Eye-use pilocarpine nitrate pharmaceutical composition

Abstract

The invention relates to an ophthalmic composition containing pilocarpine nitrate. The ophthalmic composition contains active ingredients, namely pilocarpine nitrate, poloxamer 407 and trehalose dihydrate or trehalose anhydrate. The invention also relates to a preparation method of the ophthalmic composition. The ophthalmic composition has good biological activity and preparation stability.

Description

Technical Field

[0001] The present invention belongs to the field of preparation of ophthalmic drugs, and particularly provides a stable ophthalmic thermosensitive gel preparation formula of pilocarpine nitrate. Background Art

[0002] Presbyopia, commonly known as presbyopia or hyperopia, is a refractive error disease, that is, distant objects are seen clearly and near objects are blurred. It is common in people over 40 years old and seriously affects people's quality of life. People often improve it by wearing glasses, implanting intraocular lenses, etc. However, patients have poor compliance and there are also great safety risks in surgery. Therefore, drug treatment is a convenient and effective treatment method. Pilocarpine nitrate is a muscarinic receptor agonist that can stimulate the pupil sphincter and ciliary muscle, and has the effects of miosis, reducing intraocular pressure and regulating ciliary spasm. It was discovered as early as 1874 and was early used for the treatment of sweating, xerostomia, ophthalmic diseases such as glaucoma, etc.

[0003] In terms of the treatment of presbyopia, there are currently two pilocarpine eye drops products on the market in the United States. One is Vuity, a multi-dose pilocarpine hydrochloride with a concentration of 1.25%, and the other is QLOSI, a single-dose pilocarpine hydrochloride eye drop (0.4%). The above two eye drops, Vuity, have high drug concentration and many side effects, and QLOSI may need to be used twice a day, which is a problem of patient adaptability.

[0004] In view of the problems existing in the marketed products, the present invention starts from the dosage form aspect and studies the thermosensitive gel dosage form in order to solve the problems encountered by the currently marketed products and develop the second-generation pilocarpine drugs. The aqueous solution of pilocarpine eye drops is unstable and will rapidly hydrolyze and deteriorate under alkaline conditions. Even under neutral and slightly acidic conditions, it can slowly decompose (Investigation on the stability of pilocarpine nitrate eye drops. Herald of Medicine 18.4 (1999): 2.).

[0005] In the current reports on temperature-sensitive gels, traditional methods have been adopted, such as using poloxamer 407 / poloxamer 188, the thickener carbomer 974P, and osmotic pressure regulators (Preparation and evaluation of pilocarpine nitrate in situ gelling eye drops. "Chinese Traditional and Herbal Drugs 5(2010):5.), which can achieve a sustained-release effect. However, the types of added components are numerous, and the stability of pilocarpine has not been studied. In addition, Chinese Patent CN108338967B is a temperature-sensitive gel for the sustained release of fibroblast growth factor 10, and its excipients include collagen, poloxamer 407, glycerol, and trehalose, and their weight ratios are (fibroblast growth factor 0.1-1.0):(collagen 1.8-5.0):(poloxamer 407 15-25):(glycerol 0.5-5.0):(trehalose 0.2-2.0), which can ensure the stability of FGF10 at room temperature for 3 months. The main problem is that the added components are more and more complex.

[0006] The main technical problems existing in the existing pilocarpine temperature-sensitive gels are that there are more and more complex added components in terms of excipients, and the stability of pilocarpine is not high. Therefore, it is very crucial to develop a stable and simple temperature-sensitive gel pilocarpine eye drop formulation. Summary of the Invention

[0007] Through a large number of experiments and creative work, the inventors of the present invention have prepared an ophthalmic composition of pilocarpine nitrate and confirmed that it has good biological activity and formulation stability, thus completing the present invention.

[0008] In the first aspect of the present invention, the present invention provides an ophthalmic composition of pilocarpine nitrate, which contains the active ingredient pilocarpine nitrate, poloxamer 407, and trehalose dihydrate. Among them, the mass-volume percentage content of pilocarpine nitrate is 0.4% to 0.6%, the mass-volume percentage content of poloxamer 407 is 13.0% to 15.0%, and the mass-volume percentage content of trehalose dihydrate is 0.5% to 1.0%.

[0009] In the present invention, the "mass-volume percentage content" refers to the percentage content expressed in terms of mass and volume, indicating the number of grams of solute contained in every 100 ml of solution. For example, 20% means that there are 20 g of solute in every 100 ml of solution.

[0010] In some embodiments, in the above ophthalmic composition, the mass-volume percentage content of poloxamer 407 is 14.0% to 15.0%.

