclodextrin or ⁇ -cyclodextrin)).
  • solubilizers for example, emulsifiers, and surfactants (for example, cyclodextrin (for example, ⁇ -cyclodextrin or ⁇ -cyclodextrin)).
  • Non-aqueous solvents for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, dimethyl sulfoxide (DMSO), biocompatible oils (for example, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, And its mixture (for example, DMSO/corn oil), and incorporated into a liquid dosage form (and a dosage form suitable for reduction).
  • DMSO dimethyl sulfoxide
  • compositions, shape and type of pharmaceutical preparations will vary depending on their use.
  • a dosage form used for the acute treatment of a disease may contain a larger amount of one or more active ingredients than the dosage form used for the chronic treatment of the same disease.
  • a parenteral dosage form may contain a smaller amount of one or more active ingredients than an oral dosage form for treating the same disease. Accordingly, the dosage adjustment between the different dosage forms covered by the present invention is easy to understand for those skilled in the art.
  • Another aspect of the present invention relates to a method of treating inflammatory bowel disease in an individual.
  • the method includes administering an effective amount of the drug of the present invention to the individual to improve, alleviate and/or prevent the symptoms related to the inflammatory bowel disease, wherein the drug of the present invention has the effect of promoting cell proliferation.
  • an individual's inflammatory bowel disease includes Crohn's disease (CD) and ulcerative colitis (UC), as well as a few indeterminate colitis that cannot be classified.
  • the p-hydroxybenzaldehyde of the present invention has the effect of promoting wound healing. Accordingly, yet another aspect of the present invention relates to a method for promoting wound healing in an individual. The method includes administering an effective amount of the drug of the present invention to the individual to promote the healing of the wound.
  • the pharmaceutical composition containing p-hydroxybenzaldehyde of the present invention helps to stimulate the proliferation of epithelial cells and the keratinocytes of the basement membrane to promote wound healing, especially skin wound healing.
  • These wounds may be superficial wounds or deep wounds, and involve damage to the dermis and epidermis of the skin.
  • the individual receiving the p-hydroxybenzaldehyde administration of the present invention may be an individual who is healing the wound at a normal speed, or an individual with impaired healing function.
  • the p-hydroxybenzaldehyde of the present invention is administered to accelerate the normal healing process.
  • administration of the p-hydroxybenzaldehyde of the present invention can promote the healing of the wound, otherwise the wound will heal slowly or not at all.
  • a body hair wound can be caused by surgical wounds, excised wounds, deep wounds involving dermal and epidermal injuries, soft tissue wounds (for example, muscle tears, eye tissue wounds, dental tissue wounds) , Oral wounds, gastrointestinal mucosal wounds and ulcers), skin ulcers, elbow ulcers, arterial ulcers, venous stasis ulcers, burns caused by heat or exposure to extreme temperatures of heat or cold or exposure to chemicals.
  • the pharmaceutical composition of the present invention can still be used to promote dermal reconstruction after skin loss; increase the tensile strength of the epidermis and the thickness of the epidermis; and increase the adhesion of the skin graft to the wound bed and stimulate the re-epithelialization of the wound bed.
  • the dosage, route of administration and dosage regimen of the p-hydroxybenzaldehyde of the present invention will depend on various factors, such as the specific indications to be treated, prevented or controlled, as well as the age, gender, and symptoms of the patient. The proportions of these factors are well known in the art and can be adjusted through routine experimental procedures.
  • the individual to be treated with the p-hydroxybenzaldehyde of the present invention is a mammal. In a specific embodiment, the mammal is a mouse. In another specific embodiment, the mammal is a human.
  • the effective amount of p-hydroxybenzaldehyde in the method of the present invention is between 10 micrograms/kg to 50 mg/kg (for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 or 950 ⁇ g/kg; 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 , 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg/kg) body weight range; preferably It is in the range of 0.1 to 10 mg/kg body weight; more preferably, it is in the range of 1 to 5 mg/kg body weight.
  • the effective amount of p-hydroxybenzaldehyde for example, for treating I
  • the pharmaceutical composition and/or kit of the present invention can be administered via an appropriate route known to those skilled in the art, for example, the various routes described above.
  • the most appropriate route of administration will vary with various factors, such as the nature of the pharmaceutical composition (for example, its stability in the blood circulation), and/or the individual's physiological conditions (For example, whether the individual has tolerance for intraperitoneal administration or intravenous administration) and other factors.
  • the medical staff can determine the exact dosage of the pharmaceutical composition of the present invention within the scope of reasonable medical judgment to achieve a certain medical effect.
  • the specific effective amount for a specific individual or organism will vary depending on different factors, including the disease to be treated and the severity of the disease; the activity of the specific active ingredient used; the composition used; the species, age, Weight, general health, gender and eating habits, severity of side effects or drug abnormalities; time of administration, route of administration, and rate of excretion of active ingredients; duration of treatment; and other factors known in the medical field.
  • an effective amount can be encompassed in a single dose (e.g., a single intravenous injection) or multiple doses (e.g., multiple intravenous injections).
  • the frequency of administering the multiple doses to the individual may be three doses per day, two doses per day, one dose per day, one dose every other day, and one dose every three days. Dose, one dose per week, every two weeks, one dose per month, or one dose every two months. In a specific embodiment, the frequency of administration of the multiple doses to the individual is one dose per day.
  • the interval between the first dose and the last dose is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three days. Months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the life span of an individual. In some embodiments, the interval between the first and last dose of multiple doses is three months, six months, or one year. In some embodiments, the interval between the first and last doses of multiple doses is the lifetime of the individual. In a specific embodiment, the interval between the first dose and the last dose of the multiple doses is two weeks.
