An ophthalmic formulation composition and a method of preparing the same

Abstract

The application discloses an eye preparation composition for treating presbyopia with longer action time and fewer adverse reactions and a preparation method thereof. The composition contains pilocarpine with a mass volume percentage of 0.42-1.02% (equivalent to 0.50-1.20% of hydrochloric acid pilocarpine and 0.55-1.33% of nitric acid pilocarpine), sodium carboxymethylcellulose with a mass percentage of 0.03-0.3%, hydroxyethyl p-henyl-ethyl ester with a mass percentage of 0.03-0.06%, and sodium chloride with a mass percentage of 0.6-0.8%. The prepared pilocarpine eye drops have the advantages of effectively enhancing the corneal permeability of pilocarpine, prolonging the retention time of the eye drops in eyes, reducing the use frequency while improving the pilocarpine miosis effect and treating presbyopia, reducing the irritation and damage of pilocarpine to corneas, and reducing the incidence of systemic adverse reactions compared with the related preparations on the market. In addition, the prescription pH value of the application is 4.0-5.0, which can effectively reduce the generation of impurities such as pilocarpine acid and ensure the product quality in the whole life cycle.

Description

Technical Field

[0001] This invention relates to the technical field of eye drops, specifically to a pilocarpine eye drop with longer-lasting effects, fewer adverse reactions, and treatment of presbyopia, and its preparation method. Background Technology

[0002] Pilocarpine is a viscous, oily liquid or crystal, hygroscopic, and belongs to the tertiary amine class of compounds. In vivo, it remains active as a protonated ammonium ion. The lactone ring in the pilocarpine chemical structure can be hydrolyzed under alkaline conditions, forming a pharmacologically inactive sodium rutinate that dissolves. Pilocarpine is a drug that selectively and directly acts on M-cholinergic receptors, with the most pronounced effects on the eye and glands. Under the influence of pilocarpine, the longitudinal muscles of the ciliary muscle become more active, leading to a decrease in intraocular pressure and pupil constriction. Based on this mechanism of action, pilocarpine can be used to treat glaucoma and presbyopia. Pilocarpine is commonly found in the form of hydrochloride or nitrate.

[0003]

[0004] Pilocarpine structural formula

[0005] Among the pilocarpine-related preparations marketed in China, eye drops are mainly used to treat glaucoma, and there are no eye drops marketed for the treatment of presbyopia.

[0006] In October 2021, the new ophthalmic drug Vuity (pilocarpine hydrochloride, 1.25%, eye drops) was approved by the FDA for the treatment of presbyopia in adults, with one drop per administration. However, pilocarpine eye drops have poor permeability and tend to slip off quickly after being instilled into the eye, resulting in drawbacks such as slow onset of action (25 minutes after administration), short duration of action (only lasts for 6 hours after administration), and the need for multiple administrations. Furthermore, the high concentration of the drug leads to high systemic exposure and a high risk of significant adverse reactions such as strong local irritation and headaches.

[0007] Therefore, developing a pilocarpine eye drop with good permeability, long ocular retention time, low adverse reactions, and high safety is of great clinical significance. Summary of the Invention

[0008] To address the shortcomings of the novel ophthalmic drug Vuity (1.25% pilocarpine hydrochloride eye drops) in treating presbyopia, such as slow onset of action, short duration of action, and significant side effects, the inventors, through long-term formulation and process screening and drug permeability research, have developed a new formulation and process that promotes pilocarpine penetration into the cornea, prolongs its residence time on the ocular surface, and reduces side effects. This results in a lower concentration, safer administration method for pilocarpine eye drops used to treat presbyopia, along with its preparation method.

[0009] The specific technical solution of this invention is as follows:

[0010] The formulation of pilocarpine eye drops contains pilocarpine at a mass-volume percentage of 0.42-1.02% (equivalent to pilocarpine hydrochloride 0.50-1.20% and pilocarpine nitrate 0.55-1.33%), sodium carboxymethyl cellulose at a mass-volume percentage of 0.03-0.3%, ethylparaben at a mass-volume percentage of 0.03-0.06%, sodium chloride at a mass-volume percentage of 0.6-0.8%, a pH adjuster to adjust the pH value to 4.0-5.0, and water for injection.

[0011] Specifically, the aforementioned pilocarpine can be pilocarpine nitrate or pilocarpine hydrochloride.

[0012] Specifically, the kinematic viscosity of the prepared pilocarpine eye drops was measured using a Pinton capillary viscometer with an inner diameter of 0.4–0.6 mm at 25°C, and the result was 1.2–4.2 mm. 2 Within the range of / s.

