CN114306328B - Composition containing TRPM8 agonist and preparation method and application thereof - Google Patents
Composition containing TRPM8 agonist and preparation method and application thereof Download PDFInfo
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- CN114306328B CN114306328B CN202111671379.5A CN202111671379A CN114306328B CN 114306328 B CN114306328 B CN 114306328B CN 202111671379 A CN202111671379 A CN 202111671379A CN 114306328 B CN114306328 B CN 114306328B
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- composition
- trpm8 agonist
- parts
- castor oil
- dry eye
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Abstract
The invention belongs to the technical field of medicine preparation, and particularly relates to a composition containing TRPM8 agonist, and a preparation method and application thereof. The compositions comprise a TRPM8 agonist and other active ingredients having a synergistic effect therewith, such as castor oil or a polyoxyethylene hydrogenated castor oil. The composition can be added with pharmaceutically-acceptable adjuvants to make into various medicinal preparations. Has good effects in treating xerosis syndrome, xerostomia, repeated suppurative infection of eyelid margin, conjunctivitis, xerotic conjunctivitis, keratitis sicca, corneal neovascularization and corneal ulcer, canker sore, rampant dental caries, pain, skin pruritus, xerosis cutis, chapped skin, ichthyosis, herpes, atopic dermatitis, neuritis, asthma, cough and pulmonary hypertension.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a composition containing a TRPM8 agonist, and a preparation method and application thereof.
Background
Dry eye, also known as keratoconjunctival xerosis, is a disease in which the tear film is unstable and the surface of the eye is damaged due to abnormality in the quantity or quality of tears, resulting in discomfort to the eye and even damage to vision, which is the most common ocular surface disease at present. The global incidence rate of dry eye is about 5% -34%, and the dry eye disease is an ophthalmic disease with high incidence rate. In patients with dry eye, the tear film is unstable and tears evaporate too quickly, resulting in a decrease in the surface temperature of the cornea, thereby activating cold receptors, increasing the number of basal blinks through the neuroreflex arc, and simultaneously increasing basal tear secretion. In addition, dry eye can cause ocular surface damage, and cold receptors on the corneal surface can also be damaged, reducing sensitivity. This can lead to a lack of sensitivity to tear film instability, failure to increase basal tear secretion and basal blink elevations in a timely manner, and thus exacerbation of dry eye conditions.
Transient receptor potential TRPM8 (transient receptor potential-related 8), also known as cold and menthol induced receptor CMR-1 (cold and menthol induced receptor-1), is a nerve cold-sensing receptor located at the branch nerve ending of trigeminal nerve eyes, and environmental low temperature causes calcium ion inflow by activating TRPM8 receptor, and further transmits environmental temperature change information to the central nervous system by electric excitation to generate 'cold feeling' of corresponding temperature change. TRPM8 is distributed not only to the cornea but also to the eyelid; therefore, TRPM8 can be activated by topical administration to the eyelid or cornea to treat or alleviate symptoms of ocular diseases. It can also be activated by several natural compounds that produce a cooling sensation, including menthone, menthol and eucalyptol, etc. (Recent Progress in TRPM8 Modulation: an Update [ J ]. International Journal of Molecular Sciences,2019,20 (11)). Sensory dysfunction of cold receptor TRPM 8-mediated corneal surface evaporation induced temperature and osmotic pressure changes is a possible pathological mechanism of Dry Eye (TRPM 8 Channels and Dry Eye [ J ]. Pharmaceuticals, 2018.).
The number of people with xerophthalmia is huge, and clinical unmet medication requirements exist, and the cyclosporins in the dry eye medicines such as cyclosporins A anhydrous eye drops, cyclosporins gel, cyclosporins emulsion and the like have irritation at present, and symptoms such as conjunctival congestion, corneal epithelial defect, periocular dermatitis allergy and the like can be caused. Artificial tears such as sodium hyaluronate eye drops and the like need frequent eye drop application to relieve dry eye symptoms and keep eyes comfortable. The Lifitegrast ophthalmic solution (trade name Xiidra) has a problem of limited efficiency.
The invention provides a TRPM8 agonist for treating diseases such as xerophthalmia and the like, which can increase the secretion amount of tears and better stabilize the distribution of the tears, and animal experiment results show that the agonist can increase the secretion of the tears relatively quickly and durably and keep the stability of tear film, thereby bringing a new solution for treating xerophthalmia.
