An ophthalmic gel composition and a method of making the same

Abstract

This invention provides an ophthalmic gel composition comprising (1) ropinirole or a pharmaceutically acceptable salt thereof, (2) one or more thickeners, and other pharmaceutically acceptable excipients, wherein the viscosity of the ophthalmic gel composition is ≥100 mPa·s. The ophthalmic gel composition increases the viscosity of the product, prolonging the adhesion time of ropinirole to the eye. Compared with other dosage forms, it achieves both rapid onset of action and convenient administration, greatly enhancing its clinical value as an emergency medication.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a ropinirole ophthalmic gel composition and its preparation method. Background Technology

[0002] Ropinirone is a pan-dopamine agonist selective for the dopamine d2-like receptor family and was initially developed for human use to treat moderate to severe restless legs syndrome. However, ropinirone induces vomiting by activating d2-like receptors in the chemoreceptor trigger zone of the posterior brain, transmitting information to the vomiting center. The Finnish company Orion has utilized this mechanism of action to develop ropinirone hydrochloride eye drops for inducing vomiting in dogs, which was launched in the EU in 2018 under the brand name CLEVOR®, and subsequently launched in the US and other countries.

[0003] CN105592889A discloses a ropinirole hydrochloride eye drop and its preparation method. The product obtained is a true solution. Because it is a true solution with low viscosity, it has poor adhesion to the eye. Therefore, a large amount of the solution is lost during clinical use. In particular, when dogs are unconscious or uncooperative due to food poisoning, about half of the solution is lost along the corner of the eye, resulting in a great waste of the drug and affecting the onset time.

[0004] Therefore, it is essential to develop a new formulation of ropinirole that can be fully absorbed and has a rapid onset of action. Summary of the Invention

[0005] In view of the above-mentioned shortcomings in the prior art, the main objective of the present invention is to provide a ropinirole ophthalmic gel composition. The ophthalmic gel composition improves the viscosity of the product and prolongs the adhesion time of ropinirole to the eye. Compared with other dosage forms, it can achieve rapid onset of action and convenient administration, which greatly improves its clinical value as an emergency medicine.

[0006] The ophthalmic gel composition of the present invention comprises (1) ropinirole or a pharmaceutically acceptable salt thereof, (2) one or more thickeners, and other pharmaceutically acceptable excipients, wherein the viscosity of the ophthalmic gel composition is ≥100 mPa·s. Preferably, the viscosity of the ophthalmic gel composition is 100-1000 mPa·s, more preferably 400-900 mPa·s.

[0007] The thickener described in this invention is selected from natural or synthetic hydrophilic polymer materials. In some embodiments, the proportion of hydrophilic groups in the polymer material is ≥10%, preferably ≥30%. The hydrophilic groups include, but are not limited to, one or more of carboxylic acid groups, hydroxyl groups, hydroxypropoxy groups, and methoxy groups.

[0008] In a preferred embodiment of the present invention, the thickener is selected from any one or a combination of chitosan, hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, and methylcellulose. In some embodiments of the present invention, the thickener is selected from any one or a combination of hydroxypropyl methylcellulose and sodium hyaluronate.

[0009] In a preferred embodiment of the present invention, the thickener accounts for ≥0.3% by weight (w / w), preferably 0.5%-5.0%, and more preferably 0.5%-1.0%. In some embodiments of the present invention, the thickener accounts for 0.8%-1.0%.

[0010] In a preferred embodiment of the present invention, the pharmaceutically acceptable salts of ropinirole include, but are not limited to, hydrochloride, phosphate, sulfate, sulfite, and succinate. Further, the proportion of ropinirole and the pharmaceutically acceptable salts (calculated as ropinirole) is 1.0-5.0%, preferably 2.0-4.0%. In some embodiments of the present invention, the salt is selected from ropinirole hydrochloride.

[0011] In a preferred embodiment of the present invention, the ophthalmic gel composition further comprises a buffer. The buffer is selected from weak acid / base systems or weak base / acid systems, including but not limited to phosphate buffers, boric acid / borax buffers, bicarbonate buffers, citrate buffers, and tromethamine. In some embodiments of the present invention, the buffer comprises 0.1-1.0%, preferably 0.5-0.8%.

