CN113786380A - Pilocarpine nitrate ophthalmic gel and preparation method thereof - Google Patents
Pilocarpine nitrate ophthalmic gel and preparation method thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/06—Antiglaucoma agents or miotics
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Abstract
The invention provides a pilocarpine nitrate ophthalmic gel and a preparation method thereof, wherein the ophthalmic gel comprises the following components in parts by weight: 150-250 parts of pilocarpine nitrate, 60-80 parts of carbomer and 6-8 parts of dextran. The preparation method of the ophthalmic gel comprises mixing carbomer and dextran, dissolving the mixture in water for injection, heating to 70-90 deg.C, adjusting pH to 4-6, adding pilocarpine nitrate, filtering, sterilizing, and packaging. The invention can realize quick and convenient drug delivery, can hygienically, reliably and effectively cover the action part of the eyes, forms a good protective film, reduces the drug frequency, and thus the antibacterial drug can well exert the curative effect. The preparation method provided by the invention is simple and convenient to operate, has low requirements on equipment, and can realize the high-efficiency production of the pilocarpine nitrate ophthalmic gel.
Description
Technical Field
The invention relates to the technical field of eye medicine preparation, in particular to pilocarpine nitrate eye gel and a preparation method thereof.
Background
Glaucoma is a slowly progressive degeneration of retinal ganglion cells and optic nerve axons that, if undiagnosed or untreated, can lead to irreversible blindness. Glaucoma is the second leading cause of blindness worldwide, accounting for 12.3% of all blindness. Modern researches show that pilocarpine hydrochloride has obvious effects of reducing intraocular pressure and controlling inflammation, can treat primary glaucoma including open-angle glaucoma and closed-angle glaucoma, and is a first-line medicament for clinically treating glaucoma.
The clinically used ophthalmic topical administration forms: the eye drop accounts for more than 60 percent of the eye preparation, is convenient to use and has low cost. But has short retention time and low bioavailability. The volume of the conjunctival sac of the human eye is about 30 mu L. In general, about 70% of the liquid medicine is estimated to overflow from the eye and cause loss, and 90% of the liquid medicine is estimated to be lost when the eye is blinked. The overflowed liquid medicine mostly flows down along the cheek, or enters the nasal cavity or the digestive tract through the nasolacrimal duct and is finally absorbed by the whole body. Eye ointments have a long drug retention time, but are poorly adapted to patients due to inaccurate dosage, susceptibility to blurring and eyelid blister, and are usually used only before sleep.
Advances in drug delivery aim to improve bioavailability by increasing drug residence time on the corneal surface and corneal permeability. A large number of clinical tests find that the pilocarpine nitrate eye drops need to press the inner canthus of the eye when being dropped into the eye, so as to prevent inhalation poisoning. Frequent administration of the drugs can cause systemic toxic reactions due to excessive absorption. This causes great trouble for clinical use. In view of the defects of the traditional pilocarpine nitrate eye drops, scholars at home and abroad are dedicated to the research on pilocarpine nitrate eye preparations. In recent years, other preparations such as nano-preparations, liposomes, cyclodextrins and the like are reported in succession in the prior literature reports, but the new preparations have many problems, such as unstable preparation properties, high cost, heavy economic burden on patients, unsuitability for large-scale industrial production, obvious clinical side effects and the like, and thus the production and the use of the new preparations are not put into the market. In the existing literature reports, the pilocarpine nitrate gel generally adopts gellan gum, chitosan, guar gum/polyvinyl alcohol, HPMC and the like as a gel system, and sodium alginate and hydroxypropyl cellulose as thickeners. The disadvantage is that the comfort of the patient is poor when the common gel is administered. The gel is unevenly coated in eyes, has strong foreign body sensation, and easily stimulates the secretion of tears, thereby reducing the curative effect.
Therefore, the continuous search for an ophthalmic preparation of pilocarpine nitrate with high stability, low cost and little side effect is still the subject of active search by researchers in the industry. In the prior art, the ophthalmic gel prepared from the pilocarpine nitrate has large irritation to the cornea, is unstable in related substances, is easy to cause adverse reaction, and has poor medicine permeability, poor stability and poor treatment effect.
Disclosure of Invention
The invention aims to provide pilocarpine nitrate ophthalmic gel and a preparation method thereof, and aims to solve the problems that in the prior art, pilocarpine nitrate prepared into ophthalmic gel has large irritation to cornea, is unstable in related substances, is easy to cause adverse reaction, and has poor drug permeability, poor stability and poor treatment effect.