[0011] In some embodiments, in the above ophthalmic composition, the mass-volume percentage content of poloxamer 407 is 14.7%.

[0012] In some embodiments, in the above ophthalmic composition, the mass-volume percentage content of trehalose dihydrate is 0.7% to 0.8%.

[0013] In some embodiments, in the above ophthalmic composition, the mass-volume percentage content of trehalose dihydrate is 0.75%.

[0014] In some embodiments, in the above ophthalmic composition, the mass-volume percentage content of pilocarpine nitrate is 0.5%.

[0015] In some embodiments, in the above ophthalmic composition, trehalose dihydrate is replaced with trehalose anhydrous, and the mass-volume percentage content of trehalose anhydrous is 0.45% to 0.90%.

[0016] In some embodiments, in the above ophthalmic composition, trehalose dihydrate is replaced with trehalose anhydrous, and the mass-volume percentage content of trehalose anhydrous is 0.63% to 0.72%.

[0017] In some embodiments, in the above ophthalmic composition, trehalose dihydrate is replaced with trehalose anhydrous, and the mass-volume percentage content of trehalose anhydrous is 0.68%.

[0018] In some embodiments, in the above ophthalmic composition, the ophthalmic composition further comprises a pH regulator, and the pH regulator makes the pH of the ophthalmic composition be 5.0 to 6.0.

[0019] In some embodiments, in the above ophthalmic composition, the pH regulator is selected from one or more of phosphoric acid, phosphates, boric acid, borates, citric acid, citrates, tartaric acid, tartrates, acetic acid, acetates, hydrochloric acid, sodium hydroxide, etc.

[0020] In some embodiments, in the above ophthalmic composition, the content of the pH regulator is 0.1 to 5.0%.

[0021] In the second aspect of the present invention, the present invention provides a preparation method for the aforementioned ophthalmic composition, comprising the following steps:

[0022] a) Dissolve a certain amount of trehalose dihydrate or trehalose anhydrous in water at room temperature;

[0023] b) Prepare the pH regulator;

[0024] c) Weigh and dissolve a certain amount of pilocarpine nitrate;

[0025] d) While stirring, add a certain amount of poloxamer 407, add water, adjust the pH to 5.0 to 6.0 with the pH regulator, and make up the volume with water;

[0026] e) Sterilize by filtration and subpackage;

[0027] The amounts of trehalose dihydrate or trehalose anhydrate, pH regulator, pilocarpine nitrate, and poloxamer 407 in the above steps are such that the contents of the components in the finally prepared ophthalmic composition are as defined in the first aspect above.

[0028] In some embodiments, in the above preparation method, the pH regulator is selected from one or more of phosphoric acid, phosphates, boric acid, borates, citric acid, citrates, tartaric acid, tartrates, acetic acid, acetates, hydrochloric acid, sodium hydroxide, etc.

[0029] According to the specific embodiments, the excipients used in the present invention are all known excipients in the ophthalmic field, and further are medicinal excipients that can maintain the stability of pilocarpine nitrate.

[0030] In the third aspect of the present invention, the present invention provides the use of the aforementioned ophthalmic composition in the preparation of a medicament for treating presbyopia and / or hyperopia.

[0031] Beneficial effects

[0032] The pilocarpine nitrate thermosensitive gel eye drops of the present invention can effectively maintain the stability of pilocarpine nitrate, and do not produce excessive miosis in animal experiments. A single administration can sustain the drug effect for about 8 hours, and it is expected to become an eye drop product with low side effects and single daily administration. Specific embodiments

[0033] The following will describe the embodiments of the present invention in detail in conjunction with examples. However, those skilled in the art will understand that the following examples and experimental examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples and test examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0034] Example 1

[0035] Pilocarpine Nitrate Poloxamer 407 Trehalose Dihydrate Prescription 1-1 0.5g 9.0g 0.5g Prescription 1-2 0.5g 9.0g 1.0g Prescription 1-3 0.5g 11.0g 0.5g Prescription 1-4 0.5g 11.0g 1.0g Prescription 1-5 0.5g 13.0g 0.5g Prescription 1-6 0.5g 13.0g 1.0g Prescription 1-7 0.5g 15.0g 0.5g Prescription 1-8 0.5g 15.0g 1.0g Prescription 1-9 0.5g 17.0g 0.5g Prescription 1-10 0.5g 17.0g 1.0g

[0036] Preparation: Dissolve the prescribed amount of trehalose dihydrate and prepare the pH regulator at room temperature; then weigh and dissolve the prescribed amount of pilocarpine nitrate; add the prescribed amount of poloxamer 407 while stirring, add water to nearly 100 ml, adjust the pH to 5.0 - 6.0 with the pH regulator, add water to a constant volume of 100 ml, sterilize by filtration, and dispense.

