A Sodium Diquafosol-Sensitive Gel and Its Preparation Method

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and provides a sodium ion-sensitive gel of dequalinium phosphate and a preparation method thereof. The components of the sodium ion-sensitive gel of dequalinium phosphate provided by the present invention include dequalinium phosphate sodium, sodium alginate, thickening agent, osmotic pressure regulator, chelating agent, bacteriostatic agent, pH regulator and water. The sodium ion-sensitive gel of dequalinium phosphate provided by the present invention is a novel ophthalmic preparation, which is not affected by environmental temperature, has a suitable pH value, has little irritation to the eyes, and has good stability; and this ion-sensitive gel is in a liquid state during storage and becomes semi-solid after contacting the administration site, prolonging the residence time of the preparation in the eyes, having a good sustained-release effect, high bioavailability, being able to reduce the number of times of use by patients, and improving the compliance of patients. The preparation process of the sodium ion-sensitive gel of dequalinium phosphate provided by the present invention is simple, and it is in a solution state after being formulated, which is easy to fill and is suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a sodium dequalinium ion-sensitive gel and a preparation method thereof. Background Art

[0002] Sodium dequalinium is a P2Y2 receptor agonist and a new drug for the treatment of dry eye. Sodium dequalinium eye drops can promote the secretion of mucin, aqueous humor, and lipids, and at the same time improve the components of each layer of the tear film, comprehensively improving the stability of the tear film; it also has the effect of corneal epithelial repair, so it can be used to treat ocular surface damage caused by dry eye; for the inflammatory link involved in the pathogenesis of dry eye, it can inhibit the inflammatory pathway and the expression of inflammatory factors. At present, multi-center clinical trials have proved the advantages and effectiveness of sodium dequalinium eye drops in the treatment of dry eye. The Asian Dry Eye Consensus regards it as the first-line treatment drug for current aqueous-deficient dry eye and one of the first choices for the treatment of mucin-deficient dry eye.

[0003] Traditional ophthalmic liquid preparations have low bioavailability because of the large loss of drugs during ocular administration, small volume, and short residence time of drugs in the eye. Environment-sensitive gel preparations are in a liquid state during storage and become semi-solid after contacting the administration site. They can not only solve the problem of short retention time and low bioavailability of eye drops, but also overcome the problems of high viscosity and poor spreadability of ordinary gels and difficult dose control. Their unique solution-gel transition property makes them have the advantages of simple preparation, convenient use, strong affinity with the administration site, especially mucosal tissue, and long residence time. Currently, there are three types that have been studied in depth: temperature-sensitive type, pH-sensitive type, and ion-sensitive type. Temperature-sensitive gels have high requirements for temperature during production and use, and generally require a high concentration of excipients, which may cause harm to the body. The biodegradability problem is also a problem faced by this type of in-situ gel. For pH-sensitive gels, currently, acidic polymer materials such as carbomer are mostly used, which have strong irritation to the body. The ion-sensitive in-situ gel is not affected by the environmental temperature, and the pH can be adjusted to about 7, which can significantly improve the compliance of patients and will be widely welcomed by clinicians. However, currently, the common dosage forms of sodium dequalinium are all in the form of eye drops, and there is no relevant report on sodium dequalinium ion-sensitive gel in this field. Summary of the Invention

[0004] In view of this, the present invention provides a sodium dequalinium ion-sensitive gel and a preparation method thereof. The sodium dequalinium ion-sensitive gel provided by the present invention can prolong the residence time of the preparation in the eye, has a good sustained-release effect, reduces the drug administration frequency, and improves the bioavailability.

[0005] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0006] A sodium desoxypyridoxine ion-sensitive gel, comprising components in the following mass fractions: 3% of sodium desoxypyridoxine, 0.1-2% of sodium alginate, 0.5-5% of thickening agent, 0.011-1.6% of osmotic pressure regulator, 0.01-0.1% of chelating agent, 0.006-0.014% of bacteriostatic agent, pH regulator and the balance of water; the dosage of the pH regulator is to adjust the pH value of the sodium desoxypyridoxine ion-sensitive eye gel to 6-8.

[0007] Preferably, the thickening agent is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and polyvinylpyrrolidone thickening agents.

[0008] Preferably, the polyvinylpyrrolidone thickening agent includes one or both of povidone K30 and povidone K90.

[0009] Preferably, the chelating agent is one or both of disodium edetate and calcium disodium edetate.

[0010] Preferably, the bacteriostatic agent is one or more of silver nitrate, benzalkonium chloride, and chlorhexidine gluconate.