The technical scheme of the invention is as follows: the ophthalmic gel of the pilocarpine nitrate comprises the following components in parts by weight: 150-250 parts of pilocarpine nitrate, 60-80 parts of carbomer and 6-8 parts of dextran.
The ophthalmic gel comprises pharmaceutically acceptable auxiliary material components.
The auxiliary materials comprise sodium hydroxide and water.
The carbomer is selected from at least one of carbomer 407, carbomer 934, carbomer 974 and carbomer 980.
The preparation method of the ophthalmic gel comprises the steps of weighing the raw materials according to the component proportion, uniformly mixing carbomer and dextran, dissolving the mixture in water for injection, heating to 70-90 ℃, adjusting the pH value to 4-6 by using a sodium hydroxide solution, then adding pilocarpine nitrate, filtering, and carrying out aseptic subpackaging.
Further, the preparation method of the ophthalmic gel comprises the steps of weighing the raw materials according to the component proportion, uniformly mixing carbomer and dextran, dissolving the mixture in water for injection, heating to 85 ℃, adjusting the pH value to 5.5, then adding pilocarpine nitrate, filtering, and performing aseptic subpackage.
The invention adopts poloxamer 407 and dextran as temperature sensitive in-situ gel system. When the gel is used at room temperature, the gel enters eyes of a patient in a liquid state, the medicine can be uniformly covered on the surfaces of cornea and sclera through good fluidity, and then a uniform gel layer is formed after gelation under physiological conditions, so that the foreign body sensation of eye administration can be reduced, and the use comfort of the gel is improved. The in-situ gel prepared by combining poloxamer 407 and dextran has strong affinity with the medicine application part, especially mucosa tissue, long retention time and good drug release control performance. In addition, the gelation temperature can be conveniently and accurately controlled by adjusting the proportion of the two. Meanwhile, compared with the pH in-situ gel represented by chitosan and the ion sensitive in-situ gel represented by gellan gum, the in-situ gel prepared by the method has the advantages that the gelation process is only related to temperature and is slightly influenced by pH and ion concentration, so that the influence of individual difference of patients on the gelation process is far smaller than that of the pH in-situ gel and the ion sensitive in-situ gel, and the pharmaceutical performance of the product prepared by the method is more stable and reliable.
For the convenience of clinical use, the unit exclusively develops the ophthalmic gel preparation of the pilocarpine nitrate, and compared with the eye drops of the common dosage form of the pilocarpine, the ophthalmic gel has the following advantages:
1. carbomers and dextrans are bioadhesive, well tolerated, low toxic, almost completely non-irritating to skin and mucous membranes. The pilocarpine nitrate ophthalmic gel prepared by using the same exists in a liquid form below the lower critical solution temperature, and gels when the ambient temperature reaches or is higher than the critical solution temperature.
2. The use mode of the ophthalmic gel is greatly simplified, the ophthalmic gel can be used by dropping into eyes according to the use method of eye drop, and the comfort level of the ophthalmic gel is improved.
3. Effectively adheres to the surface of eyes, thereby prolonging the retention time of the medicine in the eyes, reducing the loss of the medicine from nasolacrimal ducts, and further reducing the adverse reaction of the medicine on the whole body.
4. The pilocarpus nitrate eye drops are easy to be diluted by tears and overflow from eyes, the dosage is inaccurate, 1 to 4 times a day, and the dosage is large; the gel is not easy to be diluted by tears, has accurate dosage and lasting effect, is used once a day and has small dosage;
5. compared with eye ointment, the gel has good water solubility, easy cleaning, low eye irritation and good safety, and is suitable for long-term use; the eye gel does not cause blurred vision, can be used day and night, and is more convenient to use.
6. Because the pilocarpine nitrate is wrapped in the gel, the pilocarpine nitrate can slowly release drug property, prolong the action time and reduce the elimination rate of the drug, thereby reducing the administration frequency and improving the compliance of patients in medication.
The successful development of the product can fill a gap of domestic ophthalmic medicines, can bring greater social and economic benefits, and is popular with doctors and patients.
Detailed Description
The present invention is further illustrated by the following examples in which the procedures and methods not described in detail are conventional and well known in the art, and the starting materials or reagents used in the examples are commercially available, unless otherwise specified, and are commercially available.
