Piribedil eye drop pharmaceutical composition and application thereof

Abstract

The invention relates to a novel pharmaceutical composition suitable for ophthalmology, in particular to a pharmaceutical composition containing 0.1-10% w / v of piribedil or pharmaceutically acceptable salts thereof, and application of the pharmaceutical composition in preparation of drugs for treating myopia, preventing myopia and / or inhibiting myopia development.

Description

Technical Field

[0001] The present invention relates to a piribedil eye drop composition, a preparation method thereof and use thereof in preventing myopia, treating myopia and / or preventing myopia progression. Background Art

[0002] Myopia is a condition in which there is a mismatch between the length of the eye and the optics of the eye, causing images to form in front of the eye's retina. This type of refraction error causes blurred vision of distant objects, while close or near objects appear normal. The most common cause is an eyeball that is longer than the optics of the eye. A longer eyeball is often the result of excessive axial (or longitudinal) growth of the eye. The condition of myopia is common worldwide, but not uniformly so. Current treatments include orthokeratology, the use of multifocal soft contact lenses, progressive eyeglasses, or bifocals, but the effectiveness of these treatments is modest at best. ("A major step forward in preventing myopia: low-dose atropine," Ophthalmology (2016) 123:232-3). In addition to the inconvenience and expense involved in correcting blurred distance vision, it also affects the long-term health of myopia in the elderly, with an increased prevalence of further visual impairment, including myopic maculopathy, retinal detachment, glaucoma, and cataracts (Curtin B J., The Myopias: Basic Science and Clinical Management. Harper & Row, Philadelphia, Pa., 1985). Therefore, it is necessary to prevent the eyes from developing higher levels of myopia. Over the years, many early prevention measures and interventions, including the use of drugs, optical and environmental interventions, have been proposed and evaluated to slow the progression of myopia. Among them, drug intervention is generally more effective in slowing myopia.

[0003] In order to treat myopia, various therapies such as surgery, vision correction using glasses or contact lenses, and drug therapy have been tried. At present, drug therapy as one of myopia therapies has been actively studied, and some drugs have been reported that can be used as medicaments for treating myopia. For example, JP2018-021007 discloses that atropine can be used to treat myopia, and WO2012 / 161655 discloses that atropine sulfate has the effect of preventing myopia progression by reducing axial elongation. However, atropine has a significant dose-related mydriatic effect, which may cause unbearable glare and photophobia, reduce depth of focus, and may allow more ultraviolet light to enter the eye. Atropine also reduces normal accommodation in a dose-dependent manner, which may lead to poor near vision. Although it is shown that low-dose atropine is still effective for reducing axial elongation and is accompanied by reduced mydriasis and loss of accommodation, the above-mentioned side effects reduce the clinical efficacy of using high-concentration atropine in a clinical setting. WO2018 / 174179 discloses that tiotropium for treating chronic obstructive pulmonary disease is effective for preventing myopia, treating myopia and / or inhibiting the progression of myopia. On the other hand, in myopia therapy using muscarinic antagonists, significantly reducing or completely preventing the side effects caused by mydriasis has become a problem. When a person's pupil is dilated, the pupil is dilated and induces glare symptoms. Glare symptoms caused by pupil dilation may affect people's daily lives. Therefore, there has long been a demand for drugs that prevent myopia, treat myopia, reduce myopia progression or prevent myopia progression. At the same time, people are in great need of developing new agents that can be used to inhibit the development or progression of visual disorders such as myopia.

[0004] Piribedil, whose chemical name is 2-[4-(1,3-benzodiazol-5-ylmethyl)-1-piperazinyl]pyrimidine, has the following structural formula:

[0005]

[0006] U.S. Patents US3299067 and US5362731 and Polish Patent PL 167397 disclose compounds that can be used to treat patients with Parkinson's disease or hyperactive bladder, and can also be used as peripheral vasodilators, analgesics, or anti-inflammatory agents. Currently, only a sustained-release tablet form of this product is marketed domestically and internationally. CN107773563 discloses the use of piribedil in the preparation of brain resuscitation drugs, FR2857594 discloses a pharmaceutical composition of piribedil for nasal administration, and EP571264 and EP468875 disclose a self-adhesive matrix system for controlled transdermal release of piribedil. Currently, there are no reports of piribedil eye drops prepared directly from piribedil, nor have any piperazine pyrimidine eye drops been submitted for clinical research and marketed. Eye drops are topical preparations that differ from tablets in their route of administration, site of action, and application methods, with significant differences in the use and requirements of various excipients. Furthermore, to date, there have been no reports on the therapeutic effects of piribedil via topical ocular administration, particularly its effects on preventing myopia, treating myopia, and / or preventing the progression of myopia. Summary of the Invention

[0007] The present invention aims to identify novel compounds that can be used to prevent, treat, and / or prevent the progression of myopia. To address the above-mentioned issues, the present inventors conducted in-depth research and discovered that piribedil, used in the treatment of Parkinson's disease and symptoms associated with lower extremity circulatory disorders, can inhibit axial elongation of the eye. Therefore, piribedil can be used to prevent, treat, and / or prevent the progression of myopia. The present invention is based on this new discovery.

[0008] In one embodiment, the present invention provides a pharmaceutical composition comprising 0.1% to 10% w / v of piribedil or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of piribedil include, but are not limited to, sulfate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, perchlorate, nitrate, phosphate, acetate, propionate, glycolate, lactate pyruvate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, benzenesulfonate, hydroxyethanesulfonate, p-toluenesulfonate, cyclohexanesulfonate, salicylate, p-aminosalicylate, 2-phenoxybenzoate, and 2-acetoxybenzoate. In a preferred embodiment, the piribedil eye drop pharmaceutical composition contains piribedil hydrochloride.

[0009] The composition of the present invention may also include sterile water for injection, also known as water for injection, as a carrier.

[0010] In one embodiment, the composition further comprises a solubilizer; and at least one excipient selected from a buffer, a tension regulator, a viscosity regulator, a chelating agent, and a pH regulator. Preferably, the solubilizer is selected from one or both of glycerol and polyvinyl alcohol.

[0011] In one embodiment, the content of the solubilizer in the composition is 1-4% w / v, more preferably 1-3% w / v, further preferably 1-2.5% w / v or 1-2.8% w / v.

[0012] In one embodiment, the ratio (w / w) of the solubilizer content to the piribedil content in the composition is 1:5 to 1:2.

[0013] In one embodiment, the composition is free of preservatives.

[0014] In one embodiment, the hair compositions of the present invention further comprise from about 0.01% w / v to about 5% w / v buffering agent.

[0015] In one embodiment, the hair composition of the present invention further comprises about 0.1% w / v to 6% w / v of a tonicity adjusting agent. Examples of osmotic / tonicity adjusting agents include sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. Other isotonicity adjusting agents may include, but are not limited to, mannitol, anhydrous dextrose, glycerol, sorbitol, trehalose, boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosphate, sodium chloride, glycerol, propylene glycol, or other inorganic or organic solutes, dextrose, or mixtures thereof.

[0016] In one embodiment, the hair composition of the present invention further comprises about 0.01% w / v to 5% w / v of a viscosity modifier to provide the composition with a viscosity greater than that of a simple aqueous solution, thereby increasing ocular absorption of the active compound by the target tissue or increasing the retention time in the eye. Such viscosity modifiers include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, or other agents known to those skilled in the art.

[0017] In one embodiment, the hair composition of the present invention further comprises about 0.001% w / v to 1% w / v of a chelating agent. The composition may also contain a complexing / chelating agent, such as one or more of disodium EDTA, sodium EDTA, ethylenediamine, ethylenediamine, 2,3-dimercapto-1-propanesulfonic acid, dimercaptosuccinic acid, dimercaptopropanol, deferoxamine mesylate, α-lipoic acid, nitrilotriacetate, penicillamine, ethylene glycol dimethacrylate, sodium oleate, anhydrous sodium sulfite, sodium ascorbate, deferoxamine, malic acid, citric acid, succinic acid, and their sodium, calcium, and magnesium salts. In some embodiments, the stabilizer is disodium EDTA.