[0012] In some embodiments of the present invention, the buffer is selected from a combination of citric acid and sodium citrate, wherein the ratio of citric acid to sodium citrate is 10:1-0.1:1, preferably 2:1-1:1.

[0013] In a preferred embodiment of the present invention, the ophthalmic gel composition further comprises a pH adjuster. The pH adjuster is selected from inorganic bases and inorganic acids. Specifically, it includes, but is not limited to, any one or a combination of sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, and phosphoric acid.

[0014] In a preferred embodiment of the present invention, the pH value of the ophthalmic gel composition is ≤7.0, preferably 3.0-5.0. In some embodiments, the pH value is 4.0±0.5.

[0015] In a preferred embodiment of the present invention, the ophthalmic gel composition further comprises an osmotic pressure regulator selected from sodium chloride or mannitol. The amount of the osmotic pressure regulator is suitable for adjusting the osmotic pressure of the ophthalmic gel composition to 200-400 mosm / kg. Preferably, the osmotic pressure of the ophthalmic gel composition is 300±30 mosm / kg.

[0016] In the preferred embodiment of this invention, the other pharmaceutically acceptable excipients include, but are not limited to, any one or a combination of antioxidants / stabilizers, antibacterial agents, and humectants. The antioxidants / stabilizers include, but are not limited to, any one or a combination of disodium edetate, sodium sulfite, and vitamin C; the antibacterial agents include, but are not limited to, any one or a combination of benzalkonium chloride, cetrimonium bromide, benzoic acid, sorbic acid, benzyl alcohol, and chlorobutanol; and the humectants include, but are not limited to, any one or a combination of glycerin, sorbitol, and polyvinyl alcohol.

[0017] In some embodiments of the present invention, the ophthalmic gel composition does not contain an antibacterial agent.

[0018] The present invention also provides an ophthalmic gel composition comprising, by weight (w / w) (1) 1-5% ropinirole hydrochloride, (2) 0.3-5.0% of one or more thickeners, (3) 0.1-1.0% of a buffer, and (4) other pharmaceutically acceptable excipients, wherein the viscosity of the ophthalmic gel composition is ≥100 mPa·s; preferably 100-1000 mPa·s.

[0019] Preferably, the thickener accounts for 0.3-1.0% and the buffer accounts for 0.4-0.6%.

[0020] Preferably, the ophthalmic gel composition further includes sodium chloride and / or mannitol as osmotic pressure regulators; preferably, the osmotic pressure of the ophthalmic gel composition is 200-400 mosm / kg, more preferably 300±30 mosm / kg.

[0021] Preferably, the ophthalmic gel composition further includes a pH adjuster. In some embodiments, the pH value of the ophthalmic gel composition is ≤7.0, preferably 3.0-5.0.

[0022] The present invention also provides an ophthalmic gel composition, comprising, by weight (w / w), 3% ropinirole hydrochloride, 0.3-1.0% sodium hyaluronate and / or hydroxypropyl methylcellulose, 0.1-1.0% buffer, and other pharmaceutically acceptable excipients, wherein the viscosity of the ophthalmic gel composition is 100-1000 mPa·s. Preferably, the buffer content is 0.4-0.6%.

[0023] This invention also provides an ophthalmic gel composition, comprising, by weight (w / w), 3% ropinirole hydrochloride, 0.3-1.0% sodium hyaluronate and / or hydroxypropyl methylcellulose, 0.4-0.6% citric acid / sodium citrate, and other pharmaceutically acceptable excipients, wherein the viscosity of the ophthalmic gel composition is ≥100 mPa·s. Preferably, the viscosity of the ophthalmic gel composition is 100-1000 mPa·s, more preferably 400-900 mPa·s. Preferably, the osmotic pressure of the ophthalmic gel composition is 200-400 mosm / kg. Preferably, the pH value of the ophthalmic gel composition is 3.0-5.0. Preferably, the ophthalmic gel composition does not contain an antibacterial agent.