The invention aims to provide a preparation method of a pilocarpine nitrate ophthalmic gel preparation, which can realize quick and convenient administration, can hygienically, reliably and effectively cover the action part of eyes to form a good protective film and reduce the administration frequency, so that an antibacterial drug can well exert the curative effect. The preparation method provided by the invention is simple and convenient to operate, has low requirements on equipment, and can realize the high-efficiency production of the pilocarpine nitrate ophthalmic gel.
Example 1
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Carbomer | 60 |
| Dextran | 6 |
| Sodium hydroxide | Proper amount of |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 75 ℃ and adjusted to pH 4.5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Example 2
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Carbomer | 60 |
| Dextran | 8 |
| Sodium hydroxide | Proper amount of |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 80 ℃ and adjusted to pH 5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Example 3
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Carbomer | 80 |
| Dextran | 6 |
| Sodium hydroxide | Proper amount of |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 85 ℃ and adjusted to pH 5.5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Example 4
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Carbomer | 80 |
| Dextran | 8 |
| Sodium hydroxide | Proper amount of |
| Water for injection | 5000 portions of |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 80 ℃ and adjusted to pH 5.5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Example 5
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Carbomer | 70 |
| Dextran | 6 |
| Sodium hydroxide | Proper amount of |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 85 ℃ and adjusted to pH 5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Example 6
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Carbomer | 70 |
| Dextran | 8 |
| Sodium hydroxide | Proper amount of |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 80 ℃ and adjusted to pH 4.5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Example 7
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 150 |
| Carbomer | 80 |
| Dextran | 7 |
| Sodium hydroxide | Proper amount of |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 80 ℃ and adjusted to pH 5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Example 8
The formula is as follows:
the preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing and mixing the carbomer and the dextran in the prescription amount.
Step two: the mixture was dissolved in water for injection, heated to 80 ℃ and adjusted to pH 5.5 with 10% sodium hydroxide solution.
Step three: adding pilocarpine nitrate, filtering, sterilizing, and packaging.
Comparative example 1
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Sodium hyaluronate | 150 |
| Sodium hydroxide | 20 |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing a proper amount of sodium hyaluronate, adding the sodium hyaluronate into boiling water for injection, and stirring until the sodium hyaluronate is completely dissolved to obtain a solution A.
Step two: weighing the bulk drugs according to the prescription amount, adding the bulk drugs into the feed liquid, stirring, dissolving, filtering and filling to obtain the pilocarpine nitrate eye drops.
Comparative example 2
The formula is as follows:
| material(s) | Formulation (g) |
| Pilocarpine nitrate | 200 |
| Sodium hyaluronate | 100 |
| Sodium hydroxide | 20 |
| Water for injection | 5000 |
The preparation process comprises the following steps: the following materials are prepared according to the prescription amount.
The method comprises the following steps: weighing a proper amount of sodium hyaluronate, adding the sodium hyaluronate into boiling water for injection, and stirring until the sodium hyaluronate is completely dissolved to obtain a solution A.
Step two: weighing the bulk drugs according to the prescription amount, adding the bulk drugs into the feed liquid, stirring, dissolving, filtering and filling to obtain the pilocarpine nitrate eye drops.
Comparison of examples with comparative examples
Long term stability study
1. pH value comparison of examples and comparative examples
Using the ophthalmic gels of examples 1-6 and comparative examples 1-2, a comparison of long-term results was made: (investigation conditions are 25 ℃ plus or minus 2 ℃ and 60 percent plus or minus 5 percent), and the pH value, the content and related substances are used as investigation indexes to carry out detection respectively in 3 months, 6 months, 9 months and 12 months.
Table 1 shows pH analysis of examples and comparative examples. As can be seen from Table 1, the comparative examples had large changes in pH and poor long-term stability; the examples have small pH change and good long-term stability, and meet the requirements.
TABLE 1 comparison of pH of examples and comparative examples
pH standard in USP: 4.0 to 5.5
| Item | Day 0 | Length 3 | Length 6 | Length 9 | Length 12 |
| Example 1 | 5.2 | 5.1 | 4.9 | 4.8 | 4.7 |
| Example 2 | 5.2 | 5.1 | 5 | 4.9 | 4.7 |
| Example 3 | 5.3 | 5.2 | 5.2 | 5.1 | 5.0 |
| Example 4 | 5.3 | 5.1 | 4.9 | 4.8 | 4.6 |
| Example 5 | 5.1 | 5.2 | 5.1 | 5.0 | 4.8 |
| Example 6 | 5.1 | 5.0 | 4.9 | 4.8 | 4.7 |
| Example 7 | 5.1 | 5 | 4.9 | 4.8 | 4.6 |
| Example 8 | 5.2 | 5.1 | 5.0 | 4.9 | 4.7 |
| Comparative example 1 | 5.3 | 5.0 | 4.7 | 4.5 | 4.2 |
| Comparative example 2 | 5.2 | 4.9 | 4.7 | 4.4 | 4.1 |
2. Content comparison of examples and comparative examples
Table 2 shows the content analysis of examples and comparative examples. As can be seen from Table 2, the content of the comparative example is greatly changed and the long-term stability is poor, and the content of the comparative example 2 does not meet the specification after 12 months for a long time; the content change of the examples is small, the long-term stability is good, and the requirements are met.