[0037] Investigation of thermosensitive gel formation: The thermosensitive gel formation of 10 groups of prescription samples was investigated, and the results are shown in Table 1.

[0038] Table 1 Investigation of thermosensitive gel formation results

[0039]

[0040] From the results of the above table, select the formulation with a better thermosensitive gel formation temperature. Further study is carried out within the range of 0.5% pilocarpine nitrate, 13.0% - 15.0% mass percentage of poloxamer 407, and 0.5% - 1.0% concentration of trehalose dihydrate.

[0041] Example 2

[0042] Pilocarpine Nitrate Poloxamer 407 Trehalose Dihydrate Prescription 2-1 0.5g 13.0g 0.5g Prescription 2-2 0.5g 13.0g 0.7g Prescription 2-3 0.5g 13.0g 0.8g Prescription 2-4 0.5g 13.0g 1.0g Prescription 2-5 0.5g 14.0g 0.5g Prescription 2-6 0.5g 14.0g 0.7g Prescription 2-7 0.5g 14.0g 0.8g Prescription 2-8 0.5g 14.0g 1.0g Prescription 2-9 0.5g 15.0g 0.5g Prescription 2-10 0.5g 15.0g 0.7g Prescription 2-11 0.5g 15.0g 0.8g Prescription 2-12 0.5g 15.0g 1.0g

[0043] Preparation: Dissolve the prescribed amount of trehalose dihydrate and prepare the pH regulator at room temperature; then weigh and dissolve the prescribed amount of pilocarpine nitrate; add the prescribed amount of poloxamer 407 while stirring, add water to nearly 100 ml, adjust the pH to 5.0 - 6.0 with the pH regulator, make up the volume to 100 ml with water, sterilize by filtration, and dispense. Accelerated study is carried out at 40°C, and the content results of pilocarpine nitrate are shown in Table 2.

[0044] Table 2 Results of the investigation on the content of pilocarpine nitrate after being placed at 40°C for 30 days

[0045]

[0046]

[0047] From the results of the above table, select the one with better stability: Further study is carried out within the range of 0.5% pilocarpine nitrate, 14.0% - 15.0% mass percentage of poloxamer 407, and 0.7% - 0.8% concentration of trehalose dihydrate.

[0048] Example 3

[0049] Pilocarpine Nitrate Poloxamer 407 Trehalose Dihydrate Prescription 3-1 0.5g 14.0g 0.72g Prescription 3-2 0.5g 14.0g 0.75g Prescription 3-3 0.5g 14.0g 0.78g Prescription 3-4 0.5g 14.3g 0.72g Prescription 3-5 0.5g 14.3g 0.75g Prescription 3-6 0.5g 14.3g 0.78g Prescription 3-7 0.5g 14.7g 0.72g Prescription 3-8 0.5g 14.7g 0.75g Prescription 3-9 0.5g 14.7g 0.78g Prescription 3-10 0.5g 15.0g 0.72g Prescription 3-11 0.5g 15.0g 0.75g Prescription 3-12 0.5g 15.0g 0.78g

[0050] Preparation: Dissolve the prescribed amount of trehalose dihydrate and prepare the pH regulator at room temperature; then weigh and dissolve the prescribed amount of pilocarpine nitrate; add the prescribed amount of poloxamer 407 while stirring, add water to nearly 100 ml, adjust the pH to 5.0 - 6.0 with the pH regulator, make up the volume to 100 ml with water, sterilize by filtration, and dispense. Accelerated study is carried out at 40°C, and the content results of pilocarpine nitrate are shown in Table 3.

[0051] Table 3 Results of the investigation on the content of pilocarpine nitrate after being placed at 40°C for 30 days

[0052]

[0053]

[0054] As can be seen from the results in the above table, the most preferred pilocarpine nitrate is 0.5%, the mass percentage range of poloxamer 407 is 14.7%, the concentration of trehalose dihydrate is 0.75%, and the concentration of pilocarpine is selected for further study.

[0055] Example 4

[0056]

[0057] Preparation: Dissolve the prescribed amount of trehalose dihydrate or anhydrous trehalose and prepare the pH regulator at room temperature; then weigh and dissolve the prescribed amount of pilocarpine nitrate; add the prescribed amount of poloxamer 407 while stirring, add water to nearly 100 ml, adjust the pH to 5.0 - 6.0 with the pH regulator, make up the volume to 100 ml with water, sterilize by filtration and dispense. Accelerated studies were carried out at 40°C, and the content results of pilocarpine nitrate are shown in Table 4.

