CN116509831A - Use of external preparation containing crocetin or pharmaceutically acceptable salt thereof - Google Patents
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- CN116509831A CN116509831A CN202310702635.5A CN202310702635A CN116509831A CN 116509831 A CN116509831 A CN 116509831A CN 202310702635 A CN202310702635 A CN 202310702635A CN 116509831 A CN116509831 A CN 116509831A
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- pharmaceutically acceptable
- crocetin
- external preparation
- treating
- caused
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- 229950008882 polysorbate Drugs 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 238000012827 research and development Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/18—Antioxidants, e.g. antiradicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The application discloses an application of an external preparation containing crocetin or pharmaceutically acceptable salt thereof. The external preparation for treating the cheAN_SNhitis caused by chemotherapy is developed, is convenient to use, has few toxic and side effects, and can effectively relieve symptoms such as cracking, desquamation, erosion, crusting and the like of lips of the cheAN_SNhitis caused by chemotherapy; the application expands the application field of crocetin medicaments, discovers the new application of crocetin and salt thereof, can be prepared into an external preparation for preventing/treating skin inflammation or skin injury, has better effect in preventing/treating the skin injury caused by keratitis and oxidative stress caused by chemotherapy, and has better treatment effect when being combined with chlorogenic acid. The crocetin and the salt thereof are prepared into an external preparation with higher stability, and a high-purity product is easier to obtain, thus being more suitable for the development of medicines.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of an external preparation containing crocetin or pharmaceutically acceptable salt thereof.
Background
The cheAN_SNhitis caused by chemotherapy is a disease which frequently occurs when a tumor patient is subjected to chemotherapy, and the body immune system is seriously damaged during the chemotherapy due to the serious side effect of a high-intensity chemotherapeutic medicament, and the serious and persistent cheAN_SNhitis of the patient can be caused by adding body oxygen free radicals, inflammatory factors and the like caused by the chemotherapeutic medicament. Unlike common inflammation caused by infection, the latter can be treated with anti-infective drugs, but has little effect on inflammation caused by chemotherapy. Some anti-inflammatory, antioxidant, hormonal and immunosuppressant oral drugs can relieve symptoms to a certain extent, but they cannot accurately aim at the symptoms of the keratitis, and have low oral bioavailability, large toxic and side effects, heavy drug dependence and inconvenient use. At present, the external effective drugs for the targeted treatment of the keratitis caused by chemotherapy are relatively lacking, if the external preparation for treating the keratitis can be developed for symptomatic treatment, the drugs can directly act on the disease parts, the defects of large dosage of the oral preparation, relatively high toxic and side effects and poor patient compliance are avoided, and the effect of the disease treatment can be obviously improved.
In view of the above, there is a need in the art to develop an external preparation effective for chemotherapy-induced stomatitis.
Disclosure of Invention
The invention aims to provide an application of an external preparation containing crocetin and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a method for preventing and/or treating stomatitis.
It is another object of the present invention to provide a method for preventing and/or treating skin damage caused by oxidative stress.
To solve the above technical problems, the first aspect of the present invention provides an external preparation containing crocetin or a pharmaceutically acceptable salt thereof, for use in:
(i) Preventing and/or treating the keratitis caused by chemotherapy;
(ii) Preventing and/or treating skin damage caused by oxidative stress;
(iii) Preparing a medicament for preventing and/or treating the keratitis caused by chemotherapy;
(iv) Preparing a medicament for preventing and/or treating skin aging caused by oxidative stress;
(v) Improving cracking, drying, desquamation, erosion and/or crusting of lips; and/or
(vi) Improving skin redness, erythema, blister and/or erosion.
In some preferred embodiments, the oxidative stress-induced skin cell damage is hydrogen peroxide-induced skin damage.
In some preferred embodiments, the external preparation further comprises chlorogenic acid or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the mass percentage of crocetin or a pharmaceutically acceptable salt thereof and chlorogenic acid or a pharmaceutically acceptable salt thereof is (0.8-1.2): (0.8-1.2).