TABLE 2 comparison of the contents of examples and comparative examples
The content standard in the United states pharmacopoeia is 90.0 to 110.0 percent
3. Comparison of materials in examples with those in comparative examples
Tables 3 and 4 show the substance analyses of the examples and comparative examples. As can be seen from tables 3 and 4, the related substances of the comparative example have large changes and poor long-term stability, and pilocarpine and isopimacarpine in the related substances do not meet the requirements for long-term 12 months; the examples have small change of related substances and good long-term stability, and meet the requirements. The ophthalmic gel of the example is shown to be safer and less irritating.
TABLE 3 comparison of the examples with the comparative examples (pilocarpine)
The ophthalmic gel of pilocarpine nitrate is a unique product of North China pharmaceutical, and the standard of related substances (pilocarpine acid) in the quality standard of the finished product is less than or equal to 8.0 percent
| Item | Day 0 | Length 3 | Length 6 | Length 9 | Length 12 |
| Example 1 | 0.83 | 0.9 | 1 | 1.2 | 1.5 |
| Example 2 | 0.82 | 1.0 | 1.1 | 1.4 | 1.7 |
| Example 3 | 0.75 | 0.82 | 0.98 | 1.1 | 1.3 |
| Example 4 | 0.83 | 1.1 | 1.2 | 1.5 | 1.7 |
| Example 5 | 0.83 | 1.0 | 1.2 | 1.4 | 1.7 |
| Example 6 | 0.85 | 1.2 | 1.4 | 1.6 | 1.8 |
| Example 7 | 0.84 | 1.1 | 1.4 | 1.6 | 1.9 |
| Example 8 | 0.84 | 1.2 | 1.5 | 1.7 | 2.0 |
| Comparative example 1 | 1.2 | 3.1 | 4.4 | 5.9 | 8.5 |
| Comparative example 2 | 1.3 | 3.5 | 4.7 | 6.2 | 8.7 |
TABLE 4 comparison of the examples with the substances of interest of the comparative example (isopimarutine)
The pilocarpine nitrate ophthalmic gel is a unique product of North China pharmaceutical industry, and the related substance in the quality standard of the finished product is not more than 1.0 percent of the pilocarpine nitrate ophthalmic gel
| Item | Day 0 | Length 3 | Length 6 | Length 9 | Length 12 |
| Example 1 | 0.19 | 0.23 | 0.36 | 0.49 | 0.6 |
| Example 2 | 0.19 | 0.22 | 0.38 | 0.52 | 0.65 |
| Example 3 | 0.13 | 0.19 | 0.22 | 0.28 | 0.3 |
| Example 4 | 0.2 | 0.23 | 0.37 | 0.46 | 0.58 |
| Example 5 | 0.18 | 0.22 | 0.36 | 0.41 | 0.54 |
| Example 6 | 0.17 | 0.21 | 0.34 | 0.42 | 0.64 |
| Example 7 | 0.17 | 0.22 | 0.37 | 0.45 | 0.59 |
| Example 8 | 0.16 | 0.21 | 0.36 | 0.44 | 0.68 |
| Comparative example 1 | 0.32 | 0.53 | 0.57 | 0.78 | 1.12 |
| Comparative example 2 | 0.26 | 0.60 | 0.74 | 0.80 | 1.14 |
Accelerated stability test
1. pH comparison of examples with comparative examples
Accelerated examination results were compared using the ophthalmic gels of examples 1 to 6 and comparative examples 1 to 2: (investigation conditions 40 ℃ +/-2 ℃ and 65% +/-5%) and taking pH value, content and related substances as investigation indexes, and detecting for 1 month, 2 months and 3 months respectively.