  • the mouse leukemia cell line RAW 264.7 cells (American Culture Collection TIB-71 TM ) and human colorectal cancer cell line Caco-2 cells (American Culture Collection HTB-37 TM ) was cultured in Dulbecco’s Modified Eagle’s Medium (containing 4 millimolar L-glutamine, 3.7 g/L sodium bicarbonate and 4.5 g/L glucose) (Dulbecco's Modified Eagle's Medium, DMEM, Gibco, USA), and add 10% fetal bovine serum (FBS) (Gibco, USA). The cells were cultured in a humidified incubator containing 5% CO 2 at 37°C.
  • Dulbecco’s Modified Eagle’s Medium containing 4 millimolar L-glutamine, 3.7 g/L sodium bicarbonate and 4.5 g/L glucose
  • FBS fetal bovine serum
  • RAW 264.7 cells were seeded in a 96-well plate at an amount of 1 ⁇ 10 5 cells per well and cultured at 37°C for 24 hours, then replaced with a serum-free medium and cultured overnight. During the experiment, the cells were placed in the presence of lipopolysaccharide (LPS) (Sigma-Aldrich), and then different concentrations of p-hydroxybenzaldehyde (Sigma-Aldrich) were added and cultured for 24 hours. In the evaluation part of the cytotoxicity test, MTS analysis was used to test the survival rate of the remaining attached cells.
  • LPS lipopolysaccharide
  • p-hydroxybenzaldehyde Sigma-Aldrich
  • Plant Caco-2 cells in a culture insert with an amount of 5 ⁇ 10 5 cells per well. After the cells are attached, the culture container is removed and a micropipette tip is used to create a uniform cell gap (500 ⁇ 100 microns), then add 1 micromolar molar concentration of p-hydroxybenzaldehyde, and analyze the degree of cell migration after 48 hours to evaluate the ability of the cells to heal the wound.
  • a micropipette tip is used to create a uniform cell gap (500 ⁇ 100 microns), then add 1 micromolar molar concentration of p-hydroxybenzaldehyde, and analyze the degree of cell migration after 48 hours to evaluate the ability of the cells to heal the wound.
  • mice were changed to free drinking pure water ( ddH 2 O).
  • specific drugs including sham operation group, carrier control group, mesalazine (Sigma-Aldrich), and p-hydroxybenzaldehyde, etc. were given by feeding tube from the 5th day of the experimental schedule.
  • the animals were scored daily for weight change, diarrhea and bloody stool, and these scores were used to calculate the disease activity index (DAI).
  • DAI disease activity index
  • the experimental data is presented as the mean ⁇ SD.
  • the two-way ANOVA test is used to analyze the differences between different samples/groups, and the difference represented by the P value is less than 0.05 as statistically significant.
  • Example 1 The effect of p-hydroxybenzaldehyde on cell or wound healing
  • the purpose of this example is to test the effects of p-hydroxybenzaldehyde on cells, including cytotoxicity, anti-inflammatory effects, and ability to heal wounds of cells.
  • test the anti-inflammatory effect of p-hydroxybenzaldehyde within the aforementioned test concentration range ie 100, 30, 10, 3, 1 micromolar concentration
  • LPS lipopolysaccharide
  • the experimental results refer to the panel B of Figure 1, indicating that p-hydroxybenzaldehyde has an anti-inflammatory effect on cells and can inhibit the release of NO caused by LPS.
  • This example also tested the effect of p-hydroxybenzaldehyde on cell repair, and the test was evaluated by a wound healing test.
  • the cells were cultured at a molar concentration of 1 microvolume of p-hydroxybenzaldehyde. After 48 hours, the experimental results showed that compared with the cells in the control group, the cells treated with p-hydroxybenzaldehyde had better cell healing Effect (Small A in Figure 2).
  • the quantitative analysis diagram of the related experimental results is shown in Figure 2B small diagram.
  • Example 2 The efficacy of p-hydroxybenzaldehyde in the treatment of intestinal inflammation in mice
  • This example further tests the efficacy of p-hydroxybenzaldehyde in treating inflammatory bowel diseases in vivo.
  • the experimental results are shown in the panels A and B of Figure 3.
  • mesalazine the current first-line drug for the treatment of IBD, as the control drug, the dosage is 180 mg/kg
  • the dose is 30 mg/kg.
  • Treating mice with p-hydroxybenzaldehyde can significantly improve the index trend of disease activity index (DAI) (calculated by the scores of items such as changes in animal weight, diarrhea, and bloody stool) (Figure 3, Panel A), And significantly improved its weight change (Figure 3, Panel B).
  • DAI disease activity index
  • the present invention has provided specific experimental results, confirming that p-hydroxybenzaldehyde has an effective anti-inflammatory effect and has the function of promoting wound healing without causing cytotoxicity.
  • p-hydroxybenzaldehyde also has a significant therapeutic effect on inflammatory diseases in animals (for example, IBD). Accordingly, the p-hydroxybenzaldehyde of the present invention has the potential to be developed as a medicine for treating inflammation or promoting wound healing.