[0024] The present invention also provides a method for preparing the above-mentioned ophthalmic gel composition, the specific steps of which are as follows:

[0025] (1) Preparation of drug solution: Place an appropriate amount of water in a mixing tank, add other excipients except thickener and stir until completely dissolved, add the drug and stir to dissolve, adjust the pH value to 3.0-7.0 with pH adjuster to obtain drug solution;

[0026] (2) Add the thickener or the thickener gel prepared by adding water to the drug solution and stir evenly. Add water for injection to the full volume to obtain the drug solution.

[0027] In some embodiments of the present invention, the thickener gel in step (2) can be heated to fully swell during the preparation process and then cooled. If necessary, a sterilization step can be performed.

[0028] In some embodiments of the present invention, step (2) may also involve adding the drug solution to a thickener gel prepared by adding water in advance.

[0029] The preparation method of the present invention further includes a sterilization step, namely, maintaining the drug gel prepared in step (2) in a solution state for moist heat sterilization or filtration sterilization. In some embodiments of the present invention, the filtration sterilization is performed at room temperature.

[0030] The preparation method of the present invention further includes a packaging step, wherein the drug gel prepared in step (2) is kept in a solution state, filled into a semi-permeable ampoule (such as a low-density polyethylene ampoule, a polypropylene ampoule, etc.), and packaged in an aluminum-plastic composite film bag. In some embodiments, the filling step is filled with inert gas, and the packaging step is performed by filling with inert gas or vacuum packaging.

[0031] The preparation method of the present invention may further include a step of introducing an inert gas, including but not limited to nitrogen and argon. In some embodiments of the present invention, the step of introducing the inert gas may be carried out throughout the entire preparation process or in certain steps, such as the preparation of the drug solution or thickener gel, the filling step, or the packaging step.

[0032] In the preparation method of the present invention, the step of adjusting the pH value can also be performed before adding water for injection to the full volume in step (2).

[0033] In some embodiments of the present invention, the pH adjuster is selected from inorganic bases and inorganic acids. Specifically, it includes, but is not limited to, any one or a combination of sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, and phosphoric acid.

[0034] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0035] (1) This invention develops an ophthalmic gel with a specific viscosity, which is specifically designed for use in mammals in the unwell state of poisoning due to accidental ingestion. Compared with the solution, it is not only convenient to use, but also ensures that the drug is retained in the eye to the maximum extent for rapid absorption and to reach the effective concentration. It is particularly suitable for ropinirole for rapid vomiting and emergency treatment.

[0036] (2) The ophthalmic gel of the present invention minimizes the types of excipients, which can avoid other excipients from irritating the eyes and causing the drug to be expelled from the application site, thereby ensuring that the drug can be absorbed to the maximum extent and is not wasted.

[0037] (3) The present invention conducted a comparative study on the types and amounts of thickeners and found that ophthalmic gels prepared with a specific dose of sodium hyaluronate had good clinical effects, no serious adverse reactions, and overall mild adverse reactions were controllable.

[0038] (4) The ophthalmic gel described in this invention has good preparation process stability and high production efficiency, and is suitable for industrial mass production.

[0039] The pharmaceutically acceptable salts described in this invention refer to organic or inorganic salts that are acceptable to mammals and are safe and free of toxic side effects. These mammals include, but are not limited to, dogs, felines, cattle, horses, and sheep.

[0040] The room temperature mentioned in this invention refers to the natural weather temperature that is suitable for the production environment, generally not exceeding 30°C, and usually refers to 10-30°C.

[0041] The proportions of ropinirole and pharmaceutically acceptable salts described in this invention are calculated by weight of ropinirole. For example, 3% ropinirole hydrochloride means that the weight percentage of ropinirole in the ophthalmic composition is the proportion of ropinirole in the composition. Detailed Implementation

[0042] The present invention is further illustrated below by way of embodiments, but these embodiments are not intended to limit the invention to the scope of the embodiments described. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

[0043] Unless otherwise stated, all other reagents and raw materials used in this invention are commercially available. The equipment used is as follows:

[0044]

[0045] Comparative Example 1

[0046] Referring to Example 4 of CN105592889A regarding ropinirole eye drops, a comparative sample was prepared according to the following formulation.