Disclosure of Invention
In order to overcome the technical problems, the invention provides a composition containing TRPM8 agonist and a preparation method and application thereof. The agonist composition can increase the secretion of tears and stabilize the distribution of tears better, the preparation method is simple,
in order to realize the purpose, the technical scheme provided by the invention is as follows:
a composition comprising a TRPM8 agonist, castor oil or a polyoxyethylated hydrogenated castor oil, said TRPM8 agonist having the structure:
Preferably, the pharmaceutically acceptable salts, including organic and inorganic salts;
preferably, the organic salt comprises any one or more of a mesylate, formate, acetate, trifluoroacetate, maleate, tartrate, succinate, fumarate, citrate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, lactate and benzoate.
Preferably, the inorganic salt comprises any one or more of a hydrochloride, hydrobromide, sulphate and phosphate salt.
Preferably, the TRPM8 agonist-containing composition comprises the following components: TRPM8 agonist, taurine, castor oil or polyoxyethylene hydrogenated castor oil, quercetin, thiamine, ophiopogonin, ascorbic acid, and phenethanol glycoside.
Preferably, the composition containing the TRPM8 agonist comprises the following components in parts by weight: 10-20 parts of TRPM8 agonist, 1-10 parts of taurine, 0.1-2 parts of castor oil or polyoxyethylene hydrogenated castor oil, 1-5 parts of quercetin, 0.01-0.2 part of thiamine, 0.1-1 part of ophiopogonin, 0.05-1 part of ascorbic acid and 0.5-5 parts of phenylethanoid glycoside.
Preferably, the composition containing the TRPM8 agonist comprises the following components in parts by weight: 10-15 parts of TRPM8 agonist, 1-5 parts of taurine, 0.1-1 part of castor oil or polyoxyethylene hydrogenated castor oil, 1-3 parts of quercetin, 0.01-0.05 part of thiamine, 0.1-0.5 part of ophiopogonin, 0.05-0.1 part of ascorbic acid and 0.5-1 part of phenylethanoid glycoside.
Another object of the present invention is to provide a method for preparing the TRPM8 agonist-containing composition, comprising the steps of:
(1) Adding a surfactant into purified water, and sequentially dispersing TRPM8 agonist, quercetin, ophiopogonin and phenylethanoid glycoside into the purified water to obtain a dispersion liquid;
(2) Dissolving taurine, thiamine, ascorbic acid, castor oil or polyoxyethylene hydrogenated castor oil in purified water, and mixing with the dispersion liquid prepared in the step (1) to obtain the composition containing the TRPM8 agonist.
Preferably, in step (1), the surfactant is at least one of polysorbate, polyoxyethylene fatty acid ester and polyoxyethylene fatty alcohol ether.
Preferably, in step (1), the surfactant is polysorbate 60 or/and polysorbate 80.
Preferably, in the step (1), the amount of the surfactant is 1-5% of the total mass of the TRPM8 agonist, the quercetin, the ophiopogonin and the phenylethanoid glycoside.
Preferably, in the step (1), the amount of the purified water is 50-500 times of the total mass of the TRPM8 agonist, the quercetin, the ophiopogonin and the phenylethanoid glycoside.
Preferably, in the step (2), the amount of the purified water is 50 to 500 times of the total mass of the taurine, the castor oil or the polyoxyethylene hydrogenated castor oil, the thiamine and the ascorbic acid.
Another object of the present invention is to provide a method for preparing the TRPM8 agonist-containing composition, comprising the steps of:
sequentially mixing TRPM8 agonist, quercetin, ophiopogonin, phenethanol glycoside, taurine, castor oil or polyoxyethylene hydrogenated castor oil, thiamine, and ascorbic acid to obtain composition containing TRPM8 agonist.
Another object of the present invention is to provide the use of the TRPM8 agonist-containing composition for the preparation of a pharmaceutical formulation.
Preferably, the medicament is a medicament for treating any one or more of sjogren's syndrome, xerostomia, repeated purulent infection of eyelid margin, conjunctivitis, xerotic conjunctivitis, keratoconjunctivitis sicca, corneal neovascularization and corneal ulcer, canker sore, rampant caries, pain, skin itch, dry skin, chapped skin, ichthyosis, herpes, atopic dermatitis, neuritis, asthma, cough and pulmonary hypertension.
Preferably, the pain comprises neuropathic pain and/or post-operative pain.