[0011] Preferably, the osmotic pressure regulator includes sodium sulfate and disodium hydrogen phosphate dodecahydrate; the mass fraction of sodium sulfate in the sodium desoxypyridoxine ion-sensitive gel is 0.01-0.6%, and the mass fraction of disodium hydrogen phosphate dodecahydrate is 0.001-1%.

[0012] Preferably, the pH regulator is sodium hydroxide and / or hydrochloric acid.

[0013] Preferably, the water is water for injection.

[0014] The present invention also provides a preparation method of the sodium desoxypyridoxine ion-sensitive gel described in the above scheme, comprising the following steps:

[0015] Mix sodium alginate with the first part of water to obtain an aqueous sodium alginate solution;

[0016] Dissolve the osmotic pressure regulator, chelating agent, bacteriostatic agent and sodium desoxypyridoxine in the second part of water, and then mix the obtained solution with the thickening agent to obtain a drug solution;

[0017] Mix the drug solution with sodium alginate, then perform sterile filtration, then use the pH regulator to adjust the pH value of the obtained filtrate to 6-8, and then mix it with the remaining water to obtain the sodium desoxypyridoxine ion-sensitive gel.

[0018] Preferably, the first part of water is 30-45% of the total amount of water; the second part of water is 40-50% of the total mass of water.

[0019] The present invention provides a sodium-sensitive gellan gum of dequalinium phosphate, comprising the following components in mass fractions: 3% of dequalinium phosphate sodium, 0.1-2% of sodium alginate, 0.5-5% of thickener, 0.011-1.6% of osmotic pressure regulator, 0.01-0.1% of chelating agent, 0.006-0.014% of bacteriostatic agent, pH regulator and the balance of water; the dosage of the pH regulator is based on adjusting the pH value of the sodium ion-sensitive gellan gum for ophthalmic use of dequalinium phosphate sodium to 6-8. The present invention uses sodium alginate as the gel matrix. Sodium alginate is an anionic copolymer. After the aqueous solution of sodium alginate contacts divalent or trivalent metal ions, gelation will occur to form a semi-solid gel; there are a large number of Na + 、K + 、Ca 2+ and other cations in tears. Sodium alginate can complex with Ca 2+ and other substances to cause conformational changes, thereby forming a gel in the eye.

[0020] The sodium ion-sensitive gellan gum of dequalinium phosphate provided by the present invention is a novel ophthalmic preparation, which is not affected by the environmental temperature, has a suitable pH value, little irritation to the eyes, and good stability; and this ion-sensitive gellan gum is in a liquid state during the storage period and becomes semi-solid after contacting the administration site, prolonging the residence time of the preparation in the eyes and having a good sustained-release effect; the usage and dosage of the dequalinium phosphate sodium eye drops currently on the market in China are generally 1 drop each time and instilled 6 times a day, with frequent administration. Using the sodium ion-sensitive gellan gum of dequalinium phosphate of the present invention can significantly reduce the administration frequency of the drug, improve the bioavailability, reduce the number of times of use by patients, and significantly improve the compliance of patients.

[0021] The present invention also provides a preparation method of the sodium ion-sensitive gellan gum of dequalinium phosphate described in the above scheme. The preparation method provided by the present invention has a simple preparation process, is in a solution state after preparation, is easy to fill, and the preparation process is suitable for large-scale industrial production. Detailed Embodiments

[0022] The present invention provides a sodium ion-sensitive gellan gum of dequalinium phosphate, comprising the following components in mass fractions: 3% of dequalinium phosphate sodium, 0.1-2% of sodium alginate, 0.5-5% of thickener, 0.011-1.6% of osmotic pressure regulator, 0.01-0.1% of chelating agent, 0.006-0.014% of bacteriostatic agent, pH regulator and the balance of water; the dosage of the pH regulator is based on adjusting the pH value of the sodium ion-sensitive gellan gum for ophthalmic use of dequalinium phosphate sodium to 6-8.

[0023] Unless otherwise specified, each raw material component used in the present invention is a commercially available product.

[0024] In terms of mass fraction, the sodium dequalinium ion-sensitive gel provided by the present invention comprises 3% of sodium dequalinium, and the sodium dequalinium is the drug active ingredient.

[0025] In terms of mass fraction, the sodium dequalinium ion-sensitive gel provided by the present invention comprises 0.1-2% of sodium alginate, preferably 0.5-1.5%. In the present invention, the sodium alginate is a gel matrix and can react with metal ions in tears to form a gel.

[0026] In terms of mass fraction, the sodium dequalinium ion-sensitive gel provided by the present invention comprises 0.5-5% of a thickener, preferably 1-4%. In the present invention, the thickener is preferably one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose and polyvinylpyrrolidone thickeners; the polyvinylpyrrolidone thickeners preferably include one or several of povidone K30 and povidone K90.