In some preferred embodiments, the mass of the crocetin or a pharmaceutically acceptable salt thereof in the external preparation is 0.5-2%, for example 1.5% of the total mass of the external preparation.
In some preferred embodiments, the mass of chlorogenic acid or a pharmaceutically acceptable salt thereof in the external preparation is 0.5-2%, for example 1.5%, of the total mass of the external preparation.
In some preferred embodiments, the external preparation further comprises pharmaceutically acceptable excipients.
In some preferred embodiments, the pharmaceutically acceptable excipients include emulsifiers, humectants, acid-base modifiers, and water.
In some preferred embodiments, the emulsifier is selected from at least one of stearic acid and glyceryl monostearate.
In some preferred embodiments, the humectant is selected from at least one of petrolatum and glycerin.
In some preferred embodiments, the acid-base modifier is sodium hydroxide.
In some preferred embodiments, the pharmaceutically acceptable excipients include stearic acid, glyceryl monostearate, petrolatum, glycerin, sodium hydroxide, and water.
In some preferred embodiments, the external preparation is used for preventing and/or treating skin cell damage caused by oxidative stress and/or preparing a medicament for preventing and/or treating skin cell damage caused by oxidative stress, so that the expression level of antioxidant enzyme superoxide dismutase can be increased; reducing malondialdehyde levels; and/or increasing hydroxyproline content of the epidermal cells.
In a second aspect, the present invention provides a method for preventing and/or treating chemotherapy-induced stomatitis, the method comprising the steps of:
a therapeutically effective amount of an external preparation containing crocetin or a pharmaceutically acceptable salt thereof is administered to a subject.
In some preferred embodiments, the frequency of administration is at least 1 time per day for at least 1 day of continuous administration.
In a third aspect the present invention provides a method of preventing and/or treating oxidative stress induced skin cell damage, the method comprising the steps of:
a therapeutically effective amount of an external preparation containing crocetin or a pharmaceutically acceptable salt thereof is administered to a subject.
In some preferred embodiments, the oxidative stress-induced skin cell damage is hydrogen peroxide-induced skin cell damage.
In some preferred embodiments, the mode of administration is at least 1 time daily for at least 1 day continuously.
A fourth aspect of the present invention provides an external preparation comprising: crocetin or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable excipients.
In some preferred embodiments, the external preparation further comprises chlorogenic acid or a pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention has at least the following advantages:
(1) The invention develops an external preparation for treating the keratitis caused by chemotherapy, has convenient use and less toxic and side effects, and effectively relieves the symptoms of lip cracks, desquamation, erosion, crusting and the like of the keratitis caused by the chemotherapy;
(2) The invention overcomes the defect that crocin is not suitable for non-injection administration, discovers the new application of crocin acid and salt thereof, can be prepared into an external preparation for preventing/treating the stomatitis caused by radiotherapy or the stomatitis caused by skin injury chemotherapy caused by oxidative stress, has better effect, and the crocin acid and salt thereof are prepared into the external preparation with higher stability, are easier to obtain high-purity products, and are more suitable for pharmaceutical development.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
One or more embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings.
FIG. 1 is a schematic illustration of the protective effect of crocetin and its sodium salt on oxidative damage to endothelial cells in accordance with an embodiment of the present invention, p < 0.01vs model group;
FIG. 2 is a high temperature stability test (8 h at 60 ℃) of crocin I according to an example of the invention;
FIG. 3 is a high temperature stability test (10 days at 60 ℃) of crocetin according to an embodiment of the present invention;
FIG. 4 is a high temperature stability test (10 days at 60 ℃) of sodium crocate according to an example of the invention.