Preferably, the herpes includes herpes simplex and herpes zoster.
Preferably, the atopic dermatitis comprises eczema.
Preferably, the pulmonary hypertension includes any one or more of arterial pulmonary hypertension, chronic thromboembolic pulmonary hypertension, left ventricular disease-associated pulmonary hypertension, and pulmonary disease/hypoxic pulmonary hypertension.
The present invention also aims to provide a pharmaceutical preparation comprising the TRPM8 agonist composition.
Preferably, the pharmaceutical formulation is any one or more of a medicament for treating sjogren's syndrome, xerostomia, repeated purulent infection of eyelid margin, conjunctivitis, xerotic conjunctivitis, keratoconjunctivitis sicca, corneal neovascularization and corneal ulcer, canker sore, rampant caries, pain, skin itch, dry skin, chapped skin, ichthyosis, herpes, atopic dermatitis, neuritis, asthma, cough and pulmonary hypertension.
Preferably, the pharmaceutical formulation comprising the TRPM8 agonist composition further comprises any one or more of a binder, a suspending agent, a disintegrant, a filler, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, a diluent, and a spray-dried dispersion.
Preferably, the pharmaceutical formulation comprising the TRPM8 agonist composition further comprises any one or more of fatty acid monoglycerides and glyceryl monostearate, sorbitan fatty acid, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene alkyl ethers, polysorbates, polyacrylic acid, carbomers, glucose polymers, propylene glycol, polyethylene glycol, vitamin E polyethylene glycol succinate, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and preservatives.
Preferably, the preservative comprises any one or more of benzenedimethylol ammonium, chlorobutanol, sodium perborate, methylparaben, ethylparaben, polyquaternium, sodium chlorite, thimerosal, benzalkonium chloride, benzalkonium bromide and phenoxyethanol.
Preferably, the pharmaceutical preparation includes any one or more of eye drops, oral preparations, injections, ointments and spray preparations.
Preferably, the concentration of the TRPM8 agonist in eye drops, oral preparations, injection solutions and/or sprays is 0.0001-0.3% w/v.
Preferably, the concentration of the TRPM8 agonist is in the range of 0.0001-0.1% w/v.
Compared with the prior art, the invention has the technical advantages that:
(1) The invention provides a composition containing TRPM8 agonist, which can be better used for preventing and treating dry eye symptoms or dry eye characteristics. Solves the problems of foreign body sensation, burning sensation, pruritus, pain, dryness, redness of eyes, reduction of tears, poor tear quality, reduction of tear film rupture time and the like.
(2) In the composition containing the TRPM8 agonist, the TRPM8 agonist and castor oil or polyoxyethylene hydrogenated castor oil, taurine, quercetin, thiamine, ophiopogonin, ascorbic acid and phenethyl alcohol glycoside have good synergistic effect, and dry eye symptoms and symptoms such as dermatitis, neuritis, asthma, cough, pulmonary hypertension and the like are effectively solved.
(3) The composition containing the TRPM8 agonist can be prepared into various pharmaceutical preparations by adding pharmaceutically conventional auxiliary materials or reagents, so that different administration modes are met; the preparation method is simple and easy to implement.
Definition of terms
The term "dry eye", also known as keratoconjunctival xerosis, is a common ophthalmic disease. The abnormal condition of the volume of the tears, the quality of the tears and the natural fluidity of the tears can be caused by insufficient secretion or excessive evaporation of the tears. Dry eye is also frequently associated with comorbidities such as diabetes, sjogren's syndrome, pterygium, allergic eye disease, and other systemic autoimmune diseases. Dry eye is often clinically classified into the following five categories according to etiology:
water-sample fluid deficient dry eye: due to the hypofunction of lacrimal gland to secrete tears, such as congenital non-lacrimal gland disease;
mucin-deficient dry eye: mucin secretion deficiency, such as dry eye caused by Stevens-Johnson syndrome, ocular pemphigoid, trachoma, etc.;
lipid-deficient dry eye: caused by meibomian gland dysfunction, since meibomian glands are lipid secreting glands;
dry eye due to abnormalities in tear dynamics (distribution): such as eyelid defects, inversion, etc., may cause incomplete blinking, tears not being evenly distributed on the surface of the eye, and dry eye symptoms;
mixed dry eye: is the most common dry eye in clinic, and is dry eye caused by two or more than two causes.