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Abstract

对羟基苯甲醛用于治疗发炎性肠道疾病或者促进伤口愈合的用途。

Description

对羟基苯甲醛于治疗发炎性肠道疾病的用途 技术领域
本发明涉及对羟基苯甲醛(4-hydroxybenzaldehyde，4-HD)的新颖用途，特别是涉及对羟基苯甲醛于治疗发炎性肠道疾病(inflammatory bowel disease，IBD)，或是促进伤口愈合(wound healing)的用途。
背景技术
发炎性肠道疾病是一种关于结肠及小肠的发炎性症状的疾病群，其中主要疾病有克隆氏症(Crohn’s disease，CD，或称克罗恩病)及溃疡性结肠炎(ulcerative colitis，UC)两类，以及少数无法归入前述两类的一些结肠病变，称为未定型结肠炎等。按疾病的好发部位来说，克隆氏症主要好发于小肠及大肠，此外，口腔、食道、胃及肛门也是常见的好发部位，而溃疡性结肠炎的好发部位则是集中在结肠及直肠的部分。
回顾1990年至2016年间有关发炎性肠道疾病流行病学的研究可知，该疾病在过往在西方国家较为常见，以北美及欧洲为例，其发生率约为每10万人口中有6.38人患病，即该二地区各有超过150万人及200万人患病，为患者本身及医疗系统均带来沉重负担。以台湾来说，该疾病的盛行率约为每10万人口中有1.05人患病，在2011至2013年间，即有471个病例报告，该疾病也已明列为全民健康保险的重大伤病。然而，近年来也有流行病学研究显示，亚洲、东欧、非洲及南美等地区，发炎性肠道疾病发生率也有上升趋势，反映出该疾病已对全球公共卫生健康造成威胁。
发炎性肠道疾病经常伴随着血便(肠胃出血)、慢性腹泻(超过3个月)、腹痛、体重下降、发烧、贫血，以及消化道以外的器官如眼 睛、皮肤及关节发炎等症状，这些症状更会终身伴随患者。一旦被诊断出患有发炎性肠道疾病后，通常会建议利用可缓解发炎反应的药物来治疗。举例来说，常见的临床用药有：氨基水杨酸制剂(例如，柳氮磺吡啶(sulfasalazine)、美沙拉嗪(mesalazine)等)；免疫抑制剂(例如，强的松(prednisone)、硫唑嘌呤(azathioprine)、甲氨蝶呤(methotrexate)、6-巯基嘌呤(6-mercaptopurine，6-MP)等)。近年来，也有生物疗法应用于治疗发炎性肠道疾病。而对于严重患者，例如对药物治疗无反应或出现严重并发症者，则需要进行手术治疗。尽管已有上述疗法的帮助，这些疗法仍存在着治疗效果有限、副作用高、无法长期使用等问题，使得现有疗法尚有进一步改善的空间。
进一步地，已有文献指出目前通过阻断或抑制发炎治疗发炎性肠道疾病的治疗方法并不适当，因这种治疗方法将过度抑制发炎反应使组织再生不足(Koji Taniguchi等人，A gp130–Src–YAP module links inflammation to epithelial regeneration，Nature volume 519,pages57–62(2015))。
有鉴于此，相关领域亟需一种抑制发炎且促进伤口再生的治疗方式来治疗发炎性肠道疾病，以改善上述现存的问题，提高治疗效果，以期提升患者的生活质量。
发明内容
下文呈现本发明的简单概要，以利读者对本发明有基本的理解。本概要并非对本发明的广泛性概观，也非用以鉴别本发明的关键性/决定性组件，或勾勒本发明的范围。它唯一的目的在于以一种简化的形式呈现本发明某些概念，作为后续呈现更多详细说明的序幕。
本发明基于发明人意外发现对羟基苯甲醛具有治疗发炎性肠道疾病或是愈合伤口的功效，因此该化合物可作为发炎性肠道疾病或是愈合伤口的治疗药物。
据此，本发明其中一方面是提供对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物于制备药物的用途，其中该药物用以治 疗发炎性肠道疾病。
在某些具体实施例中，该发炎性肠道疾病是克隆氏症(CD)及溃疡性结肠炎(UC)。
根据本发明的某些实施方式，该药物于治疗发炎性肠道疾病的有效量为1至5毫克/千克体重。在一特定实施方式中，该药物于治疗发炎性肠道疾病的有效量为3毫克/千克体重。
根据本发明的某些实施方式，该个体为人类。
本发明另一方面是提供对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物于制备药物的用途，其中该药物用以愈合伤口。
根据本发明的某些实施方式，该药物于愈合伤口的有效量为1至5毫克/千克体重。在一特定实施方式中，该药物于愈合伤口的有效量为3毫克/千克体重。
根据本发明的某些实施方式，该个体为人类。
本发明的一或多个具体实施例的细节在下文附随的说明中阐述。根据详细说明和权利要求书，本发明的其他特征和优点将显而易见。在参阅下文实施方式后，本领域技术人员当可轻易了解本发明的基本精神及其他发明目的，以及本发明所采用的技术手段与实施方式。
附图说明
在参阅以下的详细说明、权利要求书及附随图式后，本发明及其他特征、方面及优点将更明显易懂，其中：
图1为对羟基苯甲醛对细胞的毒性评估及抗发炎的效应。A小图：小鼠白血病细胞株RAW 264.7在含有脂多醣(lipopolysaccharide，LPS)的条件下，检测在以不同浓度的对羟基苯甲醛处理后的细胞存活率。B小图：RAW 264.7细胞在含有脂多醣(LPS)的条件下，检测在以不同浓度的对羟基苯甲醛处理后的细胞释放一氧化氮(nitric oxide，NO)的情形。