Detailed Description
The Chinese medicinal materials stigma croci, also called stigma croci, are derived from dry stigma croci of Iridaceae plant Crocus sativus, and have effects of promoting blood circulation, removing blood stasis, cooling blood, removing toxic substances, resolving stagnation, and tranquilizing. The main active ingredient in stigma croci comprises crocin (crocin), and the content of crocin in the medicinal materials exceeds 10%. In the prior literature, the therapeutic effect of crocin on cardiovascular diseases is reported. Because the stability of the crocin is low, the crocin is difficult to permeate the biological membrane, so that the bioavailability of the crocin is obviously low when the crocin is not injected, and the administration route of the therapeutic drug for skin diseases is mostly not injected, so that the crocin has little research on application to the aspect of treating the skin diseases. Because of the consensus that crocin has too low bioavailability when administered by non-injection, researchers in the field have no more interest in exploring its application value in diseases (e.g., skin diseases) that rely on administration by non-injection routes such as painting, external application, and the like. The inventor finds that the crocetin has better stability and remarkably better bioavailability in a non-injection way in research, and on the basis, the inventor unexpectedly finds that the crocetin or the pharmaceutically acceptable salt thereof prepared into an external preparation has remarkable effect in treating the cheilitis caused by chemotherapy.
Compounds of formula (I)
The category of the compounds of the present invention includes crocetin, its pharmaceutically acceptable salts and prodrugs thereof.
As used herein, the term "crocetin" has the structure shown in formula I below, with CAS numbers 27876-94-4.
As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases (including inorganic and organic bases). Where applicable, pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and crocetin. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, and numerous other bases well known in the pharmaceutical arts. In a preferred embodiment of the invention, the "pharmaceutically acceptable salts" are sodium, potassium, ammonium, magnesium, calcium, ferrous, zinc salts.
Indication of disease
The invention relates to application of crocetin and pharmaceutically acceptable salts thereof, which are used for:
(i) Preventing and/or treating the keratitis caused by chemotherapy; (ii) Preparing a medicament for preventing and/or treating the keratitis caused by chemotherapy; (iii) Preventing and/or treating skin cell damage caused by oxidative stress; (iv) Preparing a medicament for preventing and/or treating skin cell injury caused by oxidative stress; (v) Improving cracking, drying, desquamation, erosion and/or crusting of lips; and/or (vi) improving skin redness, erythema, blistering, and/or erosion.
As used herein, the term "keratitis" refers to the symptoms of cracking, drying, desquamation, erosion and/or crusting at lips and corners of the mouth, which are caused by the severe damage and inflammation reaction of the body due to the active oxygen free radicals, inflammatory factors and other components generated by the tumor patient during chemotherapy, and the keratitis can cause the pain of the corners of the mouth, the speaking, swallowing and other functions of the patient to be affected, and the chemotherapy dose of the patient has to be reduced when serious, so that the effect of treating tumors is affected.
External preparation
The invention also relates to an external preparation comprising crocetin or pharmaceutically acceptable salt thereof, comprising crocetin or pharmaceutically acceptable salt thereof; and pharmaceutically acceptable excipients.
In a preferred embodiment of the present invention, the external preparation further comprises chlorogenic acid (CAS No. 327-97-9) or a pharmaceutically acceptable salt thereof, and the inventors have found that when the external preparation contains crocetin or a pharmaceutically acceptable salt thereof and chlorogenic acid or a pharmaceutically acceptable salt thereof together, a remarkable synergistic effect can be produced, and a better therapeutic effect on cheAN_SNhite caused by chemotherapy is achieved.
Preferably, the crocetin or the pharmaceutically acceptable salt thereof accounts for 0.5-2% of the total mass of the external preparation.
Preferably, the mass of chlorogenic acid or pharmaceutically acceptable salt thereof accounts for 0.5-2% of the total mass of the external preparation. Preferably, m crocetin or a pharmaceutically acceptable salt thereof: m chlorogenic acid or a pharmaceutically acceptable salt thereof is (0.8-1.2): (0.8-1.2).
As used herein, the term "external preparation" refers to a preparation applied to the surface of the skin, such as a powder, lotion, patch, tincture, liniment, ointment, gel, paste, aerosol, etc., for protecting the skin, treating various skin site diseases, or treating certain systemic diseases.
