CN108853496B - Application of photosensitizer - Google Patents
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- CN108853496B CN108853496B CN201810569750.9A CN201810569750A CN108853496B CN 108853496 B CN108853496 B CN 108853496B CN 201810569750 A CN201810569750 A CN 201810569750A CN 108853496 B CN108853496 B CN 108853496B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/003—Thiazine dyes
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- 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
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- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
The invention discloses an application of a photosensitizer, which is characterized in that a photosensitizer with bipolarity benzophenoxazine derivatives is applied to the preparation of a medicament for treating hirsutism or skin beauty unhairing; the photosensitizer can excite target molecules under the condition of illumination, the target molecules transfer energy to oxygen molecules, and the high-energy oxygen molecules destroy hair follicle epithelial cells to achieve a good hair removal effect.
Description
Technical Field
The invention relates to a new application of a photosensitizer in preparing a medicament for treating hirsutism, belonging to the technical field of novel medicaments.
Background
The normal hair follicle structure of the human body comprises the hair bulge and the hair bulb part above the hair bulb, both of which contain multipotential cells, which can regenerate into a complete hair follicle, so that both parts must be destroyed simultaneously in order to achieve permanent hair removal.
Methods on the cosmetic market for hair removal generally fall into three broad categories: a mechanical depilation method, a chemical depilation method and a laser depilation method; wherein, the mechanical depilation method 1 is to adopt tweezers to pull out superfluous hair or a razor to scrape off the hair, or a wax depilation method, which has simple operation, can not eliminate the superfluous hair, has short hair regeneration time, can easily cause hair follicle allergy by adopting the repeated depilation method, and is not suitable for large-area depilation; 2. the chemical depilation method is to apply depilatory cream and the like on local skin, so that the hair shaft can be corroded and dissolved to achieve the depilation effect quickly, the effect can last for more than 2 weeks, but if the depilatory cream is repeatedly used for a long time, the skin can be damaged, or chemical and allergic dermatitis can be caused, and the method cannot be used in the areas around eyes, mucous membrane tissues and the like; 3. the laser depilation method involves irradiating the skin surface with laser light to cause protein-like degeneration on the papilla and sebaceous glands, and stopping supply of keratin, thereby inhibiting hair growth. If the damage is sufficient, the follicle can be effectively destroyed and the hair will not regrow, but this method is prone to scarring and pigment changes, and medical laser devices are not used if not specialists, are very expensive, and require long-term treatment.
Photodynamic therapy (PDT) is a medical technology which is developed rapidly in recent years, and has the advantages of safety, small toxic and side effects, no scar, strong selectivity and the like. At present, PDT is mainly applied to the treatment of skin tumors such as actinic keratosis, superficial basal cell carcinoma, Bowen's disease and the like in the treatment of skin pathology. The basic principle of PDT is that the photosensitizer is first administered by systemic or local administration. The difference of photosensitizer accumulation between target cells and surrounding normal cells is utilized to enable the photosensitizer to specifically accumulate in the target cells. Then after laser irradiation with specific wavelength, the photosensitizer is excited to generate a series of photochemical reactions to generate cytotoxic substances such as free radicals or free radical ions and the like, and target cells are specifically killed; meanwhile, the thrombus caused by the irradiation of local vascular endothelial system can be damaged, so that the irradiation of local ischemia and hypoxia can be realized, and the treatment purpose is achieved.
PDT is mainly applied to the treatment of skin tumors such as actinic keratosis, superficial basal cell carcinoma, Bowen's disease and the like in dermatology. With the insight into the mechanism of action of photodynamic therapy and the development of novel photosensitizers, the application of PDT in dermatology has expanded from neoplastic diseases to a variety of non-neoplastic diseases. There is no report on depilation by photodynamic therapy.
Disclosure of Invention
Compared with the defects in the prior art, the invention aims to provide the application of the photosensitizer in preparing the medicament for treating hirsutism or skin beautifying unhairing, the photosensitizer can effectively realize local or large-range unhairing of skin and is suitable for treating various hirsutism symptoms or skin beautifying.
In order to achieve the technical purpose, the invention provides an application of a photosensitizer, which is applied to the preparation of a medicament for treating hirsutism or skin beauty unhairing, wherein the photosensitizer has a structure shown in a formula 1;
wherein R is1、R2And R3Independently selected from alkyl groups.
Preferred photosensitizers are those in which R is1、R2And R3Is independently selected from C1～C4Alkyl groups of (a); the alkyl group may be a straight-chain alkyl group or a branched-chain alkyl group, and preferably a straight-chain alkyl group. R1、R2And R3A short chain alkyl group is selected. Not only can improve the penetrating ability of photosensitizer molecules, but also can improve the light excitation activity of the photosensitizer molecules through an electronic effect.
The photosensitizer of the invention can be synthesized by referring to the existing literature report method, such as the synthetic route (with R) as follows1And R2Is ethyl, R3For methyl or ethyl as examples):
the photosensitizer adopted in the technical scheme of the invention is a bipolar (hydrophilic and lipophilic) benzophenoxazine derivative, the benzophenoxazine derivative has high photosensitive activity, absorption wavelength of more than 650 nanometers (up to about 700 nanometers), certain fluorescence performance and no dark cell toxicity, can selectively adsorb diseased cells and higher adsorption rate, can permeate through places with larger gaps such as hair follicles, sebaceous glands and sweat glands of the skin, has higher enrichment degree in the hair follicles, and particularly has targeting property, under ultraviolet or infrared illumination, the benzophenoxazine derivative target molecule can be excited, the target molecule transmits energy to oxygen molecules, and the high-energy oxygen molecules damage the epithelial cells of the hair follicles, so that the hair removal effect is achieved.
In a preferred method of use, the hirsutism comprises familial hereditary hirsutism, adrenal hirsutism, hirsutism associated with adrenal tumors, hirsutism caused by cushing's disease, hirsutism with congenital adrenal cortical hyperplasia, central hirsutism, hypothalamic and pituitary hirsutism, ovarian hirsutism, drug-induced hirsutism, insulin resistance syndrome and hirsutism, idiopathic hirsutism, hypothyroidism hirsutism, menopausal hirsutism, or pregnancy hirsutism.
In a preferred application method, the photosensitizer is prepared into oral drugs, intravenous injection drugs, local infiltration injection drugs, air-compression needleless injection drugs, external coating drugs or surface spraying drugs.
In a more preferred application method, the photosensitizer is prepared into a local infiltration injection medicament or an air-compression needle-free injection medicament.
In the preferred application method, the light wavelength is not limited when the photosensitizer is excited by light, and in the more preferred application method, the photosensitizer can activate oxygen molecules under the illumination of light with the wavelength of 600-1000 nm to obtain high-energy oxygen capable of damaging hair follicle epithelial cells. The wavelength of light is preferably 630nm to 690nm, most preferably 650nm to 690 nm. The light source used may be one or more of a laser tube, a fuel laser, a halogen metal lamp, a white heat ray light source.
The photosensitizer of the present invention is in the form of a salt or hydrate. When used as a drug, the photosensitizer is present in the drug at a concentration of 50. mu.M to 1mM, preferably 200. mu.M to 500. mu.M.
The photosensitizer is used as a hair removal medicament, the photosensitizer is administered through oral administration, injection or external application and the like, a proper amount of photosensitizer (EtNBS) is administered to a hairy individual, when the concentration of the photosensitizer in hair follicles and hair papilla reaches the treatment concentration, the non-treatment part is protected from light, the treatment part is illuminated, the intensity and time of a treatment light source are adjusted along with the treatment effect, and the photosensitizer is applied topically in an ice way after treatment and strictly protected from light to prevent secondary photoreaction.
When the photosensitizer is excited by light, the light intensity is not particularly limited, and the irradiation time is properly prolonged when the light intensity is weakened; when the light intensity is stronger, the irradiation time is appropriately reduced or the number of irradiation times is appropriately reduced to adjust the excitation of the photosensitizer. When the photosensitizer is excited by light, the intensity of the light is preferably controlled properly, and too strong or too weak can influence the activation degree of the photosensitizer, and too strong light can cause adverse effects such as damage of surrounding normal skin tissues, and too weak light cannot permeate target tissues, so that the photoactivation effect is poor. Therefore, the light intensity range is preferably 1 to 100J/cm2The optimum range is 30 to 50J/cm2. In order to achieve good effect and no damage to normal skin around hair follicles, the optimal irradiation time is also provided except the optimal irradiation intensity, and the optimal irradiation time is 5-10 min. The time interval between the injection of the photosensitizer and the irradiation of light is 10-240 min, but the optimal time interval is 30-60 min to achieve the optimal targeting effect.
Compared with the prior art, the technology of the invention has the beneficial technical effects that: the photosensitizer of the benzophenoxazine derivative is used for preparing the medicine for treating hirsutism or skin beautifying and unhairing for the first time, and the photosensitizer can permeate through places with larger gaps such as hair follicles, sebaceous glands, sweat glands and the like of the skin and has higher enrichment degree in the hair follicles. And then the target molecules of the benzophenoxazine derivatives are excited under the illumination condition, the target molecules transfer energy to oxygen molecules, and the high-energy oxygen molecules destroy hair follicle epithelial cells to achieve a good hair removal effect.
Drawings
Fig. 1 is a pathological photograph of the skin of the back of a mouse after EtNBS photodynamic therapy, and the picture shows that the atrophy of hair follicles and hair papilla disappears.
Fig. 2 is a pathological photograph of the back skin of a normal mouse, which shows normal hair follicles and hair papilla structures.
Detailed Description
The following examples are intended to illustrate the present disclosure in detail, but not to limit the scope of the claims of the present invention.
Example 1
Test to determine the appropriate photosensitizer concentration:
first, preparation of experiment
1. Preparing experimental animals: several BALB/c mice of similar age and weight were prepared.
2. Preparing an experimental reagent: dissolving a photosensitizer EtNBS in physiological saline, preparing photosensitizer solutions with different concentrations, and filtering for sterilization; preparing 5% chloral hydrate solution, filtering and sterilizing.
3. Preparing an experimental device: surgical scissors, an insulin syringe and an LED lamp.
Second, the experimental procedure
1. The back hairs of the BALB/c mice are cut to be 1-2 mm by a surgical scissors. Applying depilatory cream for 20 min to remove hair.
2. And (3) injecting 5% chloral hydrate solution into the abdominal cavity of the mouse for anesthesia, wherein the injection amount is 400-500 mg/kg.
3. Six points are taken at the shearing part of each mouse after anesthesia for intradermal injection of photosensitizer with different concentrations, and the six injection points are kept at relatively uniform distances. Concentrations were 0, 100, 200, 300, 400 μ M EtNBS (sixth spot was injected after red irradiation, i.e., no light, as control) and an injection volume of 25 μ L. And (5) shading for 30-60 min.
4. Irradiating the part injected with the photosensitizer for 5-10 min by using an LED light source with the wavelength of 640-660 nm, wherein the irradiation power is 50-120 mW/cm2。
5. The mice were returned to cages and kept in the dark. The results were observed and recorded daily.
Third, experimental results
Hair regrowth was observed after PDT treatment:
the results show that photodynamic treatment with increasing EtNBS concentration significantly reduced hair regrowth relative to the blank group; when EtNBS reached 300 μ M, PDT treatment damaged most of the follicles, achieving permanent hair removal.
Example 2
Experiment to observe hair follicle injury:
first, preparation of experiment
1. Preparing experimental animals: the same as in example 1.
2. Preparing an experimental reagent: 300 mu M photosensitizer solution, 5 percent chloral hydrate solution, 4 percent paraformaldehyde solution, hematoxylin, eosin, sirius red dye solution and conventional reagents for preparing paraffin sections.
3. Preparing an experimental device: surgical scissors, an insulin syringe, an LED lamp, a paraffin slicer, an embedding machine and a microscope.
Second, the experimental procedure
1. The back hairs of the BALB/c mice are cut to be 1-2 mm by a surgical scissors. Applying depilatory cream for 20 min to remove hair.
2. And (3) injecting 5% chloral hydrate solution into the abdominal cavity of the mouse for anesthesia, wherein the injection amount is 400-500 mg/kg.
3. After anesthesia, the site of each mouse was tapped at the clipping site for intradermal injection of the photosensitizer. According to the results of experiment one, we selected the injection concentration to be 300. mu.M and the injection amount to be 25. mu.L. And (4) after injection, carrying out light-shielding treatment for 30-60 min.
4. Irradiating the part injected with the photosensitizer for 5-10 min by using an LED light source with the wavelength of 640-660 nm, wherein the irradiation power is 50-120 mW/cm2。
5. The mice were returned to cages and kept in the dark. The mice are sacrificed 1-21 day after the light treatment, and the skin tissue of the treated part is fixed in 4% paraformaldehyde solution.
6. After a certain time of fixation, dehydration, transparence, embedding, flaking and the like are carried out according to the steps of conventionally manufacturing paraffin sections, HE staining and sirius red staining are carried out, and the pathological structure of the tissue is observed.
Third, experimental results
FIG. 1 is a photograph of skin pathology 14 days after 300 μ M PDT.
As can be seen from FIGS. 1 and 2, the number of hair follicles in the skin tissue of the experimental group (FIG. 1) was small, the arrangement was sparse and the hair follicles were atrophic compared with that of the control group (FIG. 2), indicating that the method had a good effect on hair removal.
It will be appreciated that the EtNBS-photodynamic epilation treatment of the invention is versatile.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for persons skilled in the art, it is possible to make various modifications and improvements to the drugs and treatment schemes without departing from the spirit of the present invention, and these modifications and improvements are within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (7)
1. Use of a photosensitizer, characterized in that: applying the photosensitizer with the structure of formula 1 to prepare a medicament for treating hirsutism or skin beautifying unhairing;
wherein R is1、R2And R3Is independently selected from C1～C4Alkyl group of (1).
2. Use according to claim 1, characterized in that: the hirsutism comprises familial hereditary hirsutism, adrenal hirsutism, hirsutism accompanied by adrenal tumor, hirsutism caused by cushing's disease, androgenetic hirsutism with congenital adrenal cortical hyperplasia, central hirsutism, hypothalamic and pituitary hirsutism, ovarian hirsutism, drug-induced hirsutism, insulin resistance syndrome and hirsutism, idiopathic hirsutism, hypothyroidism hirsutism, menopausal hirsutism or pregnancy hirsutism.
3. Use according to claim 1, characterized in that: the photosensitizer is prepared into oral drugs, intravenous injection drugs, local infiltration injection drugs, air compression needleless injection drugs, external coating drugs or surface spraying drugs.
4. Use according to claim 3, characterized in that: the photosensitizer is prepared into a local infiltration injection medicament or an air-compression needle-free injection medicament.
5. Use according to any one of claims 1 to 4, characterized in that: the photosensitizer can activate oxygen molecules to obtain high-energy oxygen under the illumination of light with the wavelength of 600-1000 nm.
6. Use according to claim 5, characterized in that: the illumination intensity is 1-100J/cm2。
7. Use according to claim 1, 3 or 4, characterized in that: the concentration of the photosensitizer in the medicine is 50 mu M-1 mM.
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Citations (1)
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|---|---|---|---|---|
| WO2004091531A3 (en) * | 2003-04-15 | 2005-05-19 | Gen Hospital Corp | Methods and devices for epithelial protection during photodynamic therapy |
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| US20090259167A1 (en) * | 2008-04-04 | 2009-10-15 | The General Hospital Corporation | Methods and compositions for dose-dependent photodynamic therapy of disorders |
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|---|---|---|---|---|
| WO2004091531A3 (en) * | 2003-04-15 | 2005-05-19 | Gen Hospital Corp | Methods and devices for epithelial protection during photodynamic therapy |
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| Applications of Aminolevulinic Acid-Based Photodynamic Therapy in Cosmetic Facial Plastic Practices;Kristina Zakhary等;《AMINOLEVULINIC ACID-BASED PHOTODYNAMIC THERAPY》;20051231;第21卷(第2期);第110-116页 * |
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Application publication date: 20181123 Assignee: Hunan Gangwan Scientific Instrument Co.,Ltd. Assignor: HUNAN NORMAL University Contract record no.: X2023980053471 Denomination of invention: Application of a photosensitizer Granted publication date: 20210611 License type: Common License Record date: 20231227 |