[0047]

[0048] Preparation process: Weigh the ingredients according to the above formula for 500 vials, dissolve the excipients and drugs in water for injection, adjust the pH, filter and sterilize to obtain the final product.

[0049] Example 1: Investigation of Thickener Types

[0050]

[0051] According to the above formula, ropinirole hydrochloride gel was prepared using carbomer homopolymer type B, sodium hyaluronate, tylosap, and hydroxypropyl methylcellulose as thickeners, respectively. The preparation methods are as follows:

[0052] (1) Preparation of drug solution: Place an appropriate amount of water for injection in a mixing tank, add other excipients except thickener and stir until completely dissolved, add ropinirole hydrochloride and stir to dissolve, adjust the pH to 4 with hydrochloric acid / sodium hydroxide to obtain the drug solution;

[0053] (2) Preparation of thickener gel: Add the thickener to an appropriate amount of water for injection, stir and swell completely to obtain thickener gel;

[0054] (3) Add the thickener gel prepared in step (2) to the drug solution and stir to mix well. Add water for injection to the full volume to obtain the final product.

[0055] The viscosity of the above samples was measured. The viscosity measurement method is as follows: a digital viscometer was used, the rotation speed was 200 rpm, and the shear rate was 68 s. -1 The detection temperature was 25℃. The mixture was pre-stirred for 30 seconds before detection, and then the data was read every 5 seconds for 1 minute.

[0056] The viscosity measurement results are as follows:

[0057]

[0058] Example 2

[0059]

[0060] Preparation process:

[0061] (1) Preparation of drug solution: Place an appropriate amount of water for injection in a mixing tank, add other excipients except thickener and stir until completely dissolved, purge with nitrogen, add ropinirole hydrochloride and stir to dissolve, adjust the pH value to 4.0 with hydrochloric acid / sodium hydroxide to obtain the drug solution, and perform sterile filtration;

[0062] (2) Preparation of hydroxypropyl methylcellulose gel: Add the thickener hydroxypropyl methylcellulose to an appropriate amount of water for injection, heat it to disperse it, and then stir to make it swell completely to obtain hydroxypropyl methylcellulose gel; then perform moist heat sterilization, and cool down to no more than 30°C after sterilization.

[0063] (3) Add the gel prepared in step (2) to the drug solution and stir to mix well, then add water for injection to the total volume;

[0064] (4) Keep the drug gel prepared in step (3) at 50-60℃ in a solution state, then fill it with nitrogen to obtain the final product.

[0065] The viscosity of the above sample was measured to be 170.0 mPa·s.

[0066] Example 3

[0067]

[0068] Preparation process:

[0069] (1) Preparation of drug solution: Place an appropriate amount of water for injection in a mixing tank, add other excipients except thickener and stir until completely dissolved, add ropinirole hydrochloride and stir to dissolve, adjust the pH value to 3.0-5.0 with pH adjuster to obtain drug solution;

[0070] (2) Add the thickener sodium hyaluronate to the above-mentioned drug solution, stir until it is completely swollen, and add water for injection to the total volume;

[0071] (3) The drug gel prepared in step (2) is sterilized and filtered at room temperature, and then filled and packaged with nitrogen to obtain the final product.

[0072] Example 4

[0073]

[0074] The preparation process is the same as in Example 3.

[0075] Example 5

[0076]

[0077] The preparation process is the same as in Example 3.

[0078] Example 6

[0079] The viscosity of the samples from Examples 3-5 was measured, and the results are as follows:

[0080]

[0081] Example 7 Filterability Test

[0082] Considering that the actual filterability of the production filter may differ from that of the membrane, a blank excipient was prepared, and the filterability of this product was reconfirmed using a capsule filter of the proposed material. The blank excipient (sodium hyaluronate concentration 0.8% w / w) was filtered using a 5-inch capsule filter, and the results are as follows:

[0083]

[0084] Example 8: pH value and sample stability investigation

[0085]

[0086] Preparation process:

[0087] (1) Preparation of drug solution: Place an appropriate amount of water for injection in a mixing tank, add other excipients except thickener and stir until completely dissolved, add ropinirole hydrochloride and stir to dissolve, and adjust the pH value to 3.5 / 3.8 / 4.0 / 4.2 / 4.5 with pH adjuster to obtain drug solution;

[0088] (2) Add the thickener sodium hyaluronate to the above-mentioned drug solution, stir until it is completely swollen, and add water for injection to the total volume;

[0089] (3) The drug gel prepared in step (2) is sterilized and filtered at room temperature, and then packaged in low-density polyethylene ampoules to obtain the final product.