[0013] Specifically, the pH adjuster mentioned above can be a pH adjuster or buffer such as sodium hydroxide, sodium citrate, sodium dihydrogen phosphate, boric acid, or hydrochloric acid, to adjust the pH of the prescription to 4.0~5.0.

[0014] Specifically, sodium chloride is used in the formulation as an osmotic pressure regulator to adjust the osmotic pressure of the finished product to the range of 260~330 mOsmol / kg.

[0015] The process steps are as follows:

[0016] (1) Add sodium carboxymethyl cellulose, pilocarpine raw material, ethylparaben, and sodium chloride to water for injection and stir to dissolve and mix evenly.

[0017] (2) Measure the pH value of the solution. If it is not in the range of 4.0 to 5.0, use a pH adjuster to adjust the pH value to the range.

[0018] (3) Sterile eye drops were obtained by using a first 0.45μm filter membrane and a second 0.22μm filter membrane for sterilization filtration.

[0019] (4) Dispense the solution into 3ml vials to obtain pilocarpine eye drops.

[0020] The beneficial effects of adopting the technical solution of this invention are:

[0021] The pilocarpine eye drops of this invention, by adding a specific proportion of sodium carboxymethyl cellulose, have significant advantages over commercially available formulations. These advantages include effectively enhancing the corneal permeability of pilocarpine, prolonging the retention time of the eye drops in the eye, improving the miotic effect of pilocarpine while reducing the frequency of administration, reducing corneal irritation and damage, and decreasing the incidence of systemic adverse reactions. Furthermore, the formulation designed in this invention has a pH value of 4.0-5.0, which effectively reduces the generation of impurities such as pilocarpine acid, ensuring product quality throughout its entire lifecycle. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of protection of this invention. Unless otherwise specified, all reagents and raw materials used in this invention are commercially available products or products that can be prepared by known methods.

[0023] To better illustrate the present invention, further examples are provided below.

[0024] Example 1

[0025] Prescription composition Dosage Pilocarpine Nitrate 7.5g Sodium carboxymethyl cellulose 1.0 g Sodium chloride 6.8g Ethylparaben 0.3g pH adjuster Adjust the pH to 4.0-5.0. Add water for injection to 1000ml

[0026] Preparation process:

[0027] Add water for injection to the prepared solution system, then add sodium carboxymethyl cellulose, pilocarpine nitrate, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 4.0-5.0 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) filter and a second 0.22μm PTFE filter for sterilization. Fill into 3ml vials to obtain the finished product.

[0028] Example 2

[0029] Prescription composition Dosage Pilocarpine Nitrate 13.0g Sodium carboxymethyl cellulose 0.3g Sodium chloride 6.8g Ethylparaben 0.3g pH adjuster Adjust the pH to 4.0-5.0. Add water for injection to 1000ml

[0030] Preparation process:

[0031] Add water for injection to the prepared solution system, then add sodium carboxymethyl cellulose, pilocarpine nitrate, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 4.0-5.0 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) filter and a second 0.22μm PTFE filter for sterilization. Fill into 3ml vials to obtain the finished product.

[0032] Example 3

[0033] Prescription composition Dosage Pilocarpine Nitrate 5.5g Sodium carboxymethyl cellulose 3.0g Sodium chloride 6.8g Ethylparaben 0.6g pH adjuster Adjust the pH to 4.0-5.0. Add water for injection to 1000ml

[0034] Preparation process:

[0035] Add water for injection to the prepared solution system, then add sodium carboxymethyl cellulose, pilocarpine nitrate, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 4.0-5.0 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) filter and a second 0.22μm PTFE filter for sterilization. Fill into 3ml vials to obtain the finished product.

[0036] Example 4

[0037] Prescription composition Dosage Pilocarpine hydrochloride 12.0g Sodium carboxymethyl cellulose 0.3g Sodium chloride 6.8g Ethylparaben 0.3g pH adjuster Adjust the pH to 4.0-5.0. Add water for injection to 1000ml

[0038] Preparation process:

[0039] Add water for injection to the prepared solution system, then add sodium carboxymethyl cellulose, pilocarpine hydrochloride, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 4.0-5.0 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) membrane and a second 0.22μm PTFE membrane for sterilization. Fill into 3ml vials to obtain the finished product.

[0040] Example 5

[0041] Prescription composition Dosage Pilocarpine hydrochloride 5.0g Sodium carboxymethyl cellulose 3.0g Sodium chloride 6.8g Ethylparaben 0.6g pH adjuster Adjust the pH to 4.0-5.0. Add water for injection to 1000ml

[0042] Preparation process:

[0043] Add water for injection to the prepared solution system, then add sodium carboxymethyl cellulose, pilocarpine hydrochloride, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 4.0-5.0 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) membrane and a second 0.22μm PTFE membrane for sterilization. Fill into 3ml vials to obtain the finished product.