[0018] In one embodiment, the composition of the present invention may further include one or more buffers or pH-adjusting acids, bases, or buffering agents to maintain the pH value between 3.5 and 7.0, more preferably between 4.0 and 6.5, and more preferably between 5.5 and 6.5. Examples of acids include acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tromethamine. Salts and buffers include citrate / dextrose, sodium dihydrogen phosphate dihydrate, sodium bicarbonate, ammonium chloride, or mixtures of the above acids and bases.

[0019] One aspect of the present invention is to formulate an ophthalmic pharmaceutical composition comprising piribedil or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The ophthalmic composition of the present invention is typically administered to the affected ocular tissue by topical application of one to four drops of a sterile solution or suspension, one to four times daily. The eye drop pharmaceutical composition according to the present invention may include one or more pharmaceutically acceptable excipients suitable for preparing the same, including but not limited to suspending agents, pH adjusters, tonicity adjusters, emulsifiers or dispersants, surfactants, solubilizers, buffers, preservatives, chelating agents, wetting agents, viscosity modifiers, antioxidants, gelling agents, stabilizers, and mixtures thereof.

[0020] In a further embodiment, the hair composition of the present invention further comprises at least one excipient selected from the group consisting of a buffering agent, a tonicity adjusting agent, a viscosity adjusting agent, a chelating agent, and a pH adjusting agent.

[0021] In another embodiment, the following composition A or B is provided:

[0022] Composition A:

[0023] contain

[0024]

[0025] Composition B:

[0026] contain

[0027]

[0028]

[0029] In another embodiment, the following compositions 1-5 are provided. Composition 1:

[0030] contain

[0031]

[0032] Composition 2:

[0033] contain

[0034]

[0035] Composition 3:

[0036] contain

[0037]

[0038] Composition 4:

[0039] contain

[0040] Composition 5:

[0041] contain

[0042]

[0043] In one embodiment, the present invention provides a composition for use as eye drops.

[0044] In one embodiment, the present invention provides a use of the above-mentioned composition in the preparation of a medicament for treating myopia, preventing myopia, and / or inhibiting the progression of myopia, wherein the myopia is axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, severe myopia, high myopia, moderate myopia, low myopia, myopia combined with glaucoma, myopia at risk of glaucoma, or myopia accompanied by high intraocular pressure.

[0045] However, it will be understood that the specific dosage level and dosage frequency for any particular patient according to the present invention may vary and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, the age, weight, general health, sex, diet, mode and time of administration, rate of excretion, severity of the particular condition, and the host being treated.

[0046] The present invention provides an aqueous piribedil or physiologically acceptable salt thereof eye drop pharmaceutical composition with a rational formulation, simple processing, and excellent stability. After a 6-month accelerated test at 40°C, the sample showed no significant changes in appearance, pH, active ingredient content, or related substances. Further features and advantages of the present invention will become apparent from the detailed description below. DETAILED DESCRIPTION

[0047] The following includes the implementation of the preferred embodiment to illustrate the practice of the present invention. It is understood that the details shown are for illustrative discussion of the preferred embodiments of the present invention by way of example and purpose, and are intended to demonstrate what is considered to be the most useful and easy to understand description of the procedures for making the invention and the principles and concepts. It will be apparent to those skilled in the art that the present invention is not limited to the details of the following illustrative examples, and that the invention may be embodied in other specific forms without departing from its essential attributes. It is therefore intended that the present embodiments and examples be considered in all respects as illustrative and not restrictive. Therefore, reference is made herein to the appended claims rather than to the foregoing description, and therefore all changes that fall within the equivalent meaning and range of the claims should be included therein.

[0048] Experiment 1: Stability study in aqueous solution

[0049] Precision aspiration concentration is 1 mg·mL -1 150 μL of piribedil aqueous solution was placed in a 10 mL volumetric flask. Six portions were added to the scale with pure water, pH 1.2 hydrochloric acid solution, and phosphate buffer (pH 2.5, pH 5.8, pH 6.8, pH 7.8), respectively, to obtain a concentration of 10.223 μg.mL -1 Piribedil solution: 1.5 mL of the above six piribedil aqueous solutions were placed in EP tubes. The piribedil concentration was measured every 4 hours to observe the stability of piribedil. The experimental results are shown in Table 1.

[0050] Table 1 Effect of pH conditions on the stability of piribedil (μg mL -1 )

[0051] <![CDATA[C 4h ]]> <![CDATA[C 12h ]]> <![CDATA[C 24h ]]> RSD (%) <![CDATA[H2O]]> 15..015 15.032 14.989 1.08 pH 1.2 13.469 13.127 11.964 2.04 pH 2.5 14.026 13.682 12.097 2.81 pH 5.8 14.565 14.083 13.697 1.68 pH 6.8 12.354 11.048 10.687 4.23 pH7.8 11.258 10.386 9.157 5.37

[0052] Results: The stability of piribedil under different pH conditions was as follows: pure water > pH 5.8 > pH 2.5 >

[0053] pH1.2>pH6.8>pH7.8, among which the stability of piribedil is relatively poor at pH7.8, and is relatively stable between pH2.5 and 6.8.

[0054] Experiment 2: pH selection

[0055] The pH of eye drops directly affects eye irritation and the drug's efficacy. Normal eyes tolerate a pH range of 5.0 to 9.0, with no discomfort at pH 6.0 to 8.0. Human tears, on the other hand, have a pH of 7.4, and levels below 5.0 and above 11.4 are irritating. The choice of pH should take into account factors such as drug solubility, stability, and eye irritation. Piribedil is extremely insoluble in water, posing a significant challenge to the formulation of water-soluble eye drops. We screened the following pH ranges for the eye drops intended for the present invention:

[0056] Procedure: a) Weigh glycerol (maximum dosage 2.5% w / v) and hydroxypropyl cellulose (maximum dosage 0.35% w / v) according to the maximum dosage of FDA eye drops, add an appropriate amount of 35-40°C water for injection, sonicate and dissolve, and mix thoroughly; b) Maintain the temperature at 35-40°C and add 10% w / v piribedil and stir to dissolve; c) Separately, take sodium dihydrogen phosphate hydrate (maximum dosage 1.15% w / v) and sodium citrate hydrate (maximum dosage 0.45% w / v) according to the maximum dosage of FDA eye drops, add them to the above solution, and adjust the pH with hydrochloric acid or sodium hydroxide; d) Determine the pH and content of the solution, filter through a 0.22 μm filter membrane, fill into plastic ampoules according to specifications, and then sterilize at 121°C for 15 minutes to obtain piribedil eye drops. The results are shown in Table 2:

[0057] Table 2 Stability screening at different pH values

[0058]

[0059]

[0060] The results showed that the solubility of piribedil decreased with increasing pH, and the optimal pH value was 3.5-6.0.

[0061] Experiment 3: Selection of viscosity modifier

[0062] Thickeners are a class of viscous hydrophilic colloids. When used in eye drops, they increase the viscosity of the drug solution, reduce surface tension, increase drug retention in the conjunctival sac, prolong drug contact time with ocular tissue, and improve bioavailability. Commonly used thickeners in eye drops include sodium hyaluronate, hydropropyl methylcellulose, povidone, and sodium alginate. Hyaluronic acid and its salts are substances naturally present in the human body and were first discovered in the vitreous humor. Due to its excellent non-Newtonian fluid properties and viscoelasticity, sodium hyaluronate is often used as a thickener in eye drops. In addition to increasing solution viscosity and enhancing drug bioavailability, sodium hyaluronate can also enhance bioavailability even in low-viscosity solutions through drug binding and membrane affinity. However, it is relatively expensive. Hydroxypropyl methylcellulose (HPMC) is a commonly used thickener in eye drops. It is stable, possesses emulsifying, thickening, and suspending properties, and is safe and non-toxic. HPMC aqueous solutions have a certain viscosity and properties similar to those of viscoelastic substances in tears, making them suitable for use as artificial tears.

[0063] We screened viscosity modifiers for piribedil eye drops using HPMC, PVP (K30), and sodium alginate (SA), the most representative viscosity modifiers. Using the ocular irritation of the eye drops as an evaluation criterion, we screened for viscosity modifiers that could mitigate eye irritation and then selected their optimal dosages. For ocular preparations, the safe dosage of HPMC is 0.45%-3.5%, the safe dosage of PVP is 2%-10%, and the commonly used dosage of SA is 0.1%-0.5%. We investigated the effects of varying dosages of these three excipients on irritation (see Table 3). Piribedil solutions were prepared at the prescribed dosage and tested according to the ocular irritation test requirements outlined in the "Compilation of Guiding Principles for Preclinical Research of New (Western) Drugs." Two rabbits weighing between 2 kg and 2.5 g were selected for each dosage group. The piribedil solution was instilled into the left eye of each rabbit, while the right eye received saline as a control. Two drops (approximately 0.1 mL) of eye drops were instilled using a rubber-tipped dropper. After 10 seconds of passive eye closure, the eye was flushed with normal saline. Local reactions were recorded 15, 3, 60, and 90 minutes after administration of the test solution. The scores were assigned according to the Draize scale, with 0-3 indicating no irritation, 4-8 indicating mild irritation, 9-12 indicating moderate irritation, and 13-16 indicating severe irritation. The results are shown in Table 4.

[0064] Table 3 Tackifier dosage design

[0065]

[0066] Table 4 Irritation scores of three excipients

[0067] Serial number 1 2 3 Povidone (K30) 5 8 17 Sodium alginate 3 7 12 Hydroxypropyl methylcellulose 1 3 6

[0068] Results: The irritation of different viscosity enhancers and their dosage to rabbit eyes showed that there was a certain correlation between the irritation of viscosity enhancers and dosage. Hydroxypropyl methylcellulose was relatively less irritating, so HPMC was the most suitable viscosity enhancer. Similar hydroxypropyl cellulose, hydroxypropylethyl cellulose and hydroxyethyl cellulose were also suitable for use as viscosity enhancers.

[0069] Examples 1 to 5:

[0070] 1. Prescription

[0071]

[0072] 2. Preparation process

[0073] a) Weigh the prescribed amount of glycerin and hydroxypropyl cellulose, add appropriate amount of 35-40°C water for injection, ultrasonically dissolve and mix thoroughly;

[0074] b) maintaining the temperature at 35-40° C., adding 10% w / v piribedil and stirring to dissolve;

[0075] c) Weigh the prescribed amount of sodium dihydrogen phosphate hydrate and sodium citrate hydrate, add them to the above solution, adjust the pH with hydrochloric acid or sodium hydroxide, add water for injection to the full amount, and continue stirring for 20 minutes;

[0076] d) Determine the pH value and content of the solution, filter through a 0.22 μm filter membrane, and fill into 1 ml plastic ampoules, 0.3 ml per bottle. Sterilize at 121°C for 15 minutes to obtain the piribedil eye drops. Label, package, and obtain the finished product after passing inspection.

[0077] Examples 5 to 8:

[0078] 1. Prescription

[0079]

[0080] 2. Preparation process

[0081] Same as above.

[0082] Examples 9-12:

[0083] 1. Prescription

[0084]

[0085]

[0086] 3. Preparation process

[0087] a) Weigh the prescribed amount of polyvinyl alcohol, sodium chloride, and potassium chloride, add appropriate amount of 35-40°C water for injection, ultrasonically dissolve, and mix thoroughly;

[0088] b) maintaining the temperature at 35-40° C., adding 10% w / v piribedil and stirring to dissolve;

[0089] c) Weigh the prescribed amount of sodium citrate hydrate and add it to the above solution. Adjust the pH with hydrochloric acid or sodium hydroxide, add water for injection to the total amount, and continue stirring for 20 minutes.

[0090] d) Determine the pH value and content of the solution, filter through a 0.22 μm filter membrane, and fill into 1 ml plastic ampoules, 0.4 ml per bottle. Sterilize at 121°C for 15 minutes to obtain the piribedil eye drops. Label, package, and obtain the finished product after passing inspection.

[0091] Examples 13 to 17:

[0092] 1. Prescription

[0093]

[0094] 2. Preparation process

[0095] Same as above.

[0096] Comparative Example:

[0097] Because the water solubility of the piribedil API is 1.57 mg / ml, it is difficult to prepare a clinically acceptable concentration without the use of a solubilizer. We used conventional eye drop solubilizers Tween 80 (FDA maximum dosage 0.1-0.5%) and Poloxamer 188 (FDA maximum dosage 0.1%) to prepare the eye drops as follows:

[0098]

[0099] 2 Preparation process

[0100] Same as above.

[0101] Example 18: Stability Study

[0102] Accelerated testing was performed on Examples 1-12 and Comparative Examples 1-5. The homemade eye drops were placed in a constant temperature and humidity incubator at a humidity of 65% ± 5% and a temperature of 30°C ± 2°C for 6 months. Samples were collected at 0, 1, 2, 3, and 6 months, and their appearance, content, related substances, viscosity, osmotic pressure, and pH were measured. The results are shown in Table 5.

[0103] Table 5 Accelerated test of samples

[0104]

[0105]

[0106]

[0107] Conclusion: The eye drop composition of the present invention is relatively stable under the accelerated test. However, as the accelerated time of the composition increases, the pH increases slightly, but is within the standard limit. The stability of the comparative example is far inferior to that of the present invention.

[0108] Example 19: Study on the efficacy of preventing myopia in rats

[0109] 1 Experimental Animals 70 male rats, SPF grade, weighing 40-60 g, 21-25 days old, were used. All animal experiments were performed in accordance with the "Guidelines for Laboratory Animals" and the "Regulations on the Administration of Laboratory Animals of the People's Republic of China".

[0110] 2 Experimental methods

[0111] 2.1 Animal grouping

[0112] Before modeling, all animals underwent a basic ophthalmological examination using a slit lamp and fundus camera. Rats with anterior segment and fundus abnormalities were removed. The remaining rats were examined for binocular refraction using a strip retinoscope, and rats with a difference in refractive power greater than 2.00 D between the left and right eyes were removed. The 60 animals that passed the screening were randomly divided into four groups based on body weight: a blank control group, a model control group, a 1% dose group of the eye drops of Example 9, and a 2% dose group of the eye drops of Example 8; each group had 15 animals.

[0113] 2.2 Myopia model establishment

[0114] All animals in the model control group, Example 9 eye drops 1% dose group, and Example 8 eye drops 2% dose group were given 50 mg·mL -1 Shutai 50, 10 mg mL -1 Xylazine hydrochloride injection anesthesia, ofloxacin eye ointment as eye care drugs, applied to the ocular surface. Among them, the dose of Shutai 50 is 8mg·kg-1, and the dose of Xylazine hydrochloride injection is 8mg·kg -1 The drug was administered by intramuscular injection into the hind limbs. After confirming that the animal was deeply anesthetized, the skin around the eye to be sutured was prepared, and then local disinfection was performed from the inside out with povidone iodine. Prepare a translucent opaque eye mask and a plastic collar in advance, suture the prepared eye mask to the skin around the left eye with non-absorbable sutures, adjust the size of the plastic collar, and fix it to the rat's neck so that the base of the rat's ear can be exposed to the collar, and the rat's head cannot pass through the collar, thereby preventing the rat from damaging the eye mask and improving the success rate of the model. The eye mask was worn for 7 weeks. If it fell off, it was sutured again in time. After the operation, the health and activity restriction of the animal were observed every day, and the sutured site was disinfected and cared for with iodine.

[0115] 2.3 Dosing The day of modeling was the first day of dosing. The dosing method was unilateral eye drops with a dosing volume of 50 μL. The dosing time was fixed at 9:00 a.m. every day, once a day, and the dosing duration was consistent with the modeling, lasting for 7 weeks. Since the model control group, the 1% dose group of eye drops in Example 9, and the 2% dose group of eye drops in Example 8 were wearing opaque eye masks, the animals in each group were carefully grasped during dosing. 50 μL of the corresponding drug was extracted with a 0.5 mL disposable insulin injection needle and instilled into the model eye. After dosing, the animal's eyelids were carefully closed several times with external force to allow the drug to infiltrate the ocular surface of the animal's left eye. Among them, the drugs given to animals in each group are as follows: blank control group: 50 μL of polyvinyl alcohol eye drops; model control group: 50 μL of polyvinyl alcohol eye drops; Example 9 eye drops 1% dose group: 50 μL of the prepared Example 9 eye drops 1% dose group eye drops solution; Example 8 eye drops 2% dose group: 50 μL of the prepared Example 8 eye drops 2% dose group eye drops solution.

[0116] 3 Results

[0117] 3.1 Axis measurement

[0118] After the administration, all experimental animals underwent axial length measurement of the left eye to observe whether the form deprivation myopia rat model was successfully established and the effect of the present invention on the axial length of the myopic rats after modeling. The specific operation is as follows: after the rats were sacrificed, the eyeballs and optic nerves of both rats were immediately removed. Two to three small holes were pierced with a syringe at the 12 o'clock position of the eyeballs to mark them. The eyeballs of the rats were clamped with a vernier caliper parallel to the 12 o'clock and 6 o'clock positions. The vernier caliper was just tangential to the eyeballs, close to but not compressing the eyeballs. The length from the corneal vertex to the root of the optic nerve was measured as the axial length of the eye. The axial length data of the left eye of all animals was recorded. Results: Compared with the rats in the blank control group, the axial length of the rats in the model control group was significantly extended (P<0.01), reaching 6.95±0.011mm; compared with the rats in the model control group, the axial length of the rats in the 1% dose of Example 9 eye drops and the 2% dose of Example 8 eye drops groups was significantly shortened, among which the axial length of the rats in the 1% dose of Example 9 eye drops group was about 0.92mm shorter than that of the rats in the model control group (P<0.05), and the axial length of the rats in the 2% dose group was about 1.09mm shorter than that of the rats in the model control group (P<0.05). This experiment shows that rats can develop form deprivation myopia by wearing a light-transmitting but non-transparent eye mask for 7 weeks, and the degree of myopia is manifested as an axial length extension of 0.4mm; the eye drop compositions of the present invention at two concentrations of Example 8 and Example 9 can both delay the progression of myopia, and the 2% dose group of Example 8 eye drops has a better effect in preventing and controlling myopia than the 1% dose group of Example 9 eye drops, with a significant difference (P<0.05).

[0119] Table 6 Axis measurement results

[0120] Group Number of animals (n) Axis length (mm) Blank control group 10 5.67±0.011 Model control group 10 6.95±0.013 Example 9 Eye Drops 1% Dosage Group 10 6.03±0.017 Example 8 Eye Drops 2% Dosage Group 10 5.86±0.005

[0121] 3.2 Refractive index detection

[0122] All experimental animals were tested for refractive power before modeling to observe whether the form deprivation myopia rat model was successfully established and the changes in refractive power of the myopic rats after the modeling was completed and the administration of the present invention; after the modeling and drug administration, the equivalent refractive power of both eyes of the control group animals was recorded, and the equivalent refractive power of the modeling eye of the model control group and the dosage group of the present invention were recorded. The detection method is as follows: before measurement, drop tropicamide into the conjunctival sac of the rat to dilate the pupil. The amount of ciprofloxacin and cyperazine hydrochloride required for the rat was calculated according to the rat's weight, and the rat was deeply anesthetized. The deep anesthesia standard is: relaxation of the limb muscles, no reflex when pinching the skin, and steady breathing. Among them, the concentration of ciprofloxacin 50 is 25 mg·mL -1 The dose is 8 mg·kg-1, and the concentration of xylazine hydrochloride injection is 10 mg·mL -1 The dose was 8 mg / kg⁻¹, administered by intramuscular injection into the thigh. The ocular surface was cleaned with saline, and excess saline was removed with a cotton swab. The refractive index of all animals was measured in a dark room using a strip retinoscope. During measurement, the strip retinoscope was kept 50 cm from the eye being examined. Horizontal and vertical measurements were taken separately, and the refractive index with neither forward nor backward movement was recorded. Finally, the equivalent refractive index was recorded. Afterwards, ofloxacin eye ointment was applied to the ocular surface of both eyes as an eye care medication. Results: Compared with the rats in the blank control group, the refraction of the rats in the model control group was significantly reduced (P<0.01), reaching 2.21±0.553D. Compared with the rats in the model control group, the degree of refraction reduction of the rats in the 2% dose group of Example 8 eye drops and the 1% dose group of Example 9 eye drops was significantly less. Among them, the refraction of the rats in the 1% dose group of Example 9 eye drops was about 5.24D higher than that of the rats in the model control group, and the refraction of the rats in the 2% dose group of Example 8 eye drops was about 8.11D higher than that of the rats in the model control group. The refractive status of the rats in the different treatment groups showed that wearing a translucent but opaque eye mask for 7 weeks can cause form deprivation myopia in rats. The administration of the eye drops of the composition of the present invention at two concentrations can delay the extent of refraction reduction, and the 2% dose group of Example 8 eye drops has a better effect on preventing and controlling myopia than the 1% dose group of Example 9 eye drops, with a significant difference (P<0.05).

[0123] Table 7 Refractive index test results

[0124] Group Number of animals (n) Refraction (D) Blank control group 10 13.16±0.087 Model control group 10 2.21±0.553 Example 9 Eye Drops 1% Dosage Group 10 7.57±0.150 Example 8 Eye Drops 2% Dosage Group 10 10.32±0.236

[0125] Example 20: Safety Pharmacology Study

[0126] 1. Eye irritation test

[0127] In accordance with the relevant provisions of the Technical Guidelines for Studies on Irritation, Allergy and Hemolysis of Chemical Drugs, this experiment used a single-dose and multiple-dose method to conduct rabbit eye irritation tests.

[0128] 1.1 Single Dosage Method: Six healthy adult rabbits with normal eyes weighing 2.8 ± 0.4 kg were collected. 0.1 ml of the eye drops of Example 1 was instilled into the left eyelid, while 0.1 ml of normal saline was instilled into the right eye as a control. The cornea, conjunctiva, iris, and secretions were observed after 1 hour, 24 hours, 48 hours, and 72 hours. No irritation reactions such as congestion, tearing, photophobia, edema, or increased secretions were observed in the rabbit eyes. A handheld slit lamp was used to examine the cornea and iris, and no abnormalities were found.

[0129] 1.2 Multiple Dosing Method: Six healthy adult rabbits with normal binocular function, weighing 2.8 ± 0.4 kg, were administered 0.1 ml of the eye drops of Example 1 to the left eye and normal saline to the right eye as a control, four times daily for 14 consecutive days. The eyes were examined before daily administration and at 1 hour, 24 hours, 48 hours, and 72 hours after the last administration. Local reactions were recorded daily. No abnormalities were observed in either eye. The results showed that the drug had no specific irritation to the rabbit eyes.

Claims

1. A pharmaceutical composition, characterized in that The composition comprises 0.1% to 10% w / v of piribedil or a pharmaceutically acceptable salt thereof and water for injection.

2. The pharmaceutical composition according to claim 1, wherein Contains a solubilizer; and at least one excipient selected from a buffer, a tension regulator, a viscosity regulator, a chelating agent and a pH regulator. Preferably, the solubilizer is selected from one or both of glycerol or polyvinyl alcohol.

3. The composition according to claim 1, characterized in that The composition contains no preservatives.

4. The composition according to claim 1, characterized in that The content of the solubilizer in the composition is 1 to 4% w / v, more preferably 2 to 3% w / v, and even more preferably 2.5 to 2.8% w / v.

5. The composition according to claim 1, characterized in that The composition optionally further comprises one or more of about 0.01% w / v to 5% w / v buffer, about 0.1% w / v to 6% w / v tonicity adjuster, or about 0.001% w / v to 1% w / v chelating agent.

6. The composition according to claim 1, characterized in that The composition optionally further comprises about 0.01% w / v to 5% w / v of a viscosity modifier. Preferably, the viscosity modifier is one or more of hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxymethylcellulose or hydroxyethylcellulose.

7. The composition according to claim 1, characterized in that The pH value of the composition is 3.0-7.0, 4.0-6.5, preferably 5.5-6.

5.

8. The composition according to claim 1, characterized in that The composition contains 9. The composition according to claim 1, characterized in that The composition contains 10. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for treating myopia, preventing myopia and / or inhibiting the progression of myopia; preferably, the myopia is axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, severe myopia, high myopia, moderate myopia, low myopia, myopia combined with glaucoma, myopia with a risk of glaucoma, or myopia accompanied by high intraocular pressure.

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