Table 5 shows pH analysis of examples and comparative examples. As can be seen from Table 5, the comparative examples showed a large change in pH and poor accelerated stability; in the examples, the pH change is small, the acceleration stability is good, and the requirements are met.
TABLE 5 pH comparison of examples and comparative examples
pH standard in USP: 4.0 to 5.5
| Item | Day 0 | Plus 1 | Plus 2 | Plus 3 |
| Example 1 | 5.2 | 4.9 | 4.7 | 4.4 |
| Example 2 | 5.2 | 5.1 | 4.9 | 4.5 |
| Example 3 | 5.3 | 5.2 | 5.1 | 5.0 |
| Example 4 | 5.3 | 5.0 | 4.8 | 4.6 |
| Example 5 | 5.1 | 5.0 | 4.8 | 4.5 |
| Example 6 | 5.1 | 4.9 | 4.6 | 4.4 |
| Example 7 | 5.1 | 4.9 | 4.6 | 4.5 |
| Example 8 | 5.2 | 5.0 | 4.7 | 4.6 |
| Comparative example 1 | 5.3 | 4.7 | 4.2 | 4.0 |
| Comparative example 2 | 5.2 | 4.7 | 4.1 | 3.9 |
2. Content comparison of examples and comparative examples
Table 6 shows the content analysis of examples and comparative examples. As can be seen from Table 6, the content of the comparative example has large change and poor acceleration stability, and the content does not meet the specification after the acceleration for 3 months; the content change of the embodiment is small, the acceleration stability is good, and the requirement is met.
TABLE 6 comparison of the contents of examples and comparative examples
The content standard in the United states pharmacopoeia is 90.0 to 110.0 percent
| Item | Day 0 | Plus 1 | Plus 2 | Plus 3 |
| Example 1 | 99.1 | 98.2 | 97.4 | 95.3 |
| Example 2 | 99.3 | 98.1 | 97.3 | 95.0 |
| Example 3 | 99.5 | 98.9 | 98.4 | 98.0 |
| Example 4 | 99.3 | 98.1 | 97.1 | 95.1 |
| Example 5 | 99.1 | 98.2 | 97.2 | 95.2 |
| Example 6 | 99.1 | 98.2 | 97.3 | 95.1 |
| Example 7 | 99.4 | 98.4 | 96.6 | 95.4 |
| Example 8 | 99.2 | 98.5 | 95.9 | 94.3 |
| Comparative example 1 | 98.6 | 95.1 | 92.0 | 89.5 |
| Comparative example 2 | 98.9 | 94.1 | 91.3 | 89.1 |
3. Comparison of materials in examples with those in comparative examples
Tables 7 and 8 show the substance analyses of examples and comparative examples. As can be seen from tables 7 and 8, the related substances of the comparative example have large changes and poor acceleration stability, and the pilocarpine and the isopimacarpine in the related substances accelerated for 3 months do not meet the requirements; the examples have small change of related substances and good acceleration stability, and meet the requirements. The ophthalmic gel of the example is shown to be safer and less irritating.
TABLE 7 comparison of the examples with the comparative examples (pilocarpine)
The ophthalmic gel of pilocarpine nitrate is a unique product of North China pharmaceutical, and the standard of related substances (pilocarpine acid) in the quality standard of the finished product is less than or equal to 8.0 percent
| Item | Day 0 | Plus 1 | Plus 2 | Plus 3 |
| Example 1 | 0.83 | 0.92 | 1.1 | 1.7 |
| Example 2 | 0.82 | 0.91 | 1.4 | 1.8 |
| Example 3 | 0.75 | 0.85 | 1.1 | 1.4 |
| Example 4 | 0.83 | 0.95 | 1.5 | 2.2 |
| Example 5 | 0.83 | 0.94 | 1.4 | 2.1 |
| Example 6 | 0.85 | 0.97 | 1.6 | 2.2 |
| Example 7 | 0.84 | 1.5 | 2.0 | 2.3 |
| Example 8 | 0.84 | 1.6 | 2.1 | 2.4 |
| Comparative example 1 | 1.2 | 3.5 | 6.0 | 8.8 |
| Comparative example 2 | 1.3 | 3.7 | 6.2 | 9.0 |
TABLE 8 comparison of the examples with the relevant substances of the comparative example (isopimarutine)
The pilocarpine nitrate ophthalmic gel is a unique product of North China pharmaceutical industry, and the content of iso-pilocarpine in related substances in the quality standard of a finished product is less than or equal to 1.0 percent
| Item | Day 0 | Plus 1 | Plus 2 | Plus 3 |
| Example 1 | 0.19 | 0.26 | 0.45 | 0.65 |
| Example 2 | 0.19 | 0.27 | 0.33 | 0.7 |
| Example 3 | 0.13 | 0.2 | 0.28 | 0.36 |
| Example 4 | 0.2 | 0.25 | 0.31 | 0.8 |
| Example 5 | 0.18 | 0.26 | 0.33 | 0.75 |
| Example 6 | 0.17 | 0.24 | 0.3 | 0.7 |
| Example 7 | 0.17 | 0.38 | 0.58 | 0.79 |
| Example 8 | 0.16 | 0.37 | 0.69 | 0.81 |
| Comparative example 1 | 0.32 | 0.56 | 0.82 | 1.16 |
| Comparative example 2 | 0.26 | 0.64 | 1.84 | 1.2 |