[0044] Comparative Example 1

[0045] Product Name: Pilocarpine Hydrochloride Eye Drops

[0046] Product Name: Vuity

[0047] Manufacturer: AbbVie, LLC

[0048] Batch number: T4123

[0049] Specification: 2.5ml / bottle

[0050] Comparative Example 2

[0051] Prescription composition Dosage Pilocarpine Nitrate 7.5g Sodium carboxymethyl cellulose N / A Sodium chloride 6.8g Ethylparaben 0.3g pH adjuster Adjust the pH to 4.0-5.0. Add water for injection to 1000ml

[0052] Preparation process:

[0053] Add water for injection to the prepared solution system, then add pilocarpine nitrate, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 4.0-5.0 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) filter and a second 0.22μm PTFE filter for sterilization. Fill into 3ml vials to obtain the finished product.

[0054] Comparative Example 3

[0055] Prescription composition Dosage Pilocarpine hydrochloride 12.0g Sodium carboxymethyl cellulose N / A Sodium chloride 6.8g Ethylparaben 0.3g pH adjuster Adjust the pH to 4.0-5.0. Add water for injection to 1000ml

[0056] Preparation process:

[0057] Add water for injection to the prepared solution system, then add pilocarpine hydrochloride, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 4.0-5.0 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) filter and a second 0.22μm PTFE filter for sterilization. Fill into 3ml vials to obtain the finished product.

[0058] Comparative Example 4

[0059] Prescription composition Dosage Pilocarpine Nitrate 7.5g Sodium carboxymethyl cellulose 1.0g Sodium chloride 6.8g Ethylparaben 0.3g pH adjuster Adjust the pH to 5.5. Add water for injection to 1000ml

[0060] Preparation process:

[0061] Add water for injection to the prepared solution system, then add sodium carboxymethyl cellulose, pilocarpine nitrate, ethylparaben, and sodium chloride. Stir to dissolve, and adjust the pH to 5.5 with a pH adjuster. Filter the solution through a first 0.45μm polytetrafluoroethylene (PTFE) filter and a second 0.22μm PTFE filter for sterilization. Fill into 3ml vials to obtain the finished product.

[0062] The inventors conducted systematic stability studies (including changes in related substances, content, viscosity, etc.), corneal permeability studies, and ocular retention time studies on the formulation samples in the above embodiments and comparative examples.

[0063] Experimental Example 1

[0064] Related substances method (high performance liquid chromatography):

[0065] Chromatographic conditions:

[0066] Chromatographic column: A chromatographic column packed with octadecylsilane-bonded silica gel (carbon content not less than 19%).

[0067] Mobile phase: methanol-acetonitrile-0.002 mol / L tetrabutylammonium hydroxide solution (55:60:885) (adjust pH to 7.7 with 20% phosphoric acid solution)

[0068] Flow rate: 1.0 ml / min;

[0069] Column temperature: 30℃;

[0070] Detection wavelength: 220nm;

[0071] Injection volume: 20 μL.

[0072] Accurately measure an appropriate amount of this product and dilute it quantitatively with water to prepare a solution containing 1.0 mg of pilocarpine nitrate per 1 ml.

[0073] Accurately measure 1 ml of the test solution into a 100 ml volumetric flask, dilute with water to the mark, and shake well.

[0074] Take 5 ml of the reference solution from the content determination section of pilocarpine positioning solution, add 0.1 ml of concentrated ammonia solution, heat in a water bath for 30 minutes, cool, dilute with water to 25 ml, shake well, take 3 ml, dilute with water to 25 ml, and shake well.

[0075] The system suitability requirements stipulate that the separation between the pilocarpine peak and the pilocarpine alkaloid peak in the chromatogram of the pilocarpine localization solution should meet the requirements.

[0076] For the assay, accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms up to twice the retention time of the main component peak.

[0077] If a peak of pilocarpine appears in the chromatogram of the test solution, its peak area shall not exceed 4 times (4.0%) the area of ​​the main peak of the control solution, and the sum of the peak areas of other impurities shall not exceed 1.5 times (1.5%) the area of ​​the main peak of the control solution.

[0078] Experiment Example 2

[0079] Content method (high performance liquid chromatography):

[0080] Chromatographic conditions: Same as the method for determination of related substances.

