Naproxen solution preparation for oral administration and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an orally taken naproxen solution preparation and a preparation method and application thereof.
Background
Naproxen (Naproxen) is also known as (+) -alpha-methyl-6-methoxy-2-naphthalene acetic acid, is a non-steroidal drug widely used for treating pain, fever and inflammation, can inhibit prostaglandin synthesis to play a role of anti-inflammatory and analgesic, has a stronger effect than aspirin, is rapidly and completely absorbed, reaches the highest blood concentration in 2 hours, is suitable for rheumatoid arthritis, osteoarthritis, acute ventilation and the like, has good effect and smaller side effect, and is one of non-prescription drugs which are popular worldwide. Among naproxen oral preparation products, tablets, capsules and granules are main products widely applied clinically in the market for a long time. Besides the dosage forms, the naproxen suspension is clinically applied in European and American markets, compared with an oral solid preparation product, the oral suspension is faster to absorb, brings convenience to children, old people and dysphagia patients, and has obvious advantages that the dosage of the suspension is easy to adjust by measuring different volumes.
The naproxen suspension is in a form of solid-liquid mixed metastable state, the naproxen exists in the form of solid particles, the suspension balance is achieved by adding a plurality of necessary auxiliary agents, and the preparation process is complex. Particularly, solid particles with relatively uniform content in the original suspension can be settled at the bottom of liquid due to the actions of gravity, vibration and the like in the storage or transportation process, so that the content of the product is unevenly distributed, the accuracy of medicine taking dosage can be influenced, and the medication safety and the curative effect of a patient are finally influenced; various suspension auxiliary agents which do not generate drug effects have potential health hazard to human bodies, increase unnecessary metabolic burden of the human bodies, and are also waste of resources.
In view of this, a solution formulation of naproxen for oral administration having a simple composition was developed to solve the above-mentioned problems, and more effective and safer treatment can be provided to patients.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an orally taken naproxen solution preparation for the first time.
In order to obtain a naproxen solution formulation for oral administration, the problem of poor solubility of naproxen in water must be solved so that the dosage of naproxen for clinical use is reached in 5ml or 10ml of oral liquid. The solubility of the derived naproxen sodium in water can meet the requirement, but the uncomfortable effect of the naproxen sodium in oral cavity stimulating taste and swallowing is another difficult problem to be solved in clinical application, and the naproxen sodium aqueous solution is more alkaline, has relatively poor stability in a medium with relatively high pH value, generates decomposition products when stored for a long time, and is unfavorable for clinical application.
The naproxen solution preparation for oral administration prepared by the invention can improve the total concentration of naproxen in the solution to 25-50 mg/mL within the pH range of less than 8.0, and meanwhile, the naproxen solution preparation for oral administration is a colorless, clear and transparent solution, the naproxen and the naproxen sodium are dissolved in the solution in a molecular state, are uniformly distributed, do not generate sedimentation and precipitation phenomena, and have good physical stability; the pH value is reduced to a near neutral range, the chemical stability is good, and the preparation method has the advantages of faster drug absorption, more accurate dosage, higher bioavailability and the like.
It is an object of the present invention to provide an orally administered naproxen solution formulation.
An orally taken naproxen solution preparation, which comprises naproxen, at least one of carbonate, phosphate and citrate, sweetener, essence and purified water, wherein the total content of the naproxen is 1.5-6.0% (W/V).
Further, the total content of naproxen is preferably 2.5% (W/V) and 5.0% (W/V).
Further, the naproxen solution preparation for oral administration further comprises polyvinylpyrrolidone, and the weight ratio of the total amount of at least one or more of the carbonate, the phosphate and the citrate to the naproxen is (0.3-3): 1, wherein the content of the sweetener is 0.05-30% (W/V), the content of the essence is 0.05-3% (W/V), and the content of the polyvinylpyrrolidone is 0-3.0% (W/V).
Further, the carbonate is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
Further, the phosphate is selected from one or more of sodium phosphate, potassium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate;
further, the citrate is selected from one or more of sodium citrate, potassium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate and potassium dihydrogen citrate.
Further, the sweetener is selected from one or more of saccharin sodium, saccharin, stevioside, aspartame, sucralose, sucrose, sorbitol and sodium cyclamate, the essence is selected from one or more of orange essence and orange essence, and the polyvinylpyrrolidone is selected from one or more of K17, K30 and K90.
Further, the pH value of the naproxen solution preparation for oral administration is 7.0-8.5, preferably 7.5-8.2.