Eye irritation testing
The eye irritation test takes 5 healthy rabbits, randomly divides the rabbits into two blank groups, test groups, examines the eyes of animals 24 hours before the test, and selects the rabbits with normal eyes, no inflammation, no defect and no old corneal injury. The right eyes of two groups of rabbits were administered with physiological saline and o.lml gel for the eyes of the example, respectively, and the left eyes were not treated and used as controls. The medicine is administered 3 times a day for 3 days, and conjunctiva, iris and corneal tissues of each group of animals are observed under slit lamps at 1,24,48 and 72 hours after the last administration, and no reactions such as congestion, edema, secretion adhesion and the like are observed. The results were scored according to the skin reaction score criteria and recorded, as shown in Table 5, indicating that the instant eye gel of the present invention is safe and non-irritating to eye tissue.
The average integral per animal per day (stimulation index) was calculated according to the following formula.
The average integral per animal per day ∑ (total integral of erythema and edema 14d per animal)/(number of test animals X14).
TABLE 9 Rabbit skin irritation score
| Group of | Stimulation index |
| Example 1 | 0 |
| Example 2 | 0 |
| Example 3 | 0 |
| Example 4 | 0 |
| Example 5 | 0 |
| Example 6 | 0 |
| Example 7 | 0 |
| Example 8 | 0 |
| Comparative example 1 | 2 |
| Comparative example 2 | 3 |
In summary, the following steps: the pilocarpine nitrate ophthalmic gel prepared by the invention has the following advantages:
(1) the ophthalmic gel containing pilocarpine nitrate has good stability, low content and little change of related substances of pilocarpine acid and isopimacarpine, slow decline in the effective period of pH value, stable product quality, improved safety of preparation, no irritation to eyes, and suitability for long-term use.
(2) The improved prescription ensures that the prepared product is changed into ophthalmic gel from eye drops, is beneficial to the absorption of the cornea and improves the safety and the effectiveness.
(3) The sterilization mode is simple, the preparation process is relatively simple, the working hours are shortened, the production efficiency is improved, and the method is suitable for mass production.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (6)
1. The ophthalmic gel containing pilocarpine nitrate is characterized by comprising the following components in parts by weight: 150-250 parts of pilocarpine nitrate, 60-80 parts of carbomer and 6-8 parts of dextran.
2. The ophthalmic gel according to claim 1, characterized in that it comprises pharmaceutically acceptable auxiliary ingredients.
3. The ophthalmic gel of claim 2, wherein said excipients comprise sodium hydroxide and water.
4. The ophthalmic gel of claim 1, wherein said carbomer is selected from at least one of carbomer 407, carbomer 934, carbomer 974, and carbomer 980.
5. A process for preparing the ophthalmic gel of any one of claims 1 to 4, wherein the raw materials are weighed out according to the component proportions, carbomer and dextran are mixed uniformly, the mixture is dissolved in water for injection, heated to 70-90 ℃, adjusted to pH 4-6 with sodium hydroxide solution, and then pilocarpine nitrate is added, filtered, aseptically and separately packaged.
6. The method for preparing ophthalmic gel according to claim 5, wherein the raw materials are weighed according to the component proportion, carbomer and dextran are mixed uniformly, the mixture is dissolved in water for injection, heated to 85 ℃, the pH value is adjusted to 5.5, and then pilocarpine nitrate is added, and the ophthalmic gel is prepared by filtration and aseptic subpackage.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115089587A (en) * | 2022-08-12 | 2022-09-23 | 南京恒道医药科技股份有限公司 | Compound pilocarpine composition and preparation process and application method thereof |
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