[0058] Table 4 Results of the investigation on the content of pilocarpine nitrate after being placed at 40°C for 30 days

[0059]

[0060]

[0061] As can be seen from the results in the above table, within the range of 0.4% - 0.6%, different concentrations of pilocarpine nitrate have no effect on the stability of the main components; trehalose dihydrate and anhydrous trehalose have basically the same effect on the stability of the formulation.

[0062] Example 5: Study on the miosis effect on rabbit eyes

[0063] Twelve Japanese white rabbits were selected and divided into two groups: the pilocarpine nitrate thermosensitive gel formulation group (0.5% pilocarpine nitrate, 14.7% poloxamer 407, 0.75% trehalose dihydrate, pH 5.6) and the control group of 1.38% pilocarpine nitrate (equivalent to 1.25% pilocarpine hydrochloride) (0.6% sodium chloride, pH 5.6), with 6 rabbits in each group. 50 μl of each preparation was instilled into the left and right eyes respectively. The pupil diameters were measured with a vernier caliper at 10, 20, 30, 60, 120, 180, 240, 300, 360, 480, and 600 minutes respectively, and the changes in the pupil miosis rate over time were recorded, as shown in Table 5.

[0064] Table 5 Results of the investigation on the content of pilocarpine nitrate after being placed at 40°C for 30 days

[0065]

[0066] As can be seen from the results in the above table, the thermosensitive gel of the present invention significantly increases the bioavailability of pilocarpine nitrate, prolongs the action time of the drug in the eye, and a single administration can last for about 8 hours without over-pupil constriction affecting vision.

Claims

1. An ophthalmic composition of pilocarpine nitrate contains the active ingredient pilocarpine nitrate, poloxamer 407 and trehalose dihydrate, wherein, The mass - volume percentage content of pilocarpine nitrate is 0.4% - 0.6%, the mass - volume percentage content of poloxamer 407 is 13.0% - 15.0%, and the mass - volume percentage content of trehalose dihydrate is 0.5% - 1.0%.

2. The ophthalmic composition of claim 1, wherein, The mass - volume percentage content of poloxamer 407 is 14.0% - 15.0%, preferably 14.7%.

3. The ophthalmic composition of claim 1 or 2, wherein, The mass - volume percentage content of trehalose dihydrate is 0.7% - 0.8%, preferably 0.75%.

4. The ophthalmic composition according to any one of claims 1-3, wherein, The mass - volume percentage content of pilocarpine nitrate is 0.5%.

5. The ophthalmic composition according to any one of claims 1-4, wherein, Trehalose dihydrate is replaced with trehalose anhydrous, and the mass - volume percentage content of trehalose anhydrous is 0.45% - 0.90%, preferably 0.63% - 0.72%, more preferably 0.68%.

6. The ophthalmic composition according to any one of claims 1-5, wherein, The ophthalmic composition further comprises a pH regulator. Preferably, the pH regulator is selected from one or more of phosphoric acid, phosphates, boric acid, borates, citric acid, citrates, tartaric acid, tartrates, acetic acid, acetates, hydrochloric acid, and sodium hydroxide, and the pH regulator makes the pH of the ophthalmic composition 5.0 - 6.

0.

7. The ophthalmic composition of claim 6, wherein, The content of the pH regulator is 0.1 - 5.0%.

8. The preparation method of the ophthalmic composition according to any one of claims 1 to 7, comprising the following steps: a) Dissolve a certain amount of trehalose dihydrate or trehalose anhydrous in water at room temperature; b) Prepare the pH regulator; c) Weigh and dissolve a certain amount of pilocarpine nitrate; d) While stirring, add a certain amount of poloxamer 407, add water, adjust the pH to 5.0 - 6.0 with the pH regulator, and make up the volume with water; e) Sterilize by filtration and dispense; The dosages of trehalose dihydrate or trehalose anhydrous, pH regulator, pilocarpine nitrate, and poloxamer 407 in the above steps make the contents of each component in the finally prepared ophthalmic composition as defined in any one of claims 1 to 7; Preferably, the pH regulator is selected from one or more of phosphoric acid, phosphates, boric acid, borates, citric acid, citrates, tartaric acid, tartrates, acetic acid, acetates, hydrochloric acid, and sodium hydroxide, etc.

9. Use of the ophthalmic composition according to any one of claims 1 to 7 in the preparation of a medicament for treating presbyopia and / or hyperopia.

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