图2为对羟基苯甲醛对细胞修复的效应。A小图：以1微体积摩尔浓度的对羟基苯甲醛处理大肠癌细胞株Caco-2，并以伤口愈合试验(wound healing assay)来评估药物处理48小时后的细胞修复情形。B 小图：以直方图呈现A小图的量化数据。
图3为利用对羟基苯甲醛来治疗小鼠发炎性肠道疾病的结果。A小图：以葡聚糖硫酸钠(dextran sulfate sodium，DSS)诱发小鼠IBD后，再施予特定治疗，并在特定时间点上评估疾病活性指数(disease activity index，DAI)。B小图：每日记录实验过程中的小鼠体重变化。
图4为利用对羟基苯甲醛来治疗小鼠IBD后的组织病理学的变化情形。A小图：在施予特定治疗后，对小鼠中段结肠的组织病理学进行评分的结果。B小图：在施予特定治疗后，对小鼠中段结肠的各组织病理学指数进行评分的结果。
具体实施方式
为了使本发明的叙述更加详尽与完备，下文针对了本发明的实施方式与具体实施例提出了说明性的描述；但这并非实施或运用本发明具体实施例的唯一形式。实施方式中涵盖了多个具体实施例的特征以及用以建构与操作这些具体实施例的方法步骤与其顺序。然而，也可利用其他具体实施例来达成相同或均等的功能与步骤顺序。
I.定义
为方便起见，本说明书、实施例及所附权利要求书中所使用的特定专有名词集中在此。除非本说明书另有定义，此处所使用的科学与技术词汇的含义与本领域技术人员所理解与惯用的意义相同。并且，在不和上下文冲突的情形下，本说明书所使用的单数名词涵盖该名词的复数型，而所使用的复数名词时也涵盖该名词的单数型。具体而言，在本说明书与权利要求书中，单数形式“一”(a及an)包括复数参考值，但上下文另有指示的除外。此外，在本说明书与权利要求书中，“至少一”(at least one)与“一或多”(one or more)表述方式的意义相同，两者都代表包含了一、二、三或更多。
虽然用以界定本发明较广范围的数值范围与参数都是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所导致的标准偏差。并且， 在此处，“约”(about)一词通常指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差内，视本领域技术人员的考虑而定。除实施例以外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如，用以描述材料用量、时间长短、温度、操作条件、数量比例及其他类似的)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所公开的数值参数都为约略的数值，且可视需求而更改。至少应将此等数值参数理解为所指出的有效位数与套用一般进位法所得到的数值。
本发明所使用的“治疗”(treatment或treating)一词，可指一种治愈性或缓解性的措施。具体来说，本发明所使用的“治疗”一词，是指对一个体施用或施予一有效量的本发明所述的对羟基苯甲醛，且所述个体是患有IBD(例如，克隆氏症(CD)及溃疡性结肠炎(UC))、患有与IBD相关的症状、IBD的续发性疾病(disease)或病症(disorder)，或是具有伤口，以部分或完全地减缓(alleviate)、改善(ameliorate)、缓解(relieve)、延迟发作(delay onset)、抑制病程(inhibit progression)、降低严重度(reduce severity)，及/或降低IBD之一或多种症状或特征(feature)的发生(reduce incidence)。
在本发明中，“施予”(administered、administering或administration)一词此处可交替使用，并且是指经由口服、颅内、脊椎内、鞘内、髓内、大脑内、脑室内、静脉内、动脉内、心内、皮内、皮下的、经皮、腹腔，或肌肉内途径对一有需要治疗的个体施予本发明所述的对羟基苯甲醛的行为。
本发明所使用的“一有效量”(an effective amount)一词是指一种有效的量，在必要的剂量及时间内，使本发明所述的对羟基苯甲醛的治疗可达到期望的疗效(例如，治疗IBD、促进伤口愈合)的使用剂量。为达到治疗的目的，一有效量也指一种药物的成分的治疗利益超越该成分的毒性或有害影响。药剂的有效量不必然能够治愈疾病或病症，但能够推迟、阻碍或防止该疾病或病症的发生，或是可缓减与疾病或病症相 关的病征。可将一有效量可分成一、二或更多剂，并以适当的剂型在指定期间内施用一次、二次或更多次。具体的有效量取决于各种不同的因素，例如，所欲治疗的病症、个体的生理条件(例如，个体体重、年龄或性别)、接受治疗的物种、治疗持续时间、并行疗法(若有的话)的本质，及所用的具体剂型，以及该化合物或其衍生物的结构。可利用任何适当的方式来表示有效量。举例来说，可将药剂的有效量表示成药物总重量(例如，克、毫克或微克)，或表示成药物重量相对于体重的比例(例如，每千克体重几毫克(毫克/千克，mg/Kg))。或者，可将药剂的有效量以浓度来表示，例如，摩尔浓度(molar concentration)、质量浓度(mass concentration)、体积浓度(volume concentration)、质量摩尔浓度(molality)、摩尔分率(mole fraction)、质量分数(mass fraction)及混合比例(mixing ratio)。适当的剂量范围介于每千克体重0.01毫克至100.0毫克。当可理解，大范围地调整所需剂量也是可预期的，其视不同的组合物及不同的施予路径所致不同效力而定。举例而言，相较于静脉注射，预期口服需要较高的剂量。本领域技术人员完全理解可根据经验法则来调整剂量。本领域技术人员可基于实验动物模式取得的剂量换算成药物(例如，本发明所述的对羟基苯甲醛)的人体等效剂量(human equivalent dose，HED)。举例来说，本领域技术人员可根据美国食品药物管理局(US Food and Drug Administration，FDA)所公告的“估算成人健康志愿者在初始临床治疗测试的最大安全起始剂量”(Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers)来估算人体使用的最高安全剂量。