[0081] For the reference solution, take an appropriate amount of pilocarpine nitrate reference standard, accurately weigh it, dissolve it in water, and quantitatively dilute it to prepare a solution containing 1.0 mg per ml.

[0082] For the test solution, pilocarpine-based positioning solution, chromatographic conditions, and system suitability requirements, please refer to the section on related substances.

[0083] For the assay, accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results based on peak area using the external standard method.

[0084] Experimental Example 3

[0085] Viscosity measurement methods:

[0086] Viscosity was determined according to the Ping capillary viscometer method, Section IV, General Chapter 0633, Method I, of the 2020 edition of the Chinese Pharmacopoeia, with the temperature controlled at 25℃. The inner diameter of the capillary E of the viscometer was in the range of 0.4~0.6 mm.

[0087] Experiment Example 4

[0088] Experimental Procedure: The changes in related substances, content, pH value, osmolality, and viscosity of samples from Examples 1, 2, 3, 4, 5, Comparative Examples 1, 2, 3, and 4 under various influencing factors were detected. The results are as follows:

[0089]

[0090] The test results show that:

[0091] In Examples 1, 2, 3, 4, and 5, after investigation of influencing factors, the relevant substances, pH value, osmotic pressure, etc., were all within the qualified range.

[0092] Comparative Example 1 is a commercially available formulation of pilocarpine hydrochloride eye drops.

[0093] Comparative Example 4, with a pH of 5.5, showed a significant increase in impurities during the period of influencing factors.

[0094] Comparative Examples 2 and 3, without the addition of sodium carboxymethyl cellulose, showed similar quality indicators such as related substances to Example 1 during the period of influencing factors.

[0095] (Acceptable standards: pilocarpine: ≤4.0%; impurities other than pilocarpine: ≤1.5%; pH range: 4.0~5.0; osmolality range: 260~330 mOsmol / kg)

[0096] Experiment Example 5: Investigation of Corneal Permeability

[0097] Study objective: To evaluate the difference in permeability between the test drug and the control drug on isolated corneas.

[0098] Source of ex vivo corneas: Corneas from adult New Zealand white rabbits (2.5-3kg) were harvested and used immediately.

[0099] Experimental apparatus: The improved Huarong TD-12AT fully automatic transdermal diffusion apparatus consists of two supply and receiving cells with equal inner diameters, each with a radius of 1.0 cm and an effective diffusion area of ​​0.8 cm². 2 The volume is 12ml.

[0100] Diffusion medium: Glutathione-Sodium Bicarbonate Ringer's Solution (GBR solution) (Preparation method for Solution 1: Weigh 12.4g sodium chloride, 0.716g potassium chloride, 0.206g sodium dihydrogen phosphate monohydrate, and 4.908g sodium bicarbonate, and dissolve in 1000mL water. Preparation method for Solution 2: Weigh 0.23g calcium chloride dihydrate, 0.318g magnesium chloride pentahydrate, 1.8g glucose, and 0.184g oxidized glutathione, and dissolve in 1000mL water. Mix equal volumes of Solutions 1 and 2 thoroughly before use.)

[0101] Experimental Method: The separated corneas were rinsed three times with GBR solution. The epithelial layer was fixed between the supply and receiving cells of the fully automated transdermal diffusion apparatus, with the supply cell facing upwards. The receiving cell was filled with GBR solution and contained a stir bar. 1 mL of the sample to be tested was added to the supply cell. The entire apparatus was placed in a thermostatic magnetic stirrer at 35±1℃. 1 mL samples were taken from the receiving cell at 1, 2, 3, 4, 5, and 6 hours, and an equal volume of GBR solution at the same temperature was added simultaneously. The samples were filtered through a 0.22 μm microporous membrane, and the filtrate was collected. The concentration of pilocarpine in the samples was calculated by ultraviolet spectrophotometry. The cumulative transmittance Qn of each sample was then calculated.

[0102]

[0103] Where Cn is the drug concentration measured at time t, C i Vt represents the drug concentration measured at a point before time t, and V0 represents the total volume of the medium in the receiving cell (12 mL). i The sample volume is 1 mL.

[0104] The results of the in vitro corneal permeability test are as follows:

[0105] Cumulative permeability Qn (ug / ml) over 6 hours Remark Example 1 21.5 Formula containing sodium carboxymethyl cellulose Example 2 27.3 Formula containing sodium carboxymethyl cellulose Example 3 30.5 Formula containing sodium carboxymethyl cellulose Example 4 26.4 Formula containing sodium carboxymethyl cellulose Example 5 29.1 Formula containing sodium carboxymethyl cellulose Comparative Example 1 13.0 Pilocarpine hydrochloride eye drops, control formulation, free of sodium carboxymethyl cellulose. Comparative Example 2 11.4 Preparation of pilocarpine nitrate, without sodium carboxymethyl cellulose. Comparative Example 3 13.1 Preparation of pilocarpine hydrochloride, without sodium carboxymethyl cellulose.