[0027] In terms of mass fraction, the sodium dequalinium ion-sensitive gel provided by the present invention comprises 0.011-1.6% of an osmotic pressure regulator. In the present invention, the osmotic pressure regulator preferably includes sodium sulfate and disodium hydrogen phosphate dodecahydrate; specifically, the mass fraction of sodium sulfate in the sodium dequalinium ion-sensitive gel is preferably 0.01-0.6%, more preferably 0.05-0.5%, further preferably 0.1-0.3%, and the mass fraction of disodium hydrogen phosphate dodecahydrate in the sodium dequalinium ion-sensitive gel is preferably 0.001-1%, more preferably 0.005-0.7%, further preferably 0.01-0.5%.

[0028] In terms of mass fraction, the sodium dequalinium ion-sensitive gel provided by the present invention comprises 0.01-0.1% of a chelating agent, preferably 0.03-0.06%. In the present invention, the chelating agent is preferably one or two of disodium edetate and calcium disodium edetate; in the present invention, the chelating agent can form a stable water-soluble complex with alkaline earth metal and heavy metal ions. Because the calcium chelating strength is relatively weak, heavy metals such as iron, copper and lead are preferentially chelated, and calcium ions can be displaced from the calcium chelate to form free calcium ions, which is beneficial to the complexation of calcium ions with sodium alginate to form a non-biologically toxic gel.

[0029] In terms of mass fraction, the sodium dequalinium ion-sensitive gel provided by the present invention comprises 0.006-0.014% of an antibacterial agent, preferably 0.008-0.012%. In the present invention, the antibacterial agent is preferably one or more of silver nitrate, benzalkonium chloride and chlorhexidine gluconate.

[0030] The sodium dequalinium ion-sensitive gel provided by the present invention further comprises a pH regulator. In the present invention, the pH regulator is preferably sodium hydroxide and / or hydrochloric acid; the dosage of the pH regulator is such that the pH of the sodium dequalinium ion-sensitive ophthalmic gel is adjusted to 6-8, more preferably 6.5-7.5, and further preferably 7.

[0031] The sodium dequalinium ion-sensitive gel provided by the present invention further comprises the balance of water, and the water is preferably water for injection.

[0032] The present invention also provides a preparation method of the sodium dequalinium ion-sensitive gel described in the above solution, comprising the following steps:

[0033] Mix sodium alginate with the first portion of water to obtain an aqueous sodium alginate solution;

[0034] Dissolve the osmotic pressure regulator, chelating agent, bacteriostatic agent and sodium dequalinium in the second portion of water, and then mix the obtained solution with the thickening agent to obtain a drug solution;

[0035] Mix the drug solution with sodium alginate, then perform sterile filtration, and then use the pH regulator to adjust the pH of the obtained filtrate to 6-8, and then mix it with the remaining water to obtain the sodium dequalinium ion-sensitive gel.

[0036] In the present invention, sodium alginate is mixed with the first portion of water to obtain an aqueous sodium alginate solution. In the present invention, the first portion of water is preferably 30-45% of the total mass of water, more preferably 35-40%; in a specific embodiment of the present invention, preferably sodium alginate is added to water and stirred to make it swell and disperse completely, that is, an aqueous sodium alginate solution is obtained; the above mixing can be carried out at room temperature.

[0037] In the present invention, the osmotic pressure regulator, chelating agent, bacteriostatic agent and sodium dequalinium are dissolved in the second portion of water, and then the obtained solution is mixed with the thickening agent to obtain a drug solution. In the present invention, the second portion of water is preferably 45% of the total mass of water; in the present invention, preferably, the osmotic pressure regulator, chelating agent and bacteriostatic agent are added to the second portion of water in sequence, and the above components are stirred to dissolve completely, and then the thickening agent is slowly added, and the thickening agent is stirred to swell completely to form a homogeneous system, which is the obtained mixed solution; the above dissolution and mixing can be carried out at room temperature.

[0038] After obtaining the sodium alginate aqueous solution and the drug solution, in the present invention, the drug solution is mixed with sodium alginate and then subjected to sterilization filtration, and then the pH value of the obtained filtrate is adjusted to 6-8 using a pH regulator, and then mixed with the remaining water to obtain the dequalinium sodium ion-sensitive gel. In a specific embodiment of the present invention, it is preferred to add the drug solution to the sodium alginate aqueous solution, stir evenly and then perform sterilization filtration; the above mixing can be carried out at room temperature.