[0090] The drug stability data for samples at different pH values ​​are as follows:

[0091]

[0092] Example 9: Investigation of the preparation process

[0093] The oxygen sensitivity of this product was studied, and the quality changes of the product under nitrogen-filled and non-nitrogen-filled processes were investigated. Referring to the formulation and preparation process of Example 4, the following changes were made during the filling process:

[0094] Nitrogen-filled and non-nitrogen-filled batch information for filling and aluminum-plastic packaging

[0095]

[0096] Results of nitrogen-filled and non-nitrogen-filled tests

[0097]

[0098] Based on the above data, it can be seen that under nitrogen purging protection, the quality attributes of the product remain basically unchanged, while under non-nitrogen purging protection conditions, impurity A shows a significant increasing trend.

[0099] Example 10 Clinical Trial Assay

[0100] Test samples: Comparative Example 1 and the ropinirole hydrochloride ophthalmic gel of the present invention (Examples 2 and 4).

[0101] Experimental Methods: A total of 90 dogs were selected for the experiment, including 30 East German Shepherds, 30 Springer Spaniels, and 30 Belgian Malinois. Each breed of dog was randomly divided into 3 groups, with 10 dogs of each breed in each group. Administered medication according to the table below, with appropriate amounts of eye drops instilled topically according to the number of instillations per dog's weight. If the dog did not vomit within 20 minutes of the first administration, a second dose could be given.

[0102]

[0103] The clinical trial results are as follows:

[0104]

[0105] The researchers observed that the addition of a thickener significantly reduced the amount of medication flowing from the corner of the eye. As can be seen from the table above, the clinical onset time was significantly shorter than that of the true solution, and the drug loss was greatly reduced.

[0106] Example 11 Stability Test

[0107] Samples tested: Comparative Example 1, Examples 2 and 4

[0108] Determination method: The determination was performed by HPLC (see General Chapter 0512, Part IV, Chinese Pharmacopoeia 2020 Edition).

[0109] Chromatographic conditions and system suitability test: Octylsilane-bonded silica gel (25mm × 4.6mm 5μm Kromasil C8) was used as the stationary phase; mobile phase A: 3.85g ammonium acid was weighed, dissolved in 950ml of water, the pH was adjusted to 2.5 with dilute phosphoric acid, and water was added to 1000ml; mobile phase B: methanol-acetonitrile (30:70); linear gradient elution was performed according to the table below; the flow rate was 1ml / min; the column temperature was 40℃; and the detection wavelength was 250nm. Using mobile phase A-mobile phase B (84:16) as diluent, accurately weigh ropinirole hydrochloride reference standard and impurity A (CAS No. 102842-51-3) reference standard, dissolve and dilute with the diluent to prepare a mixed solution containing 50 μg each of ropinirole hydrochloride and impurity A per ml. The injection volume is 10 μl. In the system suitability solution chromatogram, the peak order is impurity A and ropinirole, respectively. The resolution between the impurity A peak and the ropinirole peak should not be less than 3.0, and the tailing factor of the ropinirole peak should not be greater than 1.5.

[0110]

[0111] Assay: Weigh 1 g of this product accurately, dilute with diluent to prepare a 1.2 mg / ml ropinirole hydrochloride solution as the test solution; accurately weigh an appropriate amount of ropinirole hydrochloride reference standard, add diluent to prepare a 12 μg / ml ropinirole hydrochloride solution as the reference standard; injection volume is 10 μl, and the limits for impurity A and the maximum unknown single impurity are calculated according to the external standard method of principal component as 1%, and the limit for total impurities is 2%.