[0106] The experimental results show that the cumulative permeation of pilocarpine eye drops with added sodium carboxymethyl cellulose (Examples 1-5) on isolated rabbit corneas over 6 hours was significantly higher than that of the marketed formulation Comparative Example 1 and Comparative Examples 2 and 3 without sodium carboxymethyl cellulose. This indicates that adding sodium carboxymethyl cellulose can significantly increase the permeability of the active ingredient pilocarpine in the cornea.

[0107] Experiment Example 6: Examination of Eye Retention Time

[0108] Adult New Zealand white rabbits (2.5–3 kg) were selected for the experiment and randomly divided into groups of two according to their weight. Sodium fluorescein was added to the eye drops prepared in each example and comparative example, and after mixing, each group of eye drops was applied to the lower fornix of the left eye of the rabbits (50 μL / eye). An equal volume of 0.9% physiological saline was applied to the right eye of the rabbits as a self-control. The intensity of fluorescein was monitored using a blue light-activated fluorescent lamp at the beginning of the experiment, 10 minutes, 30 minutes, and 60 minutes, and the average value was recorded. Fluorescence retention time reflects the retention time of the eye drops in the rabbit's eye. The experimental results are as follows:

[0109]

[0110] The experimental results show that Comparative Examples 1, 2, and 3 eye drops without sodium carboxymethyl cellulose were cleared after 10 minutes of application and almost completely cleared after 30 minutes. Examples 1, 2, 3, 4, and 5 still had a small amount remaining in the eye after 1 hour of application.

[0111] Therefore, eye drops containing sodium carboxymethyl cellulose can enhance the permeability of pilocarpine nitrate or pilocarpine hydrochloride in the cornea and prolong their retention time in the eye. This is beneficial for improving the bioavailability of the drug, prolonging its duration of action, enhancing the miotic effect of pilocarpine, treating presbyopia, reducing the frequency of medication, reducing the irritation and damage of pilocarpine to the cornea, and reducing the incidence of systemic adverse reactions.

Claims

1. A pilocarpine eye drop for treating presbyopia, characterized in that, It contains pilocarpine in a mass-volume percentage range of 0.42~1.02% and sodium carboxymethyl cellulose in a mass-volume percentage range of 0.03~0.3%.

2. The pilocarpine eye drops according to claim 1, characterized in that, It also includes 0.03-0.06% by weight / volume of ethylparaben, 0.6-0.8% by weight / volume of sodium chloride, a pH adjuster, and water for injection, wherein the pH adjuster adjusts the pH of the pilocarpine eye drops to 4.0-5.

0.

3. The pilocarpine eye drops according to claim 1, characterized in that, The pilocarpine is selected from pilocarpine nitrate and / or pilocarpine hydrochloride.

4. The pilocarpine eye drops according to claim 1, characterized in that, The kinematic viscosity of the pilocarpine eye drops was measured to be 1.2–4.2 mm using a Pinton capillary viscometer with an inner diameter of 0.4–0.6 mm at 25°C. 2 Within the range of / s.

5. The pilocarpine eye drops according to claim 2, characterized in that, The pH adjuster is selected from at least one of sodium hydroxide, sodium citrate, sodium dihydrogen phosphate, boric acid, and hydrochloric acid.

6. The pilocarpine eye drops according to claim 1, characterized in that, The osmotic pressure of the pilocarpine eye drops is in the range of 260~330 mOsmol / kg.

7. The pilocarpine eye drops according to claim 1, characterized in that, The content of pilocarpine impurities is within the range of 4.0%; the total content of impurities other than pilocarpine is within the range of 1.5%.

8. A method for preparing pilocarpine eye drops according to any one of claims 1-7, characterized in that, The process includes the following steps: (1) Add sodium carboxymethyl cellulose, pilocarpine raw material, ethylparaben, and sodium chloride to water for injection and stir to dissolve and mix evenly; (2) Adjust the pH value to the range of 4.0 to 5.0 using a pH adjuster; (3) Sterile eye drops are obtained by using sterile filtration or terminal sterilization processes; (4) Packaging, and you get the product.

9. According to the preparation method of claim 8, the pilocarpine eye drops can be packaged in a multi-dose package or a single-dose package.

Images