在本发明中，“个体”(subject)或“患者”(patient)一词可交替使用，是指一种可利用本发明所述的对羟基苯甲醛来治疗的动物，包括人类。除非有具体指出其中一种性别，否则“个体”及“患者”一词是指男性及女性二者。据此，“个体”及“患者”一词包含任何可从本发明所述的对羟基苯甲醛治疗中获益的哺乳动物。可利用本发明所述的对羟基苯甲醛来治疗“个体”及“患者”的实例包括，但不限于，人类、大鼠、小鼠、天竺鼠、猴子、猪、山羊、牛、马、狗、猫、鸟及鸡。 在一示例性的实施方式中，该病患是小鼠。在另一示例性的实施方式中，该病患是人类。
本发明所使用的“伤口”(wound)一词，是指对人的组织被切割(cut)、撕伤(torn)、断裂(broken)、烧伤(burned)，或以其它方式受到损伤的创伤(traumatized)，或由导致这类创伤的疾病或病症引起的创伤。
本发明所使用的“愈合”(healing)一词，是指促进或加速从伤口发生(施用本发明所述的对羟基苯甲醛)至伤口闭合(伤口完全收缩)的时间。
本发明所述的“组织”(tissue)一词，是指人体内集合在一起形成特定功能的一团细胞。组织的实例包括，但不限于，骨、皮肤、结缔组织及神经(例如，脊髓)。
“药学上可接受的”(pharmaceutically acceptable)一词是指“通常认为安全”(generally regarded as safe)的分子实体及组合物，例如，其是生理学上可耐受的，并且在施予至人类时，一般不产生过敏反应或类似的不良反应，例如反胃、头晕等。较佳地，在此使用的“药学上可接受的”一词是指由联邦政府或者州政府的管理机构所批准或是列于美国药典或者其它普遍承认的药典中，以用于动物，特别是用于人类。
II.具体实施方式
本发明至少部分是基于发明人意外地发现对羟基苯甲醛具有促进细胞增生的特性。基于促进细胞增生的特性，本发明提供一种包含对羟基苯甲醛的药学组合物，以及其于促进个体的伤口愈合，以及治疗个体的发炎性肠道疾病的方法。
1.药学组合物
据此，本发明的第一方面是关于对羟基苯甲醛于制备药物的用途，其中该药物可用于治疗个体的发炎性肠道疾病，或促进个体的伤口愈合。
根据本发明一实施方式，本发明的对羟基苯甲醛具有式(I)的化学结构：
Figure PCTCN2020128428-appb-000001
基本上，对羟基苯甲醛可反应形成盐类、酯类或溶剂合物。据此，对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物也适用于本发明的用途中。可利用本领域技术人员所熟知的制备盐类、酯类或溶剂合物的常规方法，来制备对羟基苯甲醛的盐类、酯类或溶剂合物。以制备盐类为例说明，对羟基苯甲醛可用适宜的碱中和形成碱加成盐。代表性的碱加成盐包括与有机碱或无机碱反应形成的盐。所述有机碱的实例包括，但不限于，金属醇盐(例如，醇锂、醇钠、醇钾(包括甲醇锂、甲醇钠、甲醇钾、乙醇锂、乙醇钠、乙醇钾、叔丁醇钾))；氢氧化季铵(例如，胆碱氢氧化物)；以及胺(例如，脂肪胺(即烷基胺、烯基胺、炔基胺、脂环胺)、杂环胺、芳香胺、杂芳香胺、碱性氨基酸、氨基糖、多胺)。所述无机碱的实例包括，但不限于，金属氢氧化物(例如，氢氧化锂、氢氧化钠、氢氧化钾)；金属酰胺(例如，氨基锂、氨基钠)；金属碳酸盐(例如，碳酸锂、碳酸钠、碳酸钾)；以及铵碱(例如，氢氧化铵、碳酸铵)。“溶剂合物”(solvate)一词在此代表由一化合物(例如，对羟基苯甲醛)与其周围的溶剂分子(例如，水、乙醇等)互相反应后所形成的错化物。在一实例中，所述溶合物乃是对羟基苯甲醛的水合物。
基于上述，本发明也涵盖对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物作为一药学组合物的形式，即将上述化合物与一药学上可接受的载体配制成所述药学组合物。
所述“药学上可接受的载体”(pharmaceutically acceptable carrier)一词，是指与制剂的其他成分兼容并且对其接受者无害的载体，可以是稀释剂、可药用载体、赋形剂或稳定剂，其在使用的剂量和浓度下对与之接触的人无毒性。通常生理学可接受的载体为pH缓冲水溶液。 药学上可接受的载体的实例包括，但不限于，缓冲液(例如，含磷酸盐、柠檬酸盐及其他有机酸的缓冲液)；抗氧化剂(例如，抗坏血酸)；亲水性聚合物(例如，聚乙烯吡咯烷酮)；氨基酸(例如，甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸)；单糖、双糖及其他碳水化合物(例如，葡萄糖、甘露糖或糊精)；螯合剂(例如，乙二胺四乙酸(EDTA))；糖醇(例如，甘露醇或山梨醇)；成盐平衡离子(例如，钠)；及/或非离子型表面活性剂(例如，吐温(TWEEN)、聚乙二醇(PEG)及聚氧乙烯/聚氧丙烯醚嵌段共聚物(PLURONIC)。