The term "isomer" may refer to compounds having the same composition and molecular weight but differing in physical and/or chemical properties. Structural differences may be manifested in composition (geometric or positional isomers) or in the ability to rotate the plane of polarized light (stereoisomers).
The term "treatment" refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and may be performed either for prophylaxis or in the course of clinical pathology. Desired therapeutic effects include, but are not limited to: preventing the occurrence or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, ameliorating or palliating a disease state, and lessening or improving prognosis.
Detailed Description
The present invention will be described below with reference to specific examples to make the technical aspects of the present invention easier to understand and grasp, but the present invention is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
The TRPM8 agonists used in the examples of the invention and the comparative examples were derived from-manufacturer: med Chem Express, cargo number: HY-16162.
Example 1
A composition comprising a TRPM8 agonist; the paint comprises the following components in parts by weight: 15 parts of TRPM8 agonist and 1 part of polyoxyethylene castor oil;
the preparation method of the composition comprises the following steps: adding polysorbate 60 surfactant into purified water, and dissolving the polyoxyethylene castor oil and TRPM8 agonist into the purified water, wherein the dosage of the surfactant is 3% of the total mass of the TRPM8 agonist and the polyoxyethylene castor oil, so as to obtain the composition containing the TRPM8 agonist.
Example 2
A composition containing a TRPM8 agonist comprises the following components in parts by weight: 15 parts of TRPM8 agonist, 5 parts of taurine, 1 part of polyoxyethylene castor oil, 3 parts of quercetin, 0.05 part of thiamine, 0.5 part of ophiopogonin, 0.1 part of ascorbic acid and 1 part of phenylethanoid glycoside.
The preparation method of the composition containing the TRPM8 agonist comprises the following steps:
(1) Adding polysorbate 60 surfactant into purified water, and sequentially dispersing TRPM8 agonist, quercetin, ophiopogonin and phenylethanoid glycoside into 100 times of the purified water containing surfactant to obtain dispersion; wherein the dosage of the surfactant is 3% of the total mass of the TRPM8 agonist, the quercetin, the ophiopogonin and the phenethyl alcohol glycoside;
(2) Dissolving taurine, polyoxyethylene castor oil, thiamine and ascorbic acid in 100 times of purified water, and mixing with the dispersion liquid prepared in the step (1) to obtain the composition containing the TRPM8 agonist.
Example 3
A composition containing a TRPM8 agonist comprises the following components in parts by weight: 10 parts of TRPM8 agonist, 1 part of taurine, 0.1 part of castor oil, 5 parts of quercetin, 0.01 part of thiamine, 0.1 part of ophiopogonin, 0.05 part of ascorbic acid and 5 parts of phenylethanoid glycoside.
The preparation method of the composition containing the TRPM8 agonist comprises the following steps:
(1) Adding polysorbate 80 surfactant into purified water, and sequentially dispersing TRPM8 agonist, quercetin, ophiopogonin and phenethyl alcohol glycoside into 50 times of the purified water containing surfactant to obtain dispersion; wherein the dosage of the surfactant is 1 percent of the total mass of the TRPM8 agonist, the quercetin, the ophiopogonin and the phenylethanoid glycoside;
(2) Dissolving taurine, castor oil, thiamine and ascorbic acid in 50 times of purified water, and mixing with the dispersion liquid prepared in the step (1) to obtain the composition containing the TRPM8 agonist.
Example 4
A composition containing a TRPM8 agonist comprises the following components in parts by weight: 20 parts of TRPM8 agonist, 10 parts of taurine, 2 parts of polyoxyethylene hydrogenated castor oil, 1 part of quercetin, 0.2 part of thiamine, 1 part of ophiopogonin, 1 part of ascorbic acid and 0.5 part of phenylethanoid glycoside.
The preparation method of the composition containing the TRPM8 agonist comprises the following steps:
(1) Adding polysorbate 60 surfactant into purified water, and sequentially dispersing TRPM8 agonist, quercetin, ophiopogonin and phenethyl alcohol glycoside into 500 times of the purified water containing surfactant to obtain dispersion; wherein the dosage of the surfactant is 5 percent of the total mass of the TRPM8 agonist, the quercetin, the ophiopogonin and the phenylethanoid glycoside;
(2) Dissolving taurine, polyoxyethylene hydrogenated castor oil, thiamine and ascorbic acid in 500 times of purified water, and mixing with the dispersion liquid prepared in the step (1) to obtain the composition containing the TRPM8 agonist.
Comparative example 1
The difference from the example 2 is in the composition; substituting phenylethanoid glycosides for ophiopogonin.
The composition containing the TRPM8 agonist comprises the following components in parts by weight: 15 parts of TRPM8 agonist, 5 parts of taurine, 1 part of polyoxyethylene castor oil, 3 parts of quercetin, 0.05 part of thiamine, 0.1 part of ascorbic acid and 1.5 parts of phenethyl alcohol glycoside.
The preparation method of the composition containing the TRPM8 agonist comprises the following steps:
(1) Adding polysorbate 60 surfactant into purified water, and sequentially dispersing TRPM8 agonist, quercetin and phenylethanoid glycoside into 100 times of the purified water containing surfactant to obtain dispersion; wherein the dosage of the surfactant is 3% of the total mass of the TRPM8 agonist, the quercetin and the phenethyl alcohol glycoside;
(2) Dissolving taurine, polyoxyethylene castor oil, thiamine and ascorbic acid in 100 times of purified water, and mixing with the dispersion liquid prepared in the step (1) to obtain the composition containing the TRPM8 agonist.
Comparative example 2
The difference from example 2 is in the composition; replacing phenylethanoid glycosides with ophiopogonin.
A composition containing a TRPM8 agonist comprises the following components in parts by weight: 15 parts of TRPM8 agonist, 5 parts of taurine, 1 part of polyoxyethylene castor oil, 3 parts of quercetin, 0.05 part of thiamine, 1.5 parts of ophiopogonin and 0.1 part of ascorbic acid.
The preparation method of the composition containing the TRPM8 agonist comprises the following steps:
(1) Adding polysorbate 60 surfactant into purified water, and sequentially dispersing TRPM8 agonist, quercetin and ophiopogonin into 100 times of the purified water containing surfactant to obtain dispersion; wherein the dosage of the surfactant is 3% of the total mass of the TRPM8 agonist, the quercetin and the ophiopogonin;
(2) Dissolving taurine, polyoxyethylene castor oil, thiamine and ascorbic acid in 100 times of purified water, and mixing with the dispersion liquid prepared in the step (1) to obtain the composition containing the TRPM8 agonist.
Comparative example 3
The difference from the example 2 is in the composition; taurine was used in place of quercetin.
A composition containing a TRPM8 agonist comprises the following components in parts by weight: 15 parts of TRPM8 agonist, 8 parts of taurine, 1 part of polyoxyethylene castor oil, 0.05 part of thiamine, 0.5 part of ophiopogonin, 0.1 part of ascorbic acid and 1 part of phenylethanoid glycoside.
The preparation method of the composition containing the TRPM8 agonist comprises the following steps:
(1) Adding polysorbate 60 surfactant into purified water, and sequentially dispersing TRPM8 agonist, ophiopogonin and phenylethanoid glycoside into 100 times of the purified water containing surfactant to obtain dispersion; wherein the dosage of the surfactant is 3% of the total mass of the TRPM8 agonist, the ophiopogonin and the phenethyl alcohol glycoside;
(2) Dissolving taurine, polyoxyethylene castor oil, thiamine and ascorbic acid in 100 times of purified water, and mixing with the dispersion liquid prepared in the step (1) to obtain the composition containing the TRPM8 agonist.
Comparative example 4
The difference from example 1 is in the composition; polysorbate 60 was used instead of polyoxyethylated castor oil.
A composition comprising a TRPM8 agonist; the paint comprises the following components in parts by weight: 15 parts of TRPM8 agonist and 1.48 parts of polysorbate;
the preparation method of the composition comprises the following steps: and adding a polysorbate 60 surfactant into the purified water, and adding and dissolving a TRPM8 agonist into the purified water to obtain the composition containing the TRPM8 agonist.
Effect example-test of drug efficacy in mouse xerophthalmia model
1. Dry eye modeling and drug intervention
6 weeks old female C57BL/6J mice (manufacturer: beijing Wintolite laboratory animals Co., ltd., cat # 219) were transferred to a dry fume hood, and scopolamine hydrobromide (manufacturer: shanghai Avastin Biotechnology Co., ltd., cat # S302239) was injected subcutaneously at the posterior of both lateral ears of the mice at a concentration of 5mg/ml for a fixed period of time per day in a physiological saline solution; the injection dosage of each side is 500ug, the total injection dosage per day is 1mg, and the injection is continuously carried out for 35 days; the modeling process is completed.
The mice after modeling were randomly selected and divided into groups, which were respectively a positive control (PBS (PBS-phosphate balanced physiological saline), reagent manufacturers: sammer Feishell technology (China) Co., ltd., product number: 10010002), examples 1-4 groups, comparative examples 1-4 groups, 10 mice per group, and 10 normal mice without modeling were selected as a blank control group and fed under the same conditions.
The amount of tear secretion of mice was measured by Schirmer's I test: on day 0 after modeling (i.e., on day 35 of the experimental study), each group was administered twice a day at a fixed time (see table 1 for dosing information), and drug intervention was performed for 14 days, and the amount of tear secretion was measured once a day at a fixed time, by the following method: after anesthetizing the mice, phenol red cotton thread (manufactured by Liaoning Meizilin pharmaceutical Co., ltd., product number: 178144136910) was placed at the outer canthus of the central part of the lower eyelid of the mice for 20 seconds. The wet length of the phenol red cotton thread was measured and recorded, which was the basal tear secretion of the mice.
Tear film break up time measurement in mice: on day 0 after modeling (i.e., on day 35 of the experimental study), each group was dosed twice daily at a fixed time (dosing information see table 1) for 14 days of drug intervention, tear film break-up time was measured once daily at a fixed time, and the method was measured: after the mice were anesthetized, 2. Mu.l of a 0.05% aqueous solution of fluorescein sodium (manufactured by Shanghai Aladdin Biotechnology Co., ltd., product No. F105615) was dropped onto the surface of the eyeball of the mice using a micropipette. After the fluorescein sodium solution is uniformly distributed on the eye surface of the mouse, the time for breaking the fluorescein sodium normal saline solution covered on the eyeball surface of the mouse is observed by using dispersed cobalt blue light through a slit lamp, and the time is the tear film breaking time of the mouse on the day, and the total test time is 14 days.
Experimental groups and dosing information are shown in table 1 below:
table 1 experimental grouping and dosing information
The compositions of examples 1 to 4 and comparative examples 1 to 4 were subjected to effect evaluation according to the above experimental methods; the results are shown in tables 2 and 3 below.
2. Data statistical method
Statistical analysis was performed using SPSS 16.0, in which normally distributed metrology data was tested using ANOVA
Representing; the grade data and the metering data which do not conform to the normal distribution adopt a non-parameter test method and are expressed by Mean Ranks. The difference is statistically significant when P is less than 0.05.
TABLE 2 Cotton thread Wet Length (mm)
| Test group | Day 0 | 7 days | 10 days | 14 days |
| Blank control group | 7.68±2.31 a | 7.91±1.68 a | 7.76±1.92 a | 7.77±1.35 a |
| PBS control group | 2.28±0.96 b | 2.39±0.73 b | 2.43±0.59 b | 2.40±0.71 b |
| Example 1 | 3.43±0.67 c | 3.72±1.03 c | 4.69±0.86 c | 6.06±1.22 c |
| Example 2 | 3.66±0.95 c | 4.89±0.77 d | 6.12±1.22 d | 7.58±0.94 a |
| Example 3 | 3.57±1.03 c | 4.76±0.99 d | 5.93±0.68 d | 7.46±1.13 a |
| Example 4 | 3.73±0.82 c | 4.83±1.11 d | 6.26±1.34 d | 7.59±1.05 a |
| Comparative example 1 | 3.54±0.88 c | 3.81±0.68 c | 5.11±0.87 c | 6.64±0.73 d |
| Comparative example 2 | 3.51±1.11 c | 3.76±0.81 c | 4.97±1.03 c | 6.85±1.38 d |
| Comparative example 3 | 3.47±0.89 c | 3.69±0.94 c | 5.08±1.10 c | 6.63±1.22 d |
| Comparative example 4 | 3.22±1.23 c | 3.62±0.77 c | 4.11±1.36 e | 5.37±0.86 e |
Remarking: in the unified column, the different letters have significant difference, P is less than 0.05.
TABLE 3 tear film break-up time(s)
Remarking: in the unified column, the different letters have significant difference, P is less than 0.05.
The experimental result shows that the composition provided by the invention has a good effect of treating xerophthalmia, and meanwhile, the agonist and other components such as castor oil have good synergistic effect, and the composition can effectively promote the drug effect of the composition after being acted together with other components.