[0039] The technical solutions in the present invention will be clearly and completely described below in conjunction with the embodiments in the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0040] Example 1

[0041] Take 30 mL of injection water, weigh 1.0 g of sodium alginate and add it thereto, stir to make it swell and disperse completely to obtain a sodium alginate aqueous solution, denoted as Solution 1;

[0042] Take another 45 mL of injection water, successively weigh 0.5 g of sodium sulfate, 0.2 g of disodium hydrogen phosphate dodecahydrate, 0.01 g of disodium edetate, and 0.01 g of silver nitrate and add them thereto, stir to make them dissolve completely; weigh 3.0 g of dequalinium sodium and add it thereto, stir to make it dissolve completely; slowly disperse 0.2 g of hypromellose therein, and mechanically stir to make it swell completely to form a homogeneous system to obtain a drug solution, denoted as Solution 2;

[0043] Add Solution 2 to Solution 1, stir to mix evenly and then perform sterilization filtration, adjust the pH value of the filtrate to 6.0-8.0 with NaOH and / or hydrochloric acid solution, and then make up the volume to 100 mL with injection water.

[0044] Example 2

[0045] Take 45 mL of injection water, weigh 1.5 g of sodium alginate and add it thereto, stir to make it swell and disperse completely to obtain a sodium alginate aqueous solution, denoted as Solution 1;

[0046] Take another 45 mL of injection water, successively weigh 0.5 g of sodium sulfate, 0.2 g of disodium hydrogen phosphate dodecahydrate, 0.01 g of disodium edetate, and 0.01 g of silver nitrate and add them thereto, stir to make them dissolve completely; weigh 3.0 g of dequalinium sodium and add it thereto, stir to make it dissolve completely; slowly disperse 0.2 g of hypromellose therein, and mechanically stir to make it swell completely to form a homogeneous system to obtain a drug solution, denoted as Solution 2;

[0047] Add Solution 2 to Solution 1, stir to mix evenly, then perform sterile filtration. Adjust the pH value of the filtrate to 6.0 - 8.0 with NaOH and / or hydrochloric acid solution, and make up the volume to 100 mL.

[0048] Example 3

[0049] Take 45 mL of water for injection, weigh 1.5 g of sodium alginate and add it thereto, stir to make it swell and disperse completely to obtain an aqueous sodium alginate solution, denoted as Solution 1;

[0050] Take another 45 mL of water for injection, successively weigh 0.5 g of sodium sulfate, 0.2 g of disodium hydrogen phosphate dodecahydrate, 0.01 g of disodium edetate, and 0.01 g of silver nitrate and add them thereto, stir to dissolve completely; weigh 3.0 g of dequalinium phosphate and add it thereto, stir to dissolve completely; slowly disperse 0.15 g of hypromellose therein, and mechanically stir to make it swell completely to form a homogeneous system to obtain a drug solution, denoted as Solution 2;

[0051] Add Solution 2 to Solution 1, stir to mix evenly, then perform sterile filtration. Adjust the pH value of the filtrate to 6.0 - 8.0 with NaOH and / or hydrochloric acid solution, and make up the volume to 100 mL.

[0052] Example 4

[0053] Take 30 mL of water for injection, weigh 1.0 g of sodium alginate and add it thereto, stir to make it swell and disperse completely to obtain an aqueous sodium alginate solution, denoted as Solution 1;

[0054] Take another 45 mL of water for injection, successively weigh 0.5 g of sodium sulfate, 0.2 g of disodium hydrogen phosphate dodecahydrate, 0.01 g of disodium edetate, and 0.01 g of silver nitrate and add them thereto, stir to dissolve completely; weigh 3.0 g of dequalinium phosphate and add it thereto, stir to dissolve completely; slowly disperse 0.15 g of hypromellose therein, and mechanically stir to make it swell completely to form a homogeneous system to obtain a drug solution, denoted as Solution 2;

[0055] Add Solution 2 to Solution 1, stir to mix evenly, then perform sterile filtration. Adjust the pH value of the filtrate to 6.0 - 8.0 with NaOH and / or hydrochloric acid solution, and make up the volume to 100 mL.

[0056] In vitro release experiment:

[0057] The products obtained in Examples 1 to 4 and the reference preparation of marketed diclofenac sodium eye drops were used to conduct in vitro release experiments. The specific steps were as follows: An appropriate amount of the samples in Examples 1 to 4 and the reference preparation of diclofenac sodium eye drops were weighed and placed in a dialysis bag. The release of diclofenac sodium in the preparation was determined by the second method in General Chapter 0931, Part IV of the Chinese Pharmacopoeia 2020 Edition. The dissolution medium was: artificial tears (sodium chloride 0.678%, sodium bicarbonate 0.218%, potassium chloride 0.138%, and calcium chloride dihydrate 0.0084%); the volume of the medium was 250 mL, the temperature of the medium was 34 ± 0.5 °C; the sampling volume was 3 mL; the device was: modified small cup method, and the rotation speed was 150 rpm.