As used herein, the terms "pharmaceutically acceptable adjuvant" and "pharmaceutically acceptable carrier" are used interchangeably to refer to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other components of the pharmaceutical formulation and is suitable for contact with tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In a preferred embodiment of the present invention, a "pharmaceutically acceptable excipient" is an excipient commonly used in the art for preparing a formulation for administration by a topical route such as by application, spraying, external application, etc., and exemplified by vaseline, paraffin, liquid paraffin, stearic acid or a salt thereof, glyceryl monostearate, lanolin, beeswax, spermaceti, sodium dodecyl sulfate, stearyl alcohol, cetyl alcohol, sorbitan fatty, polysorbate, methylparaben, ethylparaben, glyceryl stearate, sodium alginate, gelatin, benzyl benzoate, simethicone, glycerin, sodium hydroxide, etc. In a preferred embodiment of the present invention, the pharmaceutically acceptable excipients include emulsifiers, humectants, acid-base modifiers and water. The emulsifier is at least one selected from stearic acid and glyceryl monostearate. The humectant is at least one selected from vaseline and glycerol. The acid-base regulator is sodium hydroxide.
In a more preferred embodiment of the present invention, the external preparation comprises crocetin or a pharmaceutically acceptable salt thereof, stearic acid, glyceryl monostearate, petrolatum, glycerin, sodium hydroxide and water. As an active ingredient, crocetin or a pharmaceutically acceptable salt thereof is contained in an amount of not less than 1% by mass of the total mass of the external preparation. As pharmaceutically acceptable excipients, the components may be combined in reasonable proportions to form liquids, gels, pastes, etc., the excipients used to form these formulations and their suitable proportions are well known to those skilled in the art as a result of conventional techniques. In the present invention, preferably, the external preparation is prepared as a paste.
Therapeutic method
The invention also relates to a method for preventing and/or treating keratitis caused by chemotherapy, comprising the steps of: a therapeutically effective amount of an external preparation containing crocetin or a pharmaceutically acceptable salt thereof is administered to a subject.
As used herein, the term "preventing" refers to preventing the onset, recurrence or spread of a disease or disorder, or one or more symptoms associated with the disease or disorder. In one embodiment, the symptoms are known to those of skill in the art to be associated with the disease or condition to be prevented. In certain embodiments, the term refers to the administration of a compound of the invention with or without other additional active agents prior to the onset of symptoms in a patient at risk of suffering from a disease or disorder as described herein. The term includes inhibition and reduction of symptoms of a particular disease. In particular embodiments, patients with a family history of a disease are particularly candidates. In addition, patients with a history of recurrent symptoms are also potential preventive candidates. In this regard, the term "preventing" may be used interchangeably with the term "prophylactic treatment".
As used herein, the term "treating" refers to eradicating or ameliorating a disease or disorder, or one or more symptoms associated with the disease or disorder. In one embodiment, the symptoms are known to those of skill in the art to be associated with the disease or condition to be treated. In particular embodiments, the term refers to minimizing the spread or exacerbation of a disease or disorder by administering one or more prophylactic or therapeutic agents to a subject suffering from the disease or disorder. In some embodiments, the term refers to the administration of a compound of the invention with or without other additional active agents after onset of symptoms of a particular disease.
As used herein, the term "subject" is defined herein to include animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In a particular embodiment, the subject is a human.
As used herein, the term "therapeutically effective amount" refers to an amount of a compound that is sufficient to provide a therapeutic effect in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic effect in the treatment or management of a disease or disorder. The term "therapeutically effective amount" may include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent. Preferred dosages of the active compounds for all the mentioned conditions of the invention are in the range of about 10ng/kg to 300mg/kg, preferably 0.1 to 100 mg/kg/day. The compound is conveniently administered in any suitable unit dosage form including, but not limited to, unit dosage forms containing less than 1mg, 1mg to 3000mg, preferably 5 to 500mg of active ingredient per unit dosage form.
As used herein, the term "administration" refers to the means of administering a drug to a subject by various routes, such as oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal, sublingual, and suppository forms of administration in single or divided doses. In the present invention, the external preparation is administered by transdermal form.
Cosmetic composition
The invention also relates to a cosmetic composition comprising crocetin or a salt thereof, and a cosmetically acceptable adjuvant.