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (13)
1. A composition for treating dry eye, comprising: the paint comprises the following components in parts by weight: 10-20 parts of TRPM8 agonist, 1-10 parts of taurine, 0.1-2 parts of castor oil or polyoxyethylene hydrogenated castor oil, and 1-5 parts of quercetin0.01-0.2 part of thiamine, 0.1-1 part of ophiopogonin, 0.05-1 part of ascorbic acid and 0.5-5 parts of phenylethanoid glycoside; the TRPM8 agonist is:
or a pharmaceutically acceptable salt thereof or a solvate thereof or a deuterated product thereof,
the composition is administered topically.
2. The composition for treating dry eye of claim 1, wherein the pharmaceutically acceptable salt is an organic salt and an inorganic salt; the organic salt is any one or more of mesylate, formate, acetate, trifluoroacetate, maleate, tartrate, succinate, fumarate, citrate, benzene sulfonate, p-methyl benzene sulfonate, naphthalene sulfonate, lactate and benzoate;
the inorganic salt is any one or more of hydrochloride, hydrobromide, sulphate and phosphate.
3. The composition for treating dry eye of claim 1, comprising the following components in parts by weight: 10-15 parts of TRPM8 agonist, 1-5 parts of taurine, 0.1-1 part of castor oil or polyoxyethylene hydrogenated castor oil, 1-3 parts of quercetin, 0.01-0.05 part of thiamine, 0.1-0.5 part of ophiopogonin, 0.05-0.1 part of ascorbic acid and 0.5-1 part of phenethyl alcohol glycoside.
4. A method of preparing a composition for the treatment of dry eye as in any one of claims 1 to 3, comprising the steps of:
(1) Adding a surfactant into purified water, and sequentially dispersing TRPM8 agonist, quercetin, ophiopogonin and phenylethanoid glycoside into the purified water to obtain a dispersion liquid;
(2) Dissolving taurine, thiamine, ascorbic acid, castor oil or polyoxyethylene hydrogenated castor oil in purified water, and mixing with the dispersion liquid prepared in the step (1).
5. The method of claim 4, wherein in step (1), the surfactant is at least one of a polysorbate, a polyoxyethylene fatty acid ester, and a polyoxyethylene fatty alcohol ether; the dosage of the surfactant is 1-5% of the total mass of the TRPM8 agonist, the quercetin, the ophiopogonin and the phenylethanoid glycoside.
6. A method of preparing a composition for the treatment of dry eye as in any one of claims 1 to 3, comprising the steps of: sequentially mixing TRPM8 agonist, quercetin, ophiopogonin, phenethanol glycoside, taurine, thiamine, and ascorbic acid.
7. Use of a composition for the treatment of dry eye according to any one of claims 1 to 3 or a composition prepared by a method for the preparation of a composition for the treatment of dry eye according to any one of claims 4 to 6 for the preparation of a pharmaceutical preparation for the treatment of dry conjunctivitis, dry keratitis.
8. A pharmaceutical preparation comprising the composition for dry eye treatment according to any one of claims 1 to 3 or the composition prepared by the method for preparing the composition for dry eye treatment according to any one of claims 4 to 6, wherein the pharmaceutical preparation is used for treating dry conjunctivitis and dry keratitis sicca.
9. The pharmaceutical formulation of claim 8, further comprising any one or more of a binder, a suspending agent, a surfactant, a solubilizer, a stabilizer, a lubricant, a wetting agent, and a diluent.
10. The pharmaceutical formulation of claim 8, further comprising any one or more of fatty acid monoglycerides and glyceryl monostearate, sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene alkyl ethers, polysorbates, polyacrylic acids, carbomers, glucose polymers, propylene glycol, polyethylene glycols, vitamin E polyethylene glycol succinates, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and preservatives.
11. The pharmaceutical formulation of claim 10, wherein the preservative is selected from any one or more of benzalkonium chloride, chlorobutanol, sodium perborate, methylparaben, ethylparaben, polyquaternium, sodium chlorite, thimerosal, benzalkonium chloride, benzalkonium bromide, and phenoxyethanol.
12. The pharmaceutical formulation of claim 8, wherein the pharmaceutical formulation is selected from any one of eye drops, injection, ointment and spray formulations.
13. The pharmaceutical formulation of claim 8, wherein the concentration of the TRPM8 agonist is 0.0001-0.3% w/v.
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