In the invention, carbonate, phosphate or citrate is polybasic acid salt, mono-or disodium (potassium) salt of carbonate (sodium salt or potassium salt), tri-or disodium (potassium) salt of phosphate (sodium salt or potassium salt) or tri-sodium (potassium) salt of citrate (sodium salt or potassium salt), and the aqueous solutions of the carbonate, the phosphate or the citrate are alkaline, so that the solubility of naproxen in water can be improved; on one hand, carbonate, phosphate and citrate form a diversified composite buffer system with naproxen and naproxen sodium, so that the dissolution performance of naproxen is enhanced, and meanwhile, the pH value of the whole naproxen solution preparation oral liquid is stable, the oral liquid can be kept stable for a long time in a near neutral range, and no solid is separated out; on the other hand, the inventors found that carbonates, citrates and phosphates also have a taste-modifying effect on naproxen and naproxen sodium, which can improve the mouthfeel and inhibit the taste, and reduce or eliminate the uncomfortable feeling upon swallowing; the polyvinylpyrrolidone-medical material has solubilization, can further ensure that no solid precipitate is precipitated in the long-term storage process of the naproxen solution preparation oral liquid, and the sweetener and the essence can further improve the taste of the naproxen solution preparation oral liquid, so that the polyvinylpyrrolidone-medical material is particularly suitable for the old and the children, has good compliance, and can also be added with medicinal pigment to prepare the oral preparation more suitable for children. Through the synergistic effect of the components, the prepared naproxen solution preparation for oral administration has good chemical stability, high naproxen solubility and good taste, and is more beneficial to clinical application.
The naproxen solution preparation for oral administration, disclosed by the invention, is simple in preparation method, and can be prepared by the method described below.
The method for preparing the naproxen solution preparation for oral administration according to any one of the above claims, comprising the following steps:
s1, adding at least one of carbonate, phosphate or citrate into purified water for dissolution, then adding naproxen, adjusting the pH value of the solution to 10-12 by using sodium hydroxide or potassium hydroxide, continuing to dissolve, and then adding sweetener, essence and polyvinylpyrrolidone for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 by using an acid-base regulator, and adding purified water to a required volume to obtain a diluent;
and S3, filtering and sterilizing the diluent obtained in the step S2, and sub-packaging to obtain the naproxen solution for oral administration.
Further, in step S2, the acid-base modifier is one or more of sodium hydroxide, potassium hydroxide and hydrochloric acid.
Further, in step S3, the pore size of the filter membrane in the filter sterilization is 0.22 μm.
Further, in step S3, the packaging container used in the packaging process is a medicinal liquid glass bottle or a plastic bottle, and the volume of the packaging container is 20-500 mL, preferably 30mL,50mL,100mL,250mL.
It is a final object of the present invention to provide the use of a naproxen solution formulation for oral administration.
Use of an orally administered naproxen solution formulation according to any one of the preceding claims for the preparation of a medicament for the treatment of pain, fever and some inflammatory reactions.
Compared with the prior art, the invention has the following advantages:
1) The naproxen solution preparation for oral administration prepared by the invention is a homogeneous transparent liquid, naproxen and naproxen sodium exist in the solution in a molecular form, the collapse and dissolution processes of solid oral agents are not needed, the dissolution processes of suspension agents are avoided, the naproxen solution preparation can be directly absorbed, the occurrence of the drug effect is faster, and the bioavailability is higher;
2) The naproxen content of the orally taken naproxen solution preparation prepared by the invention is uniformly distributed in the solution, and the medicament has more accurate administration dosage, better curative effect and higher safety;
3) The naproxen solution preparation for oral administration prepared by the invention is a solution with stable physical state, but not the metastable state of a suspension, and does not have precipitation phenomenon; the pH of the solution is close to neutral, the chemical stability is good, and the solution is easy to store for a long time; the carbonate, the phosphate and the citrate in the naproxen solution preparation for oral administration prepared by the invention have the effects of inhibiting the peculiar smell and the stimulation of naproxen, have no uncomfortable feeling during swallowing, have good mouthfeel and are beneficial to clinical application;
4) The naproxen solution preparation for oral administration prepared by the invention has the advantages of less material consumption, simple preparation process, environmental protection and easy mass production;
5) The naproxen solution preparation for oral administration prepared by the invention has no preservative, and avoids the side effects of toxicity and irritation of the preservative on human bodies;
6) The naproxen solution preparation for oral administration prepared by the invention is suitable for children, the elderly and patients with dysphagia.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below. It is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments, and that all other embodiments obtained by persons of ordinary skill in the art without making creative efforts based on the embodiments in the present invention are within the protection scope of the present invention.