所述对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物的重量约占该药学组合物总重量的0.1至99％。在一些具体实施例中，对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物的重量约占该药学组合物总重量的至少1％。在某些具体实施例中，对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物的重量约占该药学组合物总重量的至少5％。在其他具体实施例中对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物的重量约占该药学组合物总重量的至少10％。在其他具体实施例中，对羟基苯甲醛、其药学上可接受的盐类、酯类或溶剂合物的重量约占该药学组合物总重量的至少25％。
当可理解，可将本发明药学组合物配制成一药学制剂。根据本发明的某些实施方式，本发明药学制剂是适用于口服、粘膜(例如，鼻、舌下、阴道、颊或直肠)、肠胃外(例如，皮下、静脉内、单次快速注射(bolus injection)、肌肉内或动脉内)等途径施用于患者的单一单位剂型。剂型的实例包括，但不限于，锭剂(tablet)；胶囊型锭剂(caplet)；胶囊(例如，弹性明胶胶囊)；扁囊药剂(cachet)；片剂(troche)；含片(lozenge)；分散液；栓剂；软膏；泥敷剂(cataplasm)(或称膏药(poultice))；糊剂；粉剂；敷料；霜剂；药膏(plaster)；溶液；贴片；气雾剂(例如，鼻喷雾剂或吸入器)；凝胶；适用于口服或粘膜给药的液体剂型，包括悬浮液(例如，水性或非水性液体悬浮液、水包油乳剂，或油包水液体乳剂)、溶液剂及酏剂(elixir)；适于肠胃外给药的液体剂型；以及可通过还原以利肠胃外给药的液体剂型的无菌固体(例如，结晶或无定形固体)等。本发明范围也涵盖这 些药学制剂。
药学制剂应配合给药模式。例如，口服给药需要肠溶衣以保护本发明药学组合物避免在胃肠道内降解。同样地，药学制剂可包含有助于将活性成分递送至作用部位的成分。举例来说，可利用脂质体制剂的形式来施予本发明药学组合物，以避免其受到降解酵素的破坏，进而促进循环系统中的运输，并达到跨细胞膜向细胞内传递的目的。
同样地，本发明药学组合物中有难溶性化合物的部分，可通过使用增溶剂、乳化剂、界面活性剂(例如，环糊精(例如，α-环糊精或β-环糊精))、非水溶剂(例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸芐酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、二甲亚砜(DMSO)、生物兼容性油(例如，棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油及芝麻油)、甘油、四氢糠醇、聚乙二醇、脱水山梨糖醇的脂肪酸酯、以及其混合物(例如，DMSO/玉米油))，而掺入液体剂型(及适用于还原的剂型)中。
药学制剂的剂型组成、形状及类型将视其用途而有所变化。举例来说，用于一种疾病的急性治疗的剂型，相较于相同疾病的慢性治疗中的剂型，可包含更大量的一或多种其包含的活性成分。同样地，肠胃外剂型可包含相较于治疗相同疾病的口服剂型更少量的一或多种其包含的活性成分。据此，本发明所涵盖的不同剂型之间的剂量调整，对于本领域技术人员来说是容易理解的。
2.治疗方法
本发明的另一方面是关于一种治疗一个体的发炎性肠道疾病的方法。该方法包含对该个体施予一有效量的本发明药物施予该个体，以改善、减轻及/或预防与该发炎性肠道疾病相关的症状，其中本发明药物具有促进细胞增生的作用。
根据本发明的特定实施方式，一个体的发炎性肠道疾病(IBD)包括克隆氏症(CD)及溃疡性结肠炎(UC)两类，以及少数无法归类的未定型结肠炎。
此外，本发明对羟基苯甲醛具有促进伤口愈合的作用。据 此，本发明的再另一方面是关于一种促进一个体的伤口愈合的方法。该方法包含对该个体施予一有效量的本发明药物，以促进该伤口的愈合。
基本上，本发明含对羟基苯甲醛的药物组合物有助于刺激上皮细胞增生及基底膜的角化细胞，以促进伤口愈合，尤其是皮肤伤口的愈合。这些伤口可能是浅表伤口或深部伤口，并涉及皮肤的真皮及表皮的损伤。接受本发明对羟基苯甲醛给药的个体可以是以正常速度愈合伤口的个体，或是愈合功能受损的个体。当给药于非属愈合功能受损的个体时，给予本发明对羟基苯甲醛以加速正常愈合的过程。当给药于愈合功能受损的个体时，给予本发明对羟基苯甲醛可以促进其伤口的愈合，否则伤口将愈合缓慢或根本不愈合。
根据本发明的某些实施方式，一个体发伤口可肇因于外科手术伤口、切除的伤口、涉及真皮及表皮损伤的深部伤口、软组织创伤(例如，肌肉撕裂、眼组织伤口、牙组织伤口、口腔伤口、胃肠粘膜的伤口及溃疡)、皮肤溃疡、肘溃疡、动脉性溃疡、静脉淤滞性溃疡、由热或曝露于热或冷的极端温度或曝露于化学品而引起的灼伤。本发明药学组合物尚可用于促进在皮肤丧失之后的真皮重建；增加表皮的抗拉强度和表皮的厚度；以及增加皮肤移植体对伤口床的黏着及刺激伤口床的上皮重新形成。
本发明对羟基苯甲醛的用量、给药途径和给剂方案将取决于各种不同的因素，例如，所欲治疗、预防或控制的具体适应症，以及患者的年龄、性别及病症等。这些因素所占比重是本领域所熟知的，并可通过常规实验步骤来调整。根据本发明的某些实施方式，利用本发明对羟基苯甲醛来治疗的个体是哺乳动物。在一具体实施例中，所述哺乳动物是小鼠。在另一具体实施例中，所述哺乳动物是人类。为达到治疗人类的目的，本发明方法所述对羟基苯甲醛的有效量是介于10微克/千克至50毫克/千克(例如，10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900或950微克/千克；1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、 29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50毫克/千克)体重的范围；较佳地，是介于0.1至10毫克/千克体重的范围；更佳地，是介于1至5毫克/千克体重的范围。在一特定实施例中，本发明方法所述对羟基苯甲醛的有效量(例如，用于治疗IBD或促进伤口愈合)是3毫克/千克体重。