As used herein, the term "cosmetic" refers to daily chemical industry products that are spread on any part of the surface of the human body (skin, hair, nails, lips, etc.) in a manner that is applied, sprayed, or otherwise similar, for the purposes of cleansing, eliminating bad odors, skin care, beauty and finishing, including, illustratively, shampoos, conditioners, lotions, creams, body lotions, lipsticks, lip glazes, lip oils, lip films, masks, foundations, facial washes, essential oils, perfumes, lotions, and the like. In a preferred embodiment of the present invention, the cosmetic means at least one of lip oil, lip enamel, lip film, lipstick and lipstick. In a preferred embodiment of the present invention, the cosmetic means at least one of an emulsion, a face cream, a face mask, a body lotion and a body lotion.
As used herein, the term "cosmetically acceptable adjuvant" is any chemical ingredient added to protect the product, facilitate storage or ease of use, such as, for example, tackifiers, humectants, sunscreens, preservatives, surfactants, antioxidants, colorants, fragrances, chelating agents, and film agents, and the like.
The present invention will be further described with reference to specific embodiments in order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated. The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs, it is to be noted that the terms used herein are used merely to describe specific embodiments and are not intended to limit the exemplary embodiments of this application.
EXAMPLE 1 prescription composition of ointment for human use and preparation method
In this example, formulations A and B were prepared and obtained as ointments containing crocetin.
Prescription a per 100g of ointment the prescription composition is as follows:
stearic acid: 15g;
glycerol monostearate: 3g;
vaseline: 10g;
sodium hydroxide: 0.5g;
glycerol: 10g;
crocetin: 1g;
water: the remainder being water.
Stearic acid: 15g; glycerol monostearate: 3g; vaseline: 10g; sodium hydroxide: 0.5g; glycerol: 10g; crocetin: slowly adding water in the process of continuously stirring after 1g of the mixture, adding water to make up 100g, and continuously stirring to form a uniform paste.
Prescription B the composition per 100g of ointment was as follows:
stearic acid: 15g;
glycerol monostearate: 3g;
vaseline: 10g;
sodium hydroxide: 0.5g;
glycerol: 10g;
crocetin: 1g;
chlorogenic acid: 1g;
water: the remainder being water.
Stearic acid: 15g; glycerol monostearate: 3g; vaseline: 10g; sodium hydroxide: 0.5g; glycerol: 10g; crocetin: 1g; chlorogenic acid: slowly adding water in the process of continuously stirring after 1g of the mixture, adding water to make up 100g, and continuously stirring to form a uniform paste.
Example 2 animal modeling method exploration of model of cheAN_SNhitis caused by chemotherapy
In this example, the method of the inventor literature (Xiaolong, etc., research progress of animal models of radiotherapy and chemotherapy oral mucositis, prevention and treatment of oral diseases, 2020, volume 28, 322-326) adopts a combination of a chemotherapeutic drug and a mechanical injury method to construct an animal model of cheAN_SNhitis caused by chemotherapy. The test method comprises the following steps:
SD rats are selected, after adaptive culture, 40mg/kg of 5-fluorouracil (5-FU) is injected into the abdominal cavity, 3 days are continued, and the lips of the rats are mechanically injured by adopting an injection needle under the precondition of anesthesia on the 4 th day. The Sonis scoring method is used for judging the severity of the stomatitis, and the scoring standard is as follows:
0 point: the lips are normal, and congestion and erosion are avoided;
1, the method comprises the following steps: erythema but no erosion of lips;
2, the method comprises the following steps: severe erythema and congestion of lips, forming superficial erosion;
3, the method comprises the following steps: severe erythema, hyperemia of the lips, one or more ulcers formed, but not more than 1/4 of the total lips;
4, the following steps: the area of the ulcer formed is approximately 1/2 of the area of the lip;
5, the method comprises the following steps: the lips showed complete flaky ulcers and the lip surface lost softness.