[0058] The test results are shown in Table 1.

[0059] Table 1 Test results of in vitro release experiments (%)

[0060]

[0061] From the data in Table 1, it can be seen that the diclofenac sodium ion-sensitive gel provided by the present invention has a good sustained-release effect, and the sustained-release effect of Example 1 is more obvious. It can maintain a stable high concentration in human tears, effectively improve the bioavailability of the drug, and reduce the frequency of drug use; and after the diclofenac sodium ion-sensitive gel of the present invention is added to artificial tears, there is an obvious gel phenomenon and it is in a semi-solid state, indicating that it has good ion sensitivity.

[0062] Stress testing:

[0063] The diclofenac sodium ion-sensitive gel prepared according to the formulation in Example 1 was filled into a low-density polyethylene medicinal eye drop bottle and placed in a stability investigation box. It was placed at 20 °C, 40 °C, and 60 °C for 30 days to investigate the key quality items of the preparation.

[0064] Method for measuring viscosity: According to the third method in General Chapter 0633, Part IV of the Chinese Pharmacopoeia 2020 Edition, the diclofenac sodium ion-sensitive gel and artificial tears were mixed in a volume ratio of 25:7, and the viscosity of the diclofenac sodium ion-sensitive gel was measured at 37 ± 0.5 °C.

[0065] The test results are shown in Table 2:

[0066] Table 2 Key quality test results of diclofenac sodium ion-sensitive gel

[0067]

[0068] It can be seen from the data in Table 2 that the sodium ion-sensitive gel of diclofenac sodium is relatively stable in each test result at different temperatures. The sodium ion-sensitive gel of diclofenac sodium of the present invention is not affected by the ambient temperature and is convenient to use.

[0069] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A sodium-sensitive gel of diclofenac sodium, characterized in that, It consists of components with the following mass fractions: sodium dequalinate 3%, sodium alginate 0.1 - 2%, thickening agent 0.5 - 5%, osmotic pressure regulator 0.011 - 1.6%, chelating agent 0.01 - 0.1%, bacteriostatic agent 0.006 - 0.014%, pH regulator and the balance of water; the dosage of the pH regulator is based on adjusting the pH value of the sodium dequalinate ion-sensitive gel to 6 - 8; the chelating agent is one or both of disodium edetate and calcium disodium edetate; the osmotic pressure regulator is sodium sulfate and disodium hydrogen phosphate dodecahydrate; the mass fraction of sodium sulfate in the sodium dequalinate ion-sensitive gel is 0.01 - 0.6%, and the mass fraction of disodium hydrogen phosphate dodecahydrate is 0.001 - 1%.

2. The sodium dequalinium ion-sensitive gelling agent according to claim 1, characterized in that, The thickening agent is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and polyvinylpyrrolidone thickening agents.

3. The sodium diquafosol-sensitive gelling agent according to claim 2, characterized in that, The polyvinylpyrrolidone thickening agents include one or both of povidone K30 and povidone K90.

4. The sodium diquafosol-sensitive hydrogel according to claim 1, characterized in that, The bacteriostatic agent is one or more of silver nitrate, benzalkonium chloride, and chlorhexidine gluconate.

5. The sodium diquafosol-sensitive gelling agent according to claim 1, characterized in that, The pH regulator is sodium hydroxide and / or hydrochloric acid.

6. The sodium diclofenac sodium ion-sensitive gelling agent according to claim 1, wherein The water is water for injection.

7. The preparation method of the quaforsodine sodium ion-sensitive gelling agent according to any one of claims 1 to 6, characterized in that, It includes the following steps: Mix sodium alginate with the first part of water to obtain an aqueous sodium alginate solution; Dissolve the osmotic pressure regulator, chelating agent, bacteriostatic agent, and sodium dequalinate in the second part of water, and then mix the resulting solution with the thickening agent to obtain a drug solution; Mix the drug solution with sodium alginate, then perform sterile filtration, and then use the pH regulator to adjust the pH value of the resulting filtrate to 6 - 8, and then mix it with the remaining water to obtain the sodium dequalinate ion-sensitive gel.

8. The preparation method according to claim 7, wherein The first part of water is 30 - 45% of the total amount of water; the second part of water is 40 - 50% of the total mass of water.

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