[0112] The results of the determination of related substances are as follows:

[0113]

Claims

1. An ophthalmic gel composition comprising (1) ropinirole or a pharmaceutically acceptable salt thereof, (2) one or more thickeners, and other pharmaceutically acceptable excipients, wherein, The viscosity of the ophthalmic gel composition is ≥100 mPa·s.

2. The ophthalmic gel composition according to claim 1, characterized in that, The thickener is selected from natural or synthetic hydrophilic polymer materials; preferably, the thickener is selected from any one or a combination of chitosan, hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, and methylcellulose; preferably, the thickener accounts for ≥0.3% by weight (w / w).

3. The ophthalmic gel composition according to claim 2, characterized in that, The ophthalmic gel composition further comprises a buffer; preferably, the buffer is selected from a weak acid / base system or a weak base / acid system; preferably, the buffer accounts for 0.1-1.0%.

4. The ophthalmic gel composition according to claim 3, characterized in that, The buffer is selected from a combination of citric acid and sodium citrate, wherein the ratio of citric acid to sodium citrate is 10:1 to 0.1:

1.

5. The ophthalmic gel composition according to any one of claims 1-4, characterized in that, The ophthalmic gel composition further comprises a pH adjuster; preferably, the pH value of the ophthalmic gel composition is ≤7.

0.

6. The ophthalmic gel composition according to any one of claims 1-5, characterized in that, The ophthalmic gel composition further comprises an osmotic pressure regulator; preferably, the osmotic pressure of the ophthalmic gel composition is 200-400 mosm / kg.

7. The ophthalmic gel composition according to any one of claims 1-6, characterized in that, Other pharmaceutically acceptable excipients include, but are not limited to, any one or a combination of antioxidants / stabilizers, antibacterial agents, and humectants.

8. The ophthalmic gel composition according to any one of claims 1-7, characterized in that, The ophthalmic gel composition does not contain antibacterial agents.

9. An ophthalmic gel composition as described in claims 1-8, characterized in that, The ophthalmic gel composition comprises, by weight (w / w), (1) 1-5% ropinirole hydrochloride, (2) 0.3-5.0% of one or more thickeners, (3) 0.1-1.0% of a buffer, and (4) other pharmaceutically acceptable excipients, wherein the viscosity of the ophthalmic gel composition is ≥100 mPa·s.

10. An ophthalmic gel composition as claimed in claim 9, characterized in that, The ophthalmic gel composition comprises, by weight (w / w), 3% ropinirole hydrochloride, 0.3-1.0% sodium hyaluronate and / or hydroxypropyl methylcellulose, 0.1-1.0% buffer, and other pharmaceutically acceptable excipients, wherein the viscosity of the ophthalmic gel composition is 100-1000 mPa·s.

11. An ophthalmic gel composition, by weight (w / w), comprising 3% ropinirole hydrochloride, 0.3-1.0% sodium hyaluronate and / or hydroxypropyl methylcellulose, 0.4-0.6% citric acid / sodium citrate, and other pharmaceutically acceptable excipients, wherein, The viscosity of the ophthalmic gel composition is ≥100 mPa·s; preferably, the ophthalmic gel composition does not contain antibacterial agents.

12. A method for preparing the ophthalmic gel composition according to claims 1-11, comprising the following steps: (1) Preparation of drug solution: Place an appropriate amount of water in a mixing tank, add other excipients except thickener and stir until completely dissolved, add the drug and stir to dissolve, adjust the pH value to 3.0-7.0 with pH adjuster to obtain drug solution; (2) Add the thickener or the thickener gel prepared by adding water to the drug solution and stir evenly. Add water for injection to the full volume to obtain the drug solution.

13. The preparation method according to claim 12, characterized in that, Step (2) may also involve adding the drug solution to a thickener gel prepared by adding water in advance; preferably, it also includes a sterilization step, that is, keeping the drug gel prepared in step (2) in a solution state and performing moist heat sterilization or filtration sterilization operation; preferably, it also includes a packaging step, that is, keeping the drug gel prepared in step (2) in a solution state, filling it into a semi-permeable ampoule, and packaging it in an aluminum-plastic composite film bag; preferably, the preparation process may also include an operation step of filling with inert gas.

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