EXAMPLE 3 therapeutic Effect of external preparation on stomatitis caused by chemotherapy injury
In this example, the test drug and placebo used were prepared as follows:
drug for test: respectively weighing 50 mg, 100mg and 200mg of crocetin (or sodium crocetin) and dissolving in 2mL of dimethyl sulfoxide (DMSO), adding 10g of Vaseline, and uniformly mixing to prepare low, medium and high dose group ointments for later use.
Placebo: 2mL of DMSO is added to 10g of vaseline and mixed well for use.
In this example, we selected the model animal modeling method described in example 2 to study the therapeutic effect of the pharmaceutical composition on the treatment of keratitis caused by chemotherapy injury, and the specific groupings are as follows: animals in each group 10
Healthy animal group: the test animals were not modelled and placebo without drug was used;
placebo group: modeling of the test animals using placebo without drug;
saffron low (L), medium (M), high (H) dose groups: modeling an experimental animal, and using a medicament containing crocetin (50, 100 and 200 mg) to administer the medicament to the animal in a mode of external use;
low (L), medium (M), high (H) dose groups of sodium crocetin: modeling an experimental animal, and using a medicament containing sodium crocetin (50, 100 and 200 mg) to administer the medicament to the animal in a mode of external use;
the experimental method is simply introduced as follows:
after the test animals are adaptively cultured, the test animals are randomly selected to be grouped, modeling is started, and corresponding medicines or placebo (2 times per day) are externally used for lips after daily modeling treatment according to grouping conditions. After the fourth day of mechanical injury molding was completed, medication was continued until the 6 th, 8 th, 10 th and 12 th day of scoring, and the results were recorded in table 1.
Table 1 therapeutic effect (score) of pharmaceutical compositions on chemotherapy-induced stomatitis (mean±sd, n=10)
* Model group p < 0.05vs, model group p < 0.01vs
As can be seen from table 1 above, the animals of the model group exhibited more typical symptoms of stomatitis compared to the healthy animals, and the symptoms of stomatitis gradually improved after the modeling was terminated. Compared with the model group, both the crocetin and sodium crocetin salt group show better treatment effect, especially in the high-dose group, the symptoms of the stomatitis are obviously lighter than those of the model group, and most data show obvious differences. The active sites of the crocetin and the sodium salt thereof are acid radical parts of the crocetin and the sodium salt thereof are irrelevant to metal ions forming salt, and the treatment effect produced by the same dosage is similar, so that the mixture with different proportions can still produce similar treatment effect and the treatment effect similar to that of the crocetin with the same dosage can be presumed.
EXAMPLE 4 therapeutic Effect of sodium crocetin and chlorogenic acid Compound on chemotherapy-induced stomatitis
In the research and development process, the combined use effect of sodium crocate and different monomer medicines is researched, and as a result, the effect of treating the cheAN_SNhite caused by chemotherapy is obviously enhanced when sodium crocate and chlorogenic acid are combined.
The placebo in this example is the same as in example 3.
In this example, three drug groups of sodium crocate (200 mg), chlorogenic acid (200 mg), sodium crocate (100 mg) +chlorogenic acid (100 mg) were prepared, and the preparation method was as described in example 3.
The present embodiment is divided into the following groups:
healthy animal group: the test animals were not modelled and placebo without drug was used;
placebo group: modeling of the test animals using placebo without drug;
sodium crocetin high dose group, chlorogenic acid high dose group, sodium crocetin+chlorogenic acid high dose group: the animal is molded, and three medicines are used respectively.
In order to further study the treatment effect of the compound pharmaceutical composition on the chemotherapy of the stomatitis, the modeling method in the embodiment moderately increases the mechanical damage degree on the basis of the reference embodiment 2, so that the oral inflammation of the model animal is relatively more serious. The administration method and scoring method and criteria of this example are the same as those of example 3, and the final scoring and statistics of each group of treated experimental animals are as follows:
table 2 therapeutic effect (score) of pharmaceutical compositions on chemotherapy-induced stomatitis (mean±sd, n=10)
* Model group p < 0.05vs, model group p < 0.01vs, # p < 0.05vs, crocetin H group, # p < 0.01vs, chlorogenic acid H group Deltap < 0.05vs, chlorogenic acid H group DeltaDeltap < 0.01vs
As shown in table 2 above, when the combination is used, the drug effect of the drug replacement (crocetin or chlorogenic acid) with the same concentration is obviously better than that of the model group, most of data are better than those of the crocetin group H and the chlorogenic acid group H, and the results show that the combination has a certain synergistic effect when the combination is used, and can better resist the oral corner inflammation caused by the chemotherapeutic drugs.
EXAMPLE 5 protective Effect of pharmaceutical compositions on oxidative stress induced skin cell injury
The theory of aging free radicals suggests that damage to skin cells caused by free radical accumulation is one of the main causes of skin inflammation and aging. The high-energy ionizing radiation used in ultraviolet rays and radiotherapy and the chemotherapeutic drugs can generate a large amount of free radicals (which are also important reasons for the latter to kill cancer cells and cause healthy cell damage), thereby causing skin inflammation, cell damage and apoptosis. The dermis is mainly composed of fibroblasts, which play an important role in the skin inflammation and aging process.
In this example, the method of the inventor reference (Du Xianhua et al, H 2 O 2 Inducing in vitro cultured skin fibroblast oxidative stress injury, journal of senile science, 2011, volume 31, 644-646), selecting human dermal fibroblast, and using H 2 O 2 Inducing oxidative stress injury of cells, and determining the protective effect of the pharmaceutical composition of the invention on oxidative stress injury. The experimental method comprises the following steps:
the method of the reference cultures human dermal fibroblasts, after the adherent growth is completed, the following groupings are set:
normal cell group: normally cultured cells, without addition of H 2 O 2 Inducing damage, and adding DMSO solvent with the same volume for treating for the same time;
H 2 O 2 treatment group: cell addition 100. Mu. M H 2 O 2 Injury is induced (4 h), and colleagues add the same volume of DMSO solvent for the same time;
saffron low (L), medium (M), high (H) dose groups: cell addition 100. Mu. M H 2 O 2 Inducing injury (4 h), and simultaneously adding saffron acid DMSO solutions with different concentrations to ensure that the final concentration of the saffron acid in the culture solution is respectively 50, 100 and 200 mug/mL;
low (L), medium (M), high (H) dose groups of sodium crocetin: cell addition 100. Mu. M H 2 O 2 Inducing injury (4 h), and simultaneously adding crocetin DMSO solutions with different concentrations to make crocetin in culture solutionFinal concentrations were 50, 100, 200. Mu.g/mL, respectively;
after the above treatment, the cell viability was measured by MTT method, and data statistics were performed, and the results are shown in FIG. 1.
The results show that the crocetin and the sodium salt thereof have better resistance to H 2 O 2 The effect of the oxidative damage is caused, the activity of the epidermal cells treated by the oxidative damage is obviously increased, and the epidermal cells show better dose response relation. We speculate that the mechanism of activity may be related to antioxidant, apoptosis preventing, etc.
The procedure of reference, the same procedure was used to prepare a different batch of cells treated in groups for determining the activity and content of superoxide dismutase (SOD), malondialdehyde (MDA) and hydroxyproline (HP, an amino acid characteristic of collagen) in the cell culture broth, and the results are shown in table 3 below:
table 3 pharmaceutical composition pair H 2 O 2 Effect of induced cell damage (mean±sd, n=6)
* Model group p < 0.05vs, model group p < 0.01vs
From table 3 above, it can be seen that crocetin and sodium salt thereof can significantly increase the expression of antioxidant enzyme SOD, reduce the production of oxidation product MDA, increase the content of epidermal cell HP, and have significant difference at medium and high doses.
EXAMPLE 6 comparative study of the high temperature stability of crocin and crocin
Crocetin is rare in plant bodies, and can be prepared by hydrolyzing crocin through a chemical method and a biological method (shown as a formula II below), has poor water solubility, and can have good water solubility through forming common sodium salt, potassium salt and other forms.