在本发明方法中，可将本发明药学组合物及/或试剂盒经由本领域技术人员所熟知的适当途径来施用，例如上文所述的各种途径施予。一般来说，最适当的给药途径会随着各种不同的因素而有所变化，像是药学组合物的本质(例如，其在血液循环中的稳定性)，及/或个体的生理条件(例如，该个体对于腹腔给药或静脉内给药是否具有耐受性)等因素。
当可理解，医护人员可在合理的医学判断范围内，决定本发明药学组合物的确切用量，以达到一定的医疗功效。对特定个体或有机体的特定有效量将取决于不同因素而有所变化，包括欲治疗的疾病及疾病的严重度；所使用特定活性成分的活性；所使用的组合物；个体的物种、年龄、体重、一般健康状况、性别及饮食习惯、副作用或药物异常情形的严重度；给药时间、给药途径及活性成分的排出速度；治疗的持续时间；以及医疗领域习知的其他因素。
一有效量可以是涵盖在一单一剂量(例如，单一静脉内注射剂)中，或多次剂量(例如，多次静脉内注射剂)中。在某些实施方式中，当对个体施用多次剂量时，对个体施用所述多次剂量的频率可以是每天三剂、每天二剂、每天一剂、每隔一天一剂、每三天一剂、每周一剂、每两周一剂、每个月一剂或每两个月一剂。在一特定实施方式中，对个体施用所述多次剂量的频率是每天一剂。在某些实施方式中，当对个体施用多次剂量时，第一剂与最后一剂的间隔期间为一天、二天、四天、一周、二周、三周、一个月、二个月、三个月、四个月、六个月、九个月、一年、二年、三年、四年、五年、七年、十年、十五年、二十年，或个体的生命期。在某些实施方式中，多次剂量的第一剂与最后一剂的间隔期间为三个月、六个月，或一年。在某些实施方式中，多次剂量的第一剂与最后一剂的间隔期间为该个体的生命期。在一特定实施方式中， 多次剂量的第一剂与最后一剂的间隔期间为二周。
下文提出多个实施例来说明本发明的某些方面，以利本领域技术人员实践本发明。不应将此等实施例视为对本发明范围的限制。据信本领域技术人员在阅读此处提出的说明后，可在不需过度解读的情形下，完整利用并实践本发明。本发明引用的所有公开文献在此通过引用而并入其全文。
实施例
材料及方法
1.细胞培养
将小鼠白血病细胞株RAW 264.7细胞(美国菌种保存中心
Figure PCTCN2020128428-appb-000002
TIB-71 TM)及人类大肠癌细胞株Caco-2细胞(美国菌种保存中心
Figure PCTCN2020128428-appb-000003
HTB-37 TM)培养在达尔伯克氏改良伊格尔氏培养基(含4毫体积摩尔浓度的L-谷氨酰胺、3.7克/升的碳酸氢钠及4.5克/升的葡萄糖)(Dulbecco’s Modified Eagle’s Medium，DMEM，Gibco，U.S.A.)，并添加10％的胎牛血清(fetal bovine serum，FBS)(Gibco，U.S.A.)。将细胞培养在37℃下、含5％的CO 2的加湿培养箱中。
2.细胞毒性及抗发炎试验评估
将RAW 264.7细胞以每孔1×10 5个细胞的量种在96孔板中，并在37℃下培养24小时后，再更换为无血清培养基后培养过夜。进行实验时，使细胞处于脂多醣(LPS)(Sigma-Aldrich)存在的条件下，再加入不同浓度的对羟基苯甲醛(Sigma-Aldrich)，并培养24小时。在细胞毒性试验评估的部分，以MTS分析来测试剩余贴附细胞的存活率。以无菌PBS(Gibco，U.S.A.)清洗96孔板后，加入100微升的含有1毫克/毫升的3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧苯基)-2-(4-磺苯基)-2H-四唑盐(3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt，MTS)(Promega Corp.)的细胞培养液在37℃下培养1小时，以分光光度计分析OD490纳米的吸光值，以评估对羟基苯甲醛对细胞的毒性。
在抗发炎试验评估的部分，收集50微升的细胞培养液，加入50微升的一氧化氮(NO)呈色试剂(Cayman)后，以分光光度计分析OD550纳米的吸光值，以评估对羟基苯甲醛对细胞释放NO的影响。
3.伤口愈合试验
将Caco-2细胞以每孔5×10 5个细胞的量种于培养容器(culture insert)中，待细胞贴附后，将培养容器移除，并以微量吸管尖制造出粗细一致的细胞间隙(500±100微米)，再加入1微体积摩尔浓度的对羟基苯甲醛，48小时后分析细胞移行的程度，以评估细胞于伤口愈合的能力。
4.活体内肠道发炎实验
以葡聚糖硫酸钠(DSS)(MP Biomedicals)诱发小鼠肠道发炎模式来进行实验。配制3％的DSS水溶液使小鼠连续7天自由饮用，以诱发小鼠肠道发炎，并给予足量的一般饲料，并于实验时程第7天起改成使小鼠自由饮用纯水(ddH 2O)。有关小鼠投药时程，在实验时程第5天起以喂食管给予小鼠特定药物(包括假手术组、载体控制组、美沙拉嗪(Sigma-Aldrich)，以及对羟基苯甲醛等)，每天管喂一次，连续9天(至第5至13天)，管喂体积均为10毫升/千克，其中是将对羟基苯甲醛以0.5％的海藻酸盐(alginate)(Sigma-Aldrich)水溶液混合。在实验期间，每天针对动物体重变化、腹泻情形与血便程度进行评分，并将这些评分用以计算其疾病活性指数(DAI)。实验过后，将动物牺牲，并将其肠道组织进行组织切片判读，以评估小鼠肠道发炎、损伤的程度。
5.统计分析
本实验数据是以平均值±SD来呈现。利用Prism8软件分析定量结果。利用二因子变异数分析(Two way ANOVA)检定分析不同样本/组别之间的差异，且P值所代表的差异小于0.05视为具有统计学上的显著意义。
实施例1 对羟基苯甲醛对细胞或伤口愈合的影响
本实施例的目的在于测试对羟基苯甲醛对细胞所产生的影 响，包括细胞毒性反应、抗发炎作用，以及对细胞的伤口愈合的能力等。
首先，在细胞毒性反应的部分，参照图1的A小图的实验结果可知，以不同浓度(100、30、10、3、1微体积摩尔浓度)的对羟基苯甲醛处理RAW 264.7细胞，均不会导致细胞的存活率下降。因此，在测试浓度范围内(1至100微体积摩尔浓度)的对羟基苯甲醛均不会使细胞产生细胞毒性。
接着，测试在前述测试浓度范围内(即100、30、10、3、1微体积摩尔浓度)的对羟基苯甲醛对细胞抗发炎的作用，即抑制脂多醣(LPS)所引起的RAW 264.7细胞的一氧化氮(NO)释放，实验结果参照图1的B小图，说明对羟基苯甲醛对细胞具有抗发炎作用，可抑制LPS所引起的NO的释放。
本实施例还测试对羟基苯甲醛对细胞修护的效果，所述测试是以伤口愈合试验来进行评估。使细胞培养于1微体积摩尔浓度的对羟基苯甲醛的条件下，经48小时后，由实验结果可知，相较于控制组的细胞，以对羟基苯甲醛处理的细胞具有较佳的细胞愈合效果(图2的A小图)。相关实验结果的量化分析图如图2的B小图所示。
实施例2 对羟基苯甲醛于治疗小鼠肠道发炎的功效
本实施例进一步测试对羟基苯甲醛对于治疗活体内发炎性肠道疾病的功效。实验结果如图3的A小图及B小图所示，相较于美沙拉嗪(为现行治疗IBD的一线用药，作为对照用药，使用量为180毫克/千克)，以30毫克/千克的对羟基苯甲醛来治疗小鼠，可明显改善其疾病活性指数(DAI)的指标趋势(包括动物体重变化、腹泻情形与血便程度等项目的评分来计算之)(图3的A小图)，并显著改善其体重变化情形(图3的B小图)。此结果说明，使用对羟基苯甲醛来治疗小鼠，可使小鼠的肠道发炎情形改善，以致可改善小鼠体重的变化量。再者，相较于使用180毫克/千克的美沙拉嗪，对羟基苯甲醛的使用量仅为30毫克/千克，也可改善药物对动物体的有害副作用，以致小鼠的体重未发生剧烈变化(图3的B小图)。
观察小鼠的组织切片的病理变化情形，由组织切片的病理 学判读评分结果可知，相较于载体控制组的小鼠组织切片，以30毫克/千克的对羟基苯甲醛治疗小鼠的组织切片，其病理学判读评分明显下降(图4的A小图)。所述病理学判读评分是综合以下各项病理学指数的整体趋势来评分：(a)细胞浸润程度(白血球浸润，评分为0至5分)；(b)肠腺窝结构(肠腺窝损伤，评分为0至5分)；(c)溃疡的面积大小及相对溃疡程度(溃疡，评分为0至3分)；以及(d)水肿出现情形(0＝不出现，1＝出现)；其中，白血球浸润及肠腺窝损伤的评分为0至5分(0＝正常；1＝些微(<1％)；2＝轻度(1–25％)；3＝中度(26–50％)；4＝中重度(51–75％)；5＝极重度(76–100％)。
再以各项组织切片病理学判读评分来评估对羟基苯甲醛对于小鼠的治疗功效，由实验结果可知，相较于载体控制组的小鼠组织切片，以30毫克/千克的对羟基苯甲醛治疗小鼠的组织切片，其各项病理学指数(包括白血球浸润、肠腺窝损伤、溃疡大小及程度、水肿出现情形等)的判读评分明显下降(图4的B小图)。
综上所述，本发明已提供具体实验结果，证实对羟基苯甲醛在不造成细胞毒性的前提下，可具有有效的抗发炎作用，并有促进伤口愈合的功能。此外，对羟基苯甲醛对于动物体内的发炎病症(例如，IBD)，也具有明显的治疗效果。据此，本发明对羟基苯甲醛有潜力发展为一种治疗发炎或促进伤口愈合的药物。
应当理解的是，前述对实施方式的描述仅是以实施例的方式给出，且本领域技术人员可进行各种修改。以上说明书、实施例及实验结果提供本发明的示例性实施方式的结构与用途的完整描述。虽然上文实施方式中公开了本发明的各种具体实施例，然其并非用以限定本发明，本领域技术人员在不悖离本发明的原理与精神的情形下，当可对其进行各种更动与修饰，因此本发明的保护范围当以附随权利要求书所界定者为准。

Claims (9)

  1. 一种对羟基苯甲醛(4-hydroxybenzaldehyde，4-HD)于制备药物的用途，其特征在于该药物用以治疗个体的发炎性肠道疾病(inflammatory bowel disease，IBD)。
  2. 如权利要求1所述的用途，其中所述发炎性肠道疾病是克隆氏症(Crohn’s disease，CD)或溃疡性结肠炎(ulcerative colitis，UC)。
  3. 如权利要求1所述的用途，其中所述药物用于治疗发炎性肠道疾病的有效量为1至5毫克/千克体重。
  4. 如权利要求3所述的用途，其中所述药物用于治疗发炎性肠道疾病的有效量为3毫克/千克体重。
  5. 如权利要求1所述的用途，其中所述个体为人类。
  6. 一种对羟基苯甲醛于制备药物的用途，其中所述药物用以愈合个体的伤口。
  7. 如权利要求6所述的用途，其中所述药物用于愈合伤口的有效量为1至5毫克/千克体重。
  8. 如权利要求7所述的用途，其中所述药物用于愈合伤口的有效量为3毫克/千克体重。
  9. 如权利要求6所述的用途，其中所述个体为人类。
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