Example 1
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 8.3g of sodium phosphate dodecahydrate, adding the sodium phosphate dodecahydrate into 70mL of purified water for dissolution, then adding 5.0g of naproxen for continuous dissolution, and then adding 0.3g of saccharin sodium, 0.1g of sweet orange essence and 0.5g of polyvinylpyrrolidone-K30 for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 8.1 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain a colorless clear orally taken naproxen solution preparation with the naproxen concentration of 5% (W/V).
Example 2
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 5.8g of sodium phosphate dodecahydrate, adding the sodium phosphate dodecahydrate into 70mL of purified water for dissolution, then adding 2.5g of naproxen for continuous dissolution, and then adding 0.1g of saccharin sodium and 10g of sucrose, and dissolving 0.1g of sweet orange essence to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.4 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain a colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 3
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 6.3g of citric acid monohydrate, adding the citric acid monohydrate into 70mL of purified water for dissolution, neutralizing with 1.6g of sodium hydroxide for reaction to generate sodium citrate, then adding 2.5g of naproxen, adding 1.0mol/L of sodium hydroxide to the pH value of the solution to be 10-12, and then adding 0.2g of saccharin sodium, 0.1g of orange essence and 0.5g of polyvinylpyrrolidone-K30 for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.7 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain a colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 4
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 3.1g of citric acid monohydrate, adding the citric acid monohydrate into 70mL of purified water for dissolution, neutralizing with 2.2g of excessive sodium hydroxide for reaction to generate sodium citrate, adding 3g of sodium bicarbonate, then adding 2.5g of naproxen, adding 1.0mol/L of sodium hydroxide to the pH value of the solution to be 10-12, and then adding 0.2g of saccharin sodium and 0.1g of sweet orange essence for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.8 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by adopting a pore diameter of 0.22 mu m to obtain a colorless clear oral naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 5
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 6.5g of sodium bicarbonate, adding the sodium bicarbonate into 70mL of purified water for dissolution, adding 0.5g of sodium hydroxide for dissolution, then adding 2.5g of naproxen for continuous dissolution, adding 1.0mol/L of sodium hydroxide to the pH value of the solution to be 10-12, and then adding 0.1g of saccharin sodium and 0.3g of sweet orange essence for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 8.0 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 with a pore diameter of 0.22 mu m, and subpackaging to obtain 100mL of colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 6
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, 2.5g of naproxen is added into 40ml of purified water, 1.0mol/L sodium hydroxide is used for dissolving the naproxen into sodium naproxen, 1.0g of sodium carbonate and 1.0g of polyvinylpyrrolidone-K30 are added, then 0.5g of saccharin sodium and 0.1g of sweet orange essence are added for dissolving, and a mixed solution is obtained;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.8 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain 100mL of colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 7
The oral naproxen solution formulations prepared in examples 1-6 were subjected to stability testing at room temperature in the absence of light, and the test results are shown in table 1:
TABLE 1 physical stability test results of orally administered naproxen solution formulations
As can be seen from the results in Table 1, the orally taken naproxen solution preparations prepared in examples 1 to 6 have no phenomena of discoloration, turbidity, precipitation and the like when being stored for 12 months under the condition of being protected from light at room temperature, and have the advantages of unchanged pH value and good stability;
example 8
The total content of naproxen in the orally taken naproxen solution preparations prepared in examples 1 to 6 was tested under the condition of keeping the orally taken naproxen solution preparation in a dark place at room temperature, and the results show that the total content of naproxen in the orally taken naproxen solution preparations prepared in examples 1 to 6 is not changed at all under the condition of keeping the orally taken naproxen solution preparation in a dark place at room temperature for 12 months.
Example 9
The oral naproxen solution formulations prepared in examples 1 to 6 were subjected to taste tests, and as a result, the oral naproxen solution formulations prepared in examples 1 to 6 were found to have no irritating taste, no uncomfortable feeling when swallowed, and good taste.
The above examples are only specific embodiments of the present invention for illustrating the technical solution of the present invention, but not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the foregoing examples, it will be understood by those skilled in the art that the present invention is not limited thereto: any person skilled in the art may modify or easily conceive of the technical solution described in the foregoing embodiments, or perform equivalent substitution of some of the technical features, while remaining within the technical scope of the present disclosure; such modifications, changes or substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention, and are intended to be included in the scope of the present invention.