In this example, the inventors will compare the stability of crocin I and crocin acid, sodium salt of crocin acid. The test refers to a method for testing high-temperature influence factors in Chinese pharmacopoeia (2020 edition four), and the test is terminated in due time by combining the stability of the product.
Experiments show that the stability of the crocin is very poor, and a large amount of degradation can be caused by a high-temperature test at 60 ℃ for only 4 hours. In contrast, crocetin and its sodium salt are very stable, and only degraded slightly when left at 60 ℃ for 10 days (see fig. 2-4 for specific results).
The results of this example show that compared with crocin, crocin acid and its sodium salt, it has very strong stability, and is very suitable for its development as medicine, meeting the requirement of "quality control" of medicine. The former is very poor in stability, so that the former is likely to be degraded in shelf life when being used as a medicine for development, and cannot be used as a medicine raw material. The crocin existing in plants has various types (such as I, II, III, and the like), has similar structures and strong water solubility, so that the crocin is extremely difficult to separate and purify, and is not beneficial to developing the crocin into medicine raw materials. The saffron acid part as the main active unit is selected to be used, so that the purification difficulty can be obviously reduced, and the purity of the product can be increased.
In summary, the inventors' studies found that crocetin and its sodium salt, when used alone or as a pharmaceutical composition, have remarkable effects against cheilitis caused by radiotherapy and chemotherapy and dermatitis caused by solar irradiation. In addition, the stability is strong, and the traditional Chinese medicine composition is suitable for being used as a raw material medicine of medicines. Meanwhile, because crocetin has poor water solubility and good fat solubility, when the crocetin is used as an external medicine or daily chemical product, the crocetin is not easy to be dissolved by water, saliva, sweat and other body fluids, so that the pigment is caused to flow to the outside of an affected part to increase the cleaning difficulty, and the crocetin is more convenient in the use process, thereby being more suitable for being used as an external preparation.
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples of carrying out the invention and that various changes in form and details may be made therein without departing from the spirit and scope of the invention.
Claims (10)
1. Use of an external preparation comprising crocetin and pharmaceutically acceptable salts thereof for:
(i) Preventing and/or treating the keratitis caused by chemotherapy;
(ii) Preventing and/or treating skin damage caused by oxidative stress;
(iii) Preparing a medicament for preventing and/or treating the keratitis caused by chemotherapy;
(iv) Preparing a medicament for preventing and/or treating skin aging caused by oxidative stress;
(v) Improving cracking, drying, desquamation, erosion and/or crusting of lips; and/or
(vi) Improving skin redness, erythema, blister and/or erosion.
2. The use according to claim 1, wherein the external preparation further comprises chlorogenic acid or a pharmaceutically acceptable salt thereof.
3. The use according to claim 1, wherein the crocetin and pharmaceutically acceptable salts thereof are present in the external preparation in an amount of 0.5-2% by mass.
4. The use according to claim 2, wherein the chlorogenic acid and its pharmaceutically acceptable salts in the external preparation are present in an amount of 0.5-2% by mass.
5. The use according to claim 2, wherein in the external preparation, the mass percentage of crocetin or a pharmaceutically acceptable salt thereof and chlorogenic acid or a pharmaceutically acceptable salt thereof is (0.8-1.2): (0.8-1.2).
6. The use according to claim 1, wherein the external preparation further comprises pharmaceutically acceptable excipients.
7. The use according to claim 6, wherein the pharmaceutically acceptable excipients comprise emulsifiers, humectants, acid-base modifiers and water.
8. The use according to claim 7, wherein the emulsifier is selected from at least one of stearic acid and glycerol monostearate; and/or
The humectant is at least one of vaseline and glycerol; and/or
The acid-base regulator is sodium hydroxide.
9. A method for preventing and/or treating chemotherapy-induced keratitis, said method comprising the steps of:
a therapeutically effective amount of an external preparation containing crocetin or a pharmaceutically acceptable salt thereof is administered to a subject.
10. A method for preventing and/or treating oxidative stress induced skin cell damage, said method comprising the steps of:
a therapeutically effective amount of an external preparation containing crocetin or a pharmaceutically acceptable salt thereof is administered to a subject.
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