CN116459238A - Composition for promoting sustained release of glucosamine and application thereof - Google Patents
Composition for promoting sustained release of glucosamine and application thereof Download PDFInfo
- Publication number
- CN116459238A CN116459238A CN202310509966.7A CN202310509966A CN116459238A CN 116459238 A CN116459238 A CN 116459238A CN 202310509966 A CN202310509966 A CN 202310509966A CN 116459238 A CN116459238 A CN 116459238A
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- CN
- China
- Prior art keywords
- glucosamine
- transdermal
- pva
- stirring
- gel
- Prior art date
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- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 title claims abstract description 48
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- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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Abstract
The invention discloses a composition for promoting sustained release of glucosamine, which comprises the following components: transdermal enhancers and PVA; wherein the PVAThe dosage of the transdermal enhancer and the PVA is 2.5-10%, and the mass ratio of the transdermal enhancer to the PVA is 1:20-2:1; the accelerator is applied to the preparation of glucosamine gel paste, is easy to apply, has fresh and non-irritating skin after administration, and has an accumulated release rate of 1200 mug/cm after 24 hours 2 The medicine has the advantages of improving the effectiveness of the medicine, prolonging the acting time of the medicine, reducing the administration times and having good patient compliance.
Description
Technical Field
The invention relates to the technical field of preparation of glucosamine patches, in particular to a composition for promoting sustained release of glucosamine and application thereof.
Background
Osteoarthritis (OA) is a degenerative disease, which is mainly manifested by joint swelling and pain and a varying degree of dysfunction, leading to loss of function in severe cases. OA is highly frequently seen in middle and late years, with 70% of the elderly over 65 years having OA symptoms, the most common joint pathology, and the second leading cause of long-term disability in adults. OA is a result of imbalance in the decomposition and anabolism of chondrocytes, extracellular matrix and subchondral bone under the combined action of mechanical and biological factors, and students at home and abroad are actively searching for an ideal medicine for treating osteoarthritis while researching the etiology and mechanism thereof.
Glucosamine sulfate is a novel compound widely accepted in recent years for treating OA, and the treatment mechanism is to supplement basic substances for synthesizing aminodextran in human bodies, so as to promote the synthesis of proteoglycan in articular cartilage and achieve the aim of repairing the articular cartilage. Unlike traditional nonsteroidal anti-inflammatory medicine (aspirin, nasid) which has the disadvantages of stimulating gastrointestinal tract, causing coagulation dysfunction, anaphylactic reaction, salicylic acid reaction and the like when being used for a long time, the glucosamine sulfate can effectively avoid the adverse reaction of the traditional nonsteroidal anti-inflammatory medicine, and is a safe and easily obtained therapeutic medicine.
The existing glucosamine dosage forms all belong to the oral administration system, such as common tablets, granules and capsules, and the American FDA approved glucosamine sulfate formulation Viartril-S (glucosamine sulfate capsule). Notably, glucosamine oral formulations suffer from relatively significant dosage form deficiencies in the treatment of disease. Firstly, the glucosamine effective part is positioned at the superficial muscle layer or the bone joint cavity part, the biological factors such as the first pass effect of the liver and the like need to be overcome for oral administration, and the pathological change part is difficult to reach; in order to meet the requirement of local drug treatment concentration, the dosage of the drug needs to be increased by oral administration, adverse reactions such as gastrointestinal discomfort, adverse reactions of the liver and the like are easily caused by the excessive drug concentration, the glucosamine sulfate treatment period is continuously about 3 months, the drug needs to be repeatedly administered for a long time, and great burden is caused to the gastrointestinal tract and the liver system of a patient. Thus, there remains a need to develop additional drug delivery systems for glucosamine sulfate to improve the efficacy and safety issues thereof.
Transdermal drug delivery systems are the third type of drug dosage forms, other than oral administration and injection, i.e. drugs are absorbed through the skin, exerting full or partial effects. Compared with oral medicinal preparation, the transdermal patch can avoid first pass effect of liver and irritation of medicine to gastrointestinal tract. In addition, for OA diseases, the drug delivery mechanism in the transdermal drug delivery system is through stratum corneum, superficial layer, dermis layer, muscle tissue, bone joint and blood, which is helpful to maintain the local high concentration of the drug, so as to avoid the burden of liver caused by excessively high drug administration dose. Then, the existing glucosamine percutaneous administration system on the market is concentrated in semisolid gel preparations, has insufficient mechanical strength, is easy to remain and fall off, has short action time, and cannot meet the controllable long-term application and slow release administration purposes. On the other hand, the common gel preparation has lower drug loading rate, insufficient release capacity in the later period and a plurality of limitations in practical application.
Currently, the method for enhancing the later release capacity of the crosslinked hydrophilic gel is intended to achieve the required effect by regulating and controlling the drug loading concentration of the patch or the thickness of the patch. However, a great number of experiments prove that although the thickness of the patch can bring longer lasting action and effect, the effect is limited, and the excessive thickness of the patch increases the easy falling-off property of the preparation in the actual application process, so the patch has no practical application value.
The gel patch belongs to a percutaneous administration system, and is an external preparation prepared by taking a water-soluble polymer material as a main matrix to load a drug and coating the drug on non-woven fabrics. Wherein, the crosslinking hydrogel patch is formed by chelating and solidifying the crosslinking agent and the water-soluble polymer to form a three-dimensional network structure. The structure can greatly improve cohesive strength of the matrix, avoid phenomena of peeling, cold flow and the like of the paste, and is less prone to problems of matrix residue, clothes pollution and the like compared with a common gel preparation or a non-crosslinked gel patch. Combining the clinical application limitations of glucosamine sulfate with the good biopharmaceutical properties of gel patches, crosslinked hydrogel patches for glucosamine sulfate require sustained delivery of pharmaceutically significant doses over a 12-24 hour dosing range. The components of the hydrogel patch are regulated, so that the medicine can achieve higher medicine carrying capacity in the patch, and achieve proper balance in various aspects such as medicine delivery efficiency, application performance, stability and the like, thereby controlling the overall performance of the patch and achieving the aims of effective medicine delivery and long-term application.
Therefore, how to provide a composition capable of effectively ensuring that the effective components in the glucosamine gel patch are released for 24 hours and applying the composition to the glucosamine gel patch is a technical problem to be solved by the person skilled in the art.
Disclosure of Invention
In view of the above, the present invention provides a composition for promoting sustained release of glucosamine and use thereof.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a composition for promoting sustained release of glucosamine comprising: transdermal enhancers and PVA; wherein the dosage of PVA is 2.5-10%, and PVA comprises: EG-03-P, EG-05P, EG-05PW or GL05, and the mass ratio of the transdermal enhancer to PVA is 1:20-2:1. The PVA is contained in the gel plaster preparation matrix in an amount of 2.5-10% by mass of the total polymer matrix, preferably in a range of 3-7.5%, and more preferably in an amount of 5-6%.
PVA is promoted to present a typical 'head-tail' structure, a side chain contains a large number of hydroxyl functional groups, the pKa value rises along with the increase of the polymerization degree, the pKa of different PVA products is in the range of 4-8, the glass transition temperature is 75-85 ℃, and the film forming performance is good at normal temperature. According to two molecular structures, it is speculated that sulfuric acid functional groups and amino groups in the glucosamine sulfate can interact with hydroxyl groups of PVA side chains under the non-ionized state to form weak non-chemical bond action, and in a gel plaster matrix, the weak bond action force does not influence the thermodynamic activity of the medicine, can enhance the stability of the medicine in a system, and can improve the stability of the medicine in the matrix within a certain range, so that the addition of PVA can ensure the high medicine loading rate of the gel plaster.
According to the invention, in the process of regulating the dosage of the prescription, the glucosamine can be prepared into a stable and uniform dispersion system by regulating the dosage of PVA in the system through screening. It is noted that, the dosage of the conventional PVA ranges from 0.5% to 2.5%, when the dosage of the PVA adopted in the invention is larger than the conventional dosage (more than 5%), the PVA can play a role in assisting in stabilizing the drug, and further, when the dosage of the PVA reaches 10%, the stabilizing effect is not improved, and a certain stability reduction phenomenon occurs.
Further, PVA mainly plays a role in rapid solidification and molding in gel plaster preparations, and hard strip-shaped phenomena possibly existing in the preparation and coating processes are easy to occur when the dosage of PVA exceeds 2.5%. In order to avoid the situation, the preparation process temperature needs to be maintained at 60-80 ℃ in the preparation process, and the gel plaster is too rapidly dehydrated at the temperature above which the plaster is easy to generate hard strip phenomenon. Experiments prove that in the dosage range and at a specific temperature, excessive addition of PVA does not generate obvious damage phenomenon of paste adhesion performance, the application of PVA in the dosage range does not bring damage effect on matrix system balance, which is difficult to repair, even though the paste is too hard in coating, the risk of excessively fast shaping caused by excessive PVA can be reduced to the greatest extent by simply increasing the preparation process temperature.
Preferably, the transdermal enhancer comprises: any one or a combination of a plurality of polyols, terpenes, sulfoxides, azones, amines and amides.
The transdermal enhancer can effectively promote the release of glucosamine under the skin, and the permeation mechanism is related to the permeation enhancer which can reduce the ordering of intercellular lipid arrangement by penetrating into the stratum corneum, and change the arrangement structure of proteins in the stratum corneum.
Although amines and organic amines can increase the skin penetration ability of glucosamine sulfate, the enhancement effect of simple amines and organic amines is limited. Therefore, the invention further adds azone and polyalcohol permeation promoters on the basis of adding amine and organic amine permeation promoters, and discovers that good combined use effect is obtained. Especially, the addition of azone can obviously improve the effect of the prior glucosamine sulfate gel plaster containing amine and organic amine. Azone is a nonionic surfactant mainly comprising caprolactam heterocycle and dodecyl hydrophobic end, is commonly used in various cream preparations of cosmetics, and has good capability of embedding into skin lipid layer and changing skin permeability. In the glucosamine sulfate gel patch preparation, the effect of promoting permeation by using azone alone is limited, and the supposedly high water solubility of the medicine and the limited drug permeation capacity are obtained. When the medicine is combined, the medicine molecules and the amine substances act in a neutral form, the azone regulates the skin permeability, and the caprolactam heterocycle of the azone has higher affinity with the amine complex, so that the permeability of the medicine is improved.
Preferably, the polyols include: propylene glycol or glycerol; the terpenes include eucalyptol, d-limonene or nerolidol; the sulfoxides include dimethyl sulfoxide or decyl methyl sulfoxide; the azones include azone, 5-methyl-2-pyrrolidone or 1, 5-dimethyl-2-pyrrolidone; the amine and amide include urea, dodecyl-N, N-dimethylaminoethyl ester, dimethylformamide, dimethylacetamide or crotamiton.
As the same inventive concept as the technical scheme, the invention also claims the application of the accelerator for promoting the sustained release of the glucosamine in preparing the glucosamine gel patch.
The invention ensures stable and durable release of the glucosamine by combining the amine, azone and polyol transdermal promoters and controlling the addition of PVA, can quickly and effectively permeate the focus without increasing the thickness and the concentration of the medicine, and improves the bioavailability and the treatment effect of the glucosamine.
As the invention concept same as the technical scheme, the invention also claims a glucosamine gel patch, which comprises the following raw materials in percentage by mass: comprises 0.5-5% of glucosamine, 2.5-10% of plasticizer, 15-25% of framework material, 5-10% of filler, 0.1-1% of solubilizer, 0.5-1% of thickener, 25-35% of humectant, 0.5-2% of pH regulator, 1-5% of transdermal enhancer, 0.1-0.5% of cross-linking agent and the balance of water.
Preferably, the glucosamine is glucosamine sulfate.
Preferably, the framework material is any one or a combination of a plurality of sodium polyacrylate, polyacrylic acid and polyacrylate; the filler is titanium dioxide or talcum powder; the solubilizer is polysorbate 80; the thickener is carboxymethyl cellulose or sodium carboxymethyl cellulose; the humectant is glycerin, propylene glycol or sorbitol; the pH regulator is disodium edentate, tartaric acid, citric acid, malic acid or lactic acid; the cross-linking agent is aluminum hydroxide or aluminum glycollate.
As the invention concept same as the technical scheme, the invention also claims a preparation method of the glucosamine gel paste, which comprises the following steps:
1) Weighing the glucosamine with the formula amount, dissolving the solubilizer in water, and stirring at the rotating speed of 200-500 rpm until the glucosamine is completely dissolved;
2) Weighing framework materials, filling agents, thickening agents and transdermal promoters according to the formula amount, putting the framework materials, the filling agents, the thickening agents and the transdermal promoters into a reaction kettle, stirring for 10-50 min, adding the humectant while stirring until uniform paste is formed, slowly adding the main medicine solution, stirring for 10-30 min, and finally adding the cross-linking agents, the PVA aqueous solution and the pH regulator under the stirring condition, and stirring for 10-30 min until white to white-like uniform paste is formed.
3) Uniformly coating the paste between a backing layer and a protective layer, cutting into proper size and shape according to the requirement, putting into proper package, and standing for 14d to obtain the glucosamine gel paste.
Preferably, in the step 2), the stirring speed is in the principle of first-quick and then-slow, the initial stirring speed is 400-600 RPM, and the later stirring speed is 100-300 RPM.
Preferably, in step 3), the coating net thickness is 1mm.
Compared with the prior art, the cross-linked hydrogel patch for glucosamine sulfate needs to continuously deliver a pharmaceutically significant dose within the administration range of 12-24 hours by combining the clinical application limit of the glucosamine sulfate and the good biopharmaceutical property of the gel patch. The composition of the transdermal penetrating agent and the dosage of PVA are regulated, so that the medicine can reach higher medicine carrying capacity in the patch, and a proper balance is achieved in various aspects of medicine delivery efficiency, application performance, stability and the like, thereby controlling the overall performance of the patch and achieving the aims of effective medicine delivery and long-term application. The development of the gel emplastrum preparation product is an extremely important supplement to the prior commercial products of glucosamine sulfate, and is also a preparation upgrade for improving the therapeutic effect of the medicine.
Meanwhile, the gel patch prepared by the invention can avoid the first pass effect of liver and the stimulation of gastrointestinal tract caused by oral administration, reduce the side effect of medicine, is convenient and reliable to use, has high medicine carrying capacity, is easy to apply, has fresh and non-irritating skin after administration, and can achieve the accumulated release rate of 1200 mu g/cm for 24 hours 2 The medicine has the advantages of improving the effectiveness of the medicine, prolonging the acting time of the medicine, reducing the administration times and having good patient compliance.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the results of stability experiments for example (PVA introduced); wherein a, e and i are the stability results of the gel prepared in example 1 applied under a 10-fold microscope for 1 month, 3 months and 6 months, respectively; b. f and j are the stability results of the gel prepared in example 1 attached to a 100-fold microscope for 1 month, 3 months and 6 months, respectively; c. g and k are respectively the stability results of the gel prepared in comparative example 6 after being stuck to a microscope of 10 times for 1 month, 3 months and 6 months; d. h and l are respectively the stability results of the gel prepared in comparative example 6 after being stuck to a 100-time microscope for 1 month, 3 months and 6 months;
FIG. 2 is a graph showing the results of in vitro release experiments for examples (different transdermal enhancers).
FIG. 3 is a graph showing the results of an in vitro transdermal test of examples (different transdermal enhancers).
FIG. 4 is a graph showing the results of an in vitro transdermal test of the examples (combination of different transdermal enhancers).
FIG. 5 is a graph showing the results of an in vitro transdermal test of examples (patches of different drugs and PVA content).
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The glucosamine gel patch comprises the following raw materials in percentage by mass:
the main medicine is glucosamine sulfate, the framework material is a mixture of polyacrylic acid and sodium polyacrylate, the filler is a mixture of talcum powder and titanium dioxide, the thickener is sodium carboxymethyl cellulose, the solubilizer is polysorbate 80, the transdermal enhancer is peppermint oