CN113197937B - A composition for preventing, alleviating or treating radiodermatitis - Google Patents

Abstract

The invention provides a composition for preventing, relieving or treating radiodermatitis, preferably an external dressing composition such as a mask, which comprises 80-120 parts of astragalus membranaceus, 40-60 parts of cortex mori, 40-60 parts of cortex acanthopanacis, 5-20 parts of pseudo-ginseng powder and 1-5 parts of menthol in parts by weight. Also provided are a method for preparing the composition and its use in preparing a medicament for preventing, alleviating or treating radiodermatitis. The invention can effectively prevent or relieve the radiodermatitis, particularly acute radiodermatitis, which usually occurs in the radiotherapy process of various malignant tumor patients.

Description

A composition for preventing, alleviating or treating radiodermatitis

Technical Field

The invention relates to the technical field of pharmaceutical compositions, in particular to a composition for preventing, relieving or treating radiodermatitis, particularly acute radiodermatitis.

Background

Currently, radiation therapy (RT, generally abbreviated as radiotherapy) is a local treatment method for treating tumors by using radiation. The radiation includes alpha, beta and gamma rays generated by radioactive isotopes, and X rays, electron beams, proton beams and other particle beams generated by various X-ray therapeutic machines or accelerators. About 70% of cancer patients need radiotherapy in the process of treating cancer, about 40% of cancers can be cured by radiotherapy, therefore, the role and the position of radiotherapy in tumor treatment are increasingly prominent, and the radiotherapy becomes one of the main means for treating malignant tumors.

It has been reported that up to 95% of patients receiving radiation therapy may experience some form of Radiodermatitis or radiation-induced skin damage (see, e.g., singh M et al radiodermatisis: a review of outer current understating. Am J Clin Dermatol.2016; 17-277-92, the disclosure of which is incorporated herein by reference in its entirety). Particularly, acute dermatitis, i.e., acute radiodermatitis, is caused after receiving radiation exposure in a short time with an excessive dose. While reducing the total dose of radiation and using advanced radiation therapy modalities can help to reduce the extent of radiation damage to the skin, radiation dermatitis remains one of the most common side effects of radiation therapy.

The severity of radiodermatitis due to radiotherapy is currently assessed by the National Institutes of Health (NIH) and National Cancer Institute (NCI) published "standard of evaluation for Common Adverse Events", in which more than 3 levels of Adverse Events occur that can seriously affect the therapeutic effect of the patient and even be life-threatening, for example, radiodermatitis that requires a reduction in the dose of radiation or an interruption of the treatment regimen to avoid further deterioration can negatively affect the anti-tumor therapeutic effect, while continuing radiotherapy despite side effects can lead to a life-threatening risk of radiodermatitis.

Attempts have been made to use agents in the course of radiation therapy to prevent or reduce the radiodermatitis side effects of radiation therapy. For example, abbas H et al use triethanolamine emulsion to prevent radiodermatitis of head and neck tumors (Abbas H et al, trolamine emulsion for the prevention of radiation disorders in patients with squamous cell Cancer of the head and the neck, supplementary Care in Cancer,2012,20 (1): 185-190, the disclosure of which is incorporated herein in its entirety by reference). Alice Y et al use 0.1% Mometasone Furoate (MF) to prevent severe Acute radiodermatitis in Breast Cancer radiotherapy Patients (PMRT) (A randomised Trial of Mometasone Furoate 0.1%. To Reduce High Grade ingredient Radiation diagnosis in Breast Cancer Patients Receiving Postmastustentaction Radiation [ J ]. International Journal of Radiation Oncology Biology Physics,2018, the disclosure of which is incorporated herein by reference in its entirety. However, none of these measures can prevent the acute radiation dermatitis caused by high dose radiotherapy during radiotherapy, especially in short time, for example, the incidence of more than 3 grade acute radiation dermatitis still reaches 30-50%.

Chinese medical workers also try to prepare medicines by using unique Chinese medicinal ingredients in China to relieve the influence of radiodermatitis, but generally relate to a composition consisting of a plurality of Chinese medicaments and even dozens of Chinese medicaments, for example, chinese patent documents CN104587214A, CN104623311A, CN104706970A, CN103768237A, CN 10430666669A, CN105560744A and the like, and the disclosures of the Chinese patent documents are all incorporated by reference. From the disclosures of these documents, besides the complicated formulation, difficult quality control and unfavorable popularization, the following disadvantages exist: most of the treatment is carried out after the radiodermatitis occurs, and the radiotherapy is continued after the effect is improved, so that the operation time is still delayed, and the tumor is prevented from progressing due to untimely radiotherapy; also, from their disclosed effect, there is still some incidence of severe radiodermatitis above grade 3 after treatment.

More importantly, only radiation doses of around 40Gy are used in view of the doses disclosed in these documents. Such a dose is only used at the beginning of radiotherapy or for a tumor with high sensitivity, but for a tumor with low sensitivity, the dose is usually required to be gradually increased to 50-60 Gy or even more than 70Gy, and particularly when high-dose irradiation is required to be provided within a short time, the possibility of serious side effects of more than 3 grades, particularly acute radiodermatitis, is greatly increased, and the solution disclosed in the above document cannot solve the problem of acute radiodermatitis occurring under the condition of high dose.

Disclosure of Invention

In order to solve the defects of the prior art, the invention adopts the following technical scheme:

on one hand, the invention provides a composition for preventing, relieving or treating radiodermatitis, which comprises 80-120 parts of astragalus membranaceus, 40-60 parts of cortex mori, 40-60 parts of cortex acanthopanacis, 5-20 parts of pseudo-ginseng powder and 1-5 parts of menthol in parts by weight.

In a preferred embodiment, the composition of the present invention comprises 100 parts of astragalus root, 50 parts of cortex mori radicis, 50 parts of cortex acanthopanacis, 10 parts of panax notoginseng powder and 2 parts of menthol, wherein the parts are calculated by weight.

In a further preferred embodiment, the radiodermatitis according to the invention is acute radiodermatitis, preferably acute radiodermatitis above CTCAE standard grade 3.

In a still further preferred embodiment, the composition of the invention further comprises aloe vera gel.

In a second aspect, the invention provides an external dressing composition for preventing, relieving or treating radiodermatitis, which comprises 200-300 parts of aloe gel, 80-120 parts of astragalus membranaceus, 40-60 parts of cortex mori, 40-60 parts of cortex acanthopanacis, 5-20 parts of pseudo-ginseng powder and 1-5 parts of menthol in parts by weight.

In a preferred embodiment, the external dressing composition of the present invention comprises 250 parts of aloe vera gel, 100 parts of astragalus, 50 parts of cortex mori, 50 parts of cortex acanthopanacis, 10 parts of panax notoginseng powder, and 2 parts of menthol, all in parts by weight.

In a further preferred embodiment, the external dressing is a mask.

In a third aspect, the invention provides a method for preparing the composition, which comprises the steps of accurately weighing the astragalus, the white mulberry root-bark, the cortex acanthopanacis and the pseudo-ginseng powder in parts by weight, adding normal-temperature tap water to soak for 0.5-2 hours, boiling with strong fire, decocting with slow fire for 20-40 minutes, filtering, standing, taking supernatant, putting the supernatant together with the aloe gel and the menthol in parts by weight in a grinder, stirring and mixing for 3-5 minutes at 8000-12000r/min, filtering through gauze, taking filtrate, and preparing the filtrate and an external dressing material into an external dressing composition, preferably a facial mask.

In a third aspect, the invention provides the use of the composition in the manufacture of a medicament for the prevention, alleviation or treatment of radiodermatitis.

In a preferred embodiment, the radiodermatitis is acute radiodermatitis, preferably acute radiodermatitis above CTCAE standard grade 3.

The components selected by the composition are common traditional Chinese herbal medicine components, and the mask material aloe gel is one of the accepted beauty mask materials and belongs to components harmless to human health.

Multiple experimental studies and clinical tests show that the mask material can effectively prevent or relieve radiodermatitis, particularly acute radiodermatitis, which usually occurs in the radiotherapy process of various malignant tumor patients, and particularly for radiotherapy with the cumulative radiation dose of more than 50Gy, obvious acute radiodermatitis, such as related symptoms of acute radiodermatitis above CTCAE standard grade 3, is still not generated, so that the radiotherapy process is completely and smoothly completed.

The mask dressing is an improvement of a traditional Chinese medicine collapse method, regenerated cellulose saturated with liquid medicine is adopted to wash a face towel for wet dressing on an affected part, the moisture retention time and the medicine use time are quite long, the touch feeling is better, the skin irritation is small, and the medicine effect can be exerted to the maximum extent.

Detailed Description

The following describes embodiments of the present invention in further detail. It will be understood by those skilled in the art that the present invention is not limited to these embodiments and those skilled in the art can modify or replace some technical features of the embodiments so long as they can achieve substantially the same purpose, solve substantially the same technical problems, and achieve substantially the same technical effects, and they still fall within the scope of the present invention as claimed in the appended claims.

The term "radiodermatitis" as used herein refers to inflammatory lesions of the skin mucosa caused by irradiation with radiation (primarily beta and gamma rays and X-rays), including but not limited to patients receiving radiation therapy and those who are not seriously protected from radiation work. The term "radiodermatitis" as used herein refers not only to dermatitis that is specifically diagnosed as being due to radiation exposure, but also includes any skin reaction and damage due to radiation exposure, including but not limited to reversible erythema, dry skin, telangiectasia, desquamation, hair loss, pigmentation, edema, itching, tenderness and burning sensation, and irreversible skin atrophy, sebaceous/sweat gland destruction, permanent hair loss, fibrosis, and radionecrosis or even ulceration, as long as they are all due to radiation exposure.

The term "acute radiodermatitis" as used herein refers to acute onset, marked radiodermatitis, usually caused by one or more large doses of radiation, but also in sensitive individuals even if the dose is not very large. Acute and chronic radiodermatitis can be interconverted, whether acute or not depends on, but is not limited to, the onset time, the manifestation, physical signs, patient experiences, the stage of radiotherapy, the dose of radiation, etc., and is included in acute radiodermatitis as long as it substantially affects the progress of radiotherapy.

The term "radiotherapy" as used herein refers to radiation therapy, a local treatment for malignant tumors using radiation. The radiation includes, but is not limited to, alpha, beta, gamma rays generated by radioisotopes, and X-rays, electron beams, proton beams, and other particle beams generated by various types of X-ray treatment machines or accelerators. The high-energy X-rays used in radiotherapy produce direct and indirect ionization effects, which not only cause damage to cancer cells, but also cause damage to normal tissues. Transient mild erythema may occur within hours after radiation therapy, possibly due to telangiectasia in the patient shortly after radiation exposure, and persistent pigmentation or erythema will generally not occur until 2 to 4 weeks after treatment. Inevitably, a small proportion of rapidly proliferating cells in the basal layer of the skin are damaged or destroyed in radiotherapy, resulting in a reduction in differentiated epidermal keratinocytes. This may lead to Skin desquamation, i.e., exfoliation and exfoliation of the epidermis (see, e.g., koenig TR et al Skin in ingredients from fluoroscopically guided products: part 1, characteristics of radiation in surgery. AJR Am J Roentgenol.2001, the contents of which are incorporated herein by reference.

In the early stages of radiation therapy, hair follicles and sebaceous glands are affected, leading to dry skin and hair loss. As erythema progresses, reactions may occur that resemble sunburn, with edema, itching, tenderness and burning sensations. Impairment of the skin barrier function carries the risk of wound formation, loss of immune function and infection. In addition, radiation can also damage the microvasculature, increase the risk of tissue hypoxia and Fibrosis, and activate inflammatory cascades leading to acute and chronic skin changes (see, e.g., haase O et al fibers and cytokine mechanisms: relent in hydro thermal radiation Oncol.2004;73 (supl 2): S144-S147; bentzen SM. Preventor reduction of tissue effects of radiation: radiobiological media molecular biology. Nat Rev cancer.2006;6 702-13; and Martin M et al TGF-beta1 and radiation therapy: a master switch and a specific thermal target J radiation physiology. Phys.2000; incorporated herein by reference).

Dry desquamation is manifested as itching and flaking of the skin, which may occur at cumulative doses exceeding 20Gy over 3 to 6 weeks in radiotherapy (see, e.g., mcQuestion m. Observation-based skin care management in radiation therapy: clinical update. Semin Oncol numbers 2011;27, the contents of which are incorporated herein by reference). As radiation doses increase above 30 to 40Gy, patients may develop wet desquamation-a disease characterized by redness of the skin, breakdown, exudation of serous fluid, and hemorrhagic scabbing (see, e.g., zenda S et al A sexual vision collection for a grading atlas of radiation therapy for clinical trials in head-and-near cancer patients. J radiation Res.2016; 57-306, the contents of which are incorporated herein by reference).

Patients are often very painful due to the breakdown of the skin barrier, burning pain is associated with the ulcer surface of the skin, any postural changes that produce skin folds are aggravated, the ulcer surface is inflamed to exude, and infection aggravates this pain. Once these radiodermatitis conditions occur, the physician has to suspend radiation therapy for a period of time in order to allow adequate epithelial regeneration before the patient resumes treatment, for example calamine lotion, mild and non-irritating creams and ointments, such as vitamin E cream, cod liver oil ointment and other skin creams, which are commonly given to patients, and optionally corticosteroid creams or ointments, for skin protection and recovery. However, suspending radiation therapy can result in an insufficient cumulative radiation dose at the tumor site, which can negatively impact the local control of the tumor, and although some preventive agents used in combination with radiation therapy have been explored, as described above, the efficacy is not ideal.

The term "CACTE Criteria" as used herein refers to the "Common Adverse reaction event evaluation Criteria" (Common clinical Criteria for additive Events, abbreviated CTCAE) published by the National Institute of Health (NIH) and the National Cancer Institute (NCI). The classification criteria for radiodermatitis are shown in table 1 below (according to CTCAE 4.0 original version):

table 1: CTCAE criteria for radiodermatitis grading criteria

As used herein, the term "Gy" refers to the unit of dose delivered during radiation therapy, and is expressed in Gray, chinese as Gray, for short. Gy is an international unit derived unit, is a standard unit of physical quantity "ionizing radiation energy absorption dose", and describes the amount of ionizing radiation energy absorbed by an object per unit mass, and 1Gy represents the amount of radiation energy absorbed by one Joule per kilogram of matter, namely: 1Gy =1J/kg.

The terms "PTV" and "GTV" as used herein refer to a Radiation exposure region in radiotherapy, which is defined in accordance with the International Commission on Radiation Units and Measurements (ICRU), wherein PTV refers to a Planning Target Volume (Planning Target Volume), i.e., a region that is irradiated with magnification in consideration of errors in the movement and setup position of an irradiated organ; GTV refers to a Tumor target region (Gross Tumor Volume), and refers to a clinical lesion of a Tumor, i.e., a Tumor lesion region with a certain size, which can be determined by a general examination means, including a primary Tumor lesion and a metastasis. It can be seen that the PTV region is larger than the GTV region, and the specific irradiation region can be confirmed by the professional related to the tumor radiology field according to the specific tumor type and condition.

The traditional Chinese herbal medicine components in China often have unexpected effects on many diseases which are inelegant by western medicine stanzers, and the side effects are smaller. However, because the components of the Chinese herbal medicine are complex, the pure active ingredients are difficult to separate according to the standard of western medicine, and the Chinese herbal medicine cannot be effectively popularized. The inventor group explores a large number of Chinese herbal medicine components in the practice of tumor therapy in the hospital, comparatively screens the effective composition formula of the invention, and the components are rarely mentioned in the prevention and treatment of radiodermatitis, particularly acute radiodermatitis, let alone the combination formula.

The formula takes the astragalus root as a monarch, the cortex mori radicis and the cortex acanthopanacis as ministers, and the pseudo-ginseng powder and the menthol are used as assistants to form a complete monarch, minister, assistant and guide system, so that the medicine characteristic of treating the skin disease by using the skin medicine in the traditional Chinese medicine is reflected.

The term "radix astragali" as used herein refers to the root of Astragalus mongholicus (Fisch.) bge of Leguminosae, which is harvested in spring or autumn, removed of soil, whiskers and the like, dried until the root is six seven dry, bundled and dried in the sun to obtain a medicine; it is sweet in flavor, slightly warm in nature, and enters spleen and lung meridians. The main functional indications are as follows: invigorating qi, consolidating superficial resistance, expelling toxic materials, expelling pus, promoting urination, and promoting granulation; can be used for treating deficiency of vital energy, asthenia, chronic diarrhea, proctoptosis, spontaneous perspiration, edema, uterine prolapse, albuminuria due to chronic nephritis, diabetes, and unhealed wound.

The term "cortex Mori" as used herein refers to the dried root bark of mulberry of the family Moraceae of the dicotyledonous plant, obtained from Shen nong's herbal Jing; it is sweet and cold in nature and flavor, entering lung and spleen meridians. Cortex Mori has effects of purging lung, relieving asthma, softening hard masses, relieving swelling, removing toxic substance, relieving itching, moistening skin, and caring hair, and can be used for treating lung heat cough and asthma, oliguria edema, and swelling of skin.

The term "cortex Acanthopanacis" as used herein refers to dried root bark of Acanthopanax gracilistylus of Araliaceae, root harvested in summer and autumn, washed, root bark removed, and dried in the sun; pungent and bitter taste, warm nature; it enters liver and kidney meridians. Has effects in dispelling pathogenic wind, removing dampness, tonifying liver and kidney, strengthening muscle and bone, and inducing diuresis to alleviate edema. Research shows that the effective components have obvious antioxidant effect, and can raise the activity of glutathione peroxidase in blood and raise the content of lipid peroxide obviously. Pharmacological experiments show that the decoction has an inhibitory effect on staphylococcus aureus and pseudomonas aeruginosa.

The term "notoginseng powder" as used herein refers to a root-tuber product of plant notoginseng, which is a powder made by beating the main root of notoginseng; it is warm in nature, sweet and slightly bitter in taste, and enters liver, stomach and large intestine meridians. Has the effects of removing blood stasis, stopping bleeding, relieving swelling and pain, etc.

The term "menthol" as used herein refers to organic compounds extracted from the leaves and stems of peppermint, white crystals, natural menthol being predominantly the levorotatory isomer (L-menthol). It can be used as irritant in medicine, and has effects in refreshing and relieving itching; it can be used as wind-expelling medicine for treating headache, and inflammation of nose, pharynx, and larynx.

The term "aloe gel" as used herein means a juice (purified) obtained from the sap fraction of leaves of aloe belonging to the family Liliaceae, which is mainly composed of aloe-emodin, aloe anthraquinone, aloe anthrone, polysaccharides, enzymes, amino acids, etc., and is a pale yellow green liquid having a relative density of 0.98 to 1.02 and a pH of 4 to 6. The aloe gel is mainly used for skin and hair protection products in cosmetics, has the effects of moisturizing, sun screening, deodorization, obesity prevention, skin softening, inflammation diminishing, itching relieving, pain relieving, acne preventing, freckle removing, stain lightening and the like, and is a well-known skin beautifying and health-care product. The aloe gel used in the present invention may be obtained using any method known in the art for extracting aloe gel, the composition and properties of which are well known to those skilled in the art.

EXAMPLE 1 preparation of the composition

Accurately weighing 100g of radix astragali, 50g of cortex mori radicis, 50g of cortex acanthopanacis and 10g of radix notoginseng powder, adding tap water filtered by a normal-temperature household water purifier to soak for 1 hour, boiling with strong fire, decocting with slow fire at 100 ℃ for 30 minutes, filtering with double-layer gauze, standing, and taking supernate. And then 250g of aloe gel and 2g of menthol are accurately weighed, the aloe gel and the menthol are placed in a grinder together with the obtained supernatant to be stirred and mixed for 4 minutes at 10000r/min, and the mixture is filtered by double-layer gauze to obtain filtrate for later use.

Example 2 methods of making and using a topical mask

Regenerated cellulose fiber towels (the size is adjusted according to the skin area of the irradiation field such as PTV and GTV) are soaked in the liquid medicine prepared in the example 1, so that the fiber towels are completely wet and do not drop the liquid medicine, the regenerated cellulose fiber towels are respectively externally applied to the skin of the irradiation field of a patient 3 hours before each radiotherapy and 1 hour after each radiotherapy, the regenerated cellulose fiber towels are externally applied for 60 minutes, and the radiotherapy period is carried out 2 times every day until the radiotherapy is finished.

Example 3 spray preparation and methods of use

The liquid medicine prepared in example 1 is filled into a spray bottle, shaken up when in use, sprayed on the skin surface of the irradiation field (such as PTV or GTV) of a patient 3 hours before each radiotherapy and 1 hour after each radiotherapy, and repeatedly sprayed for a plurality of times after the liquid medicine is dried until the radiotherapy is finished.

Example 4 clinical application data for externally applied masks

From 9 months to now in 2019, 12 patients who received radiotherapy in the oncology department of our hospital applied the external application mask prepared in example 2 to prevent and treat acute radiodermatitis. Of the 12 patients, there were 1 case of supraclavicular lymph node metastasis after lung cancer surgery, 2 cases of nasopharyngeal carcinoma, 2 cases of esophageal cancer with cervical lymph node metastasis, and 7 cases of head and neck squamous cell carcinoma. All patients completed the entire course of radiotherapy (PTV above 50Gy, GTV above 60 Gy). The specific results are shown in the following table 2:

table 2 clinical experimental results of acute radiodermatitis of radiotherapy patients treated with the external application mask of the present invention

The foregoing is merely a preferred embodiment of the present invention and well known specific constructions and features thereof, which are not set forth herein in any detail, will be apparent to those skilled in the art. It should be noted that, for those skilled in the art, it is possible to make several modifications and improvements to the embodiments without departing from the spirit of the present invention, and these should also be construed as the scope of protection of the present invention as long as the implementation of the embodiments of the present invention is not affected.

Claims (12)

1. A composition for preventing, relieving or treating radiodermatitis is prepared from 80-120 parts by weight of radix astragali, 40-60 parts by weight of cortex Mori, 40-60 parts by weight of cortex Acanthopanacis, 5-20 parts by weight of radix Notoginseng powder and 1-5 parts by weight of menthol.

2. The composition of claim 1, which is prepared from 100 parts by weight of astragalus membranaceus, 50 parts by weight of cortex mori, 50 parts by weight of cortex acanthopanacis, 10 parts by weight of pseudo-ginseng powder and 2 parts by weight of menthol.

3. The composition according to claim 1 or 2, wherein said radiodermatitis is acute radiodermatitis.

4. The composition of claim 3, wherein the acute radiodermatitis is CTCAE standard grade 3 or greater acute radiodermatitis.

5. A topical dressing composition for preventing, relieving or treating radiodermatitis is prepared from aloe gel 200-300 parts, radix astragali 80-120 parts, cortex Mori 40-60 parts, cortex Acanthopanacis 40-60 parts, notoginseng radix powder 5-20 parts, and menthol 1-5 parts by weight.

6. The external dressing composition according to claim 4, which is prepared from 250 parts by weight of aloe vera gel, 100 parts by weight of astragalus, 50 parts by weight of cortex mori, 50 parts by weight of cortex acanthopanacis, 10 parts by weight of panax notoginseng powder and 2 parts by weight of menthol.

7. A topical dressing composition according to claim 4 or 5, wherein the topical dressing composition is a mask.

8. A method for preparing the composition according to any one of claims 5 to 7, which comprises accurately weighing the above-mentioned parts by weight of powders of radix astragali, cortex mori radicis, cortex acanthopanacis and radix notoginseng, adding tap water at normal temperature to soak for 0.5 to 2 hours, boiling with strong fire, decocting with slow fire for 20 to 40 minutes, filtering, standing, collecting the supernatant, mixing with the above-mentioned parts by weight of aloe gel and menthol in a pulverizer under stirring at 8000 to 12000r/min for 3 to 5 minutes, filtering with gauze, collecting the filtrate, and mixing with the dressing material for external use to prepare the dressing composition for external use.

9. The method of claim 8, wherein the topical dressing composition is a mask.

10. Use of a composition according to any one of claims 1-7 in the manufacture of a medicament for the prevention, alleviation or treatment of radiodermatitis.

11. The use of claim 10, wherein the radiodermatitis is acute radiodermatitis.

12. The use of claim 11, wherein the acute radiodermatitis is CTCAE standard grade 3 or greater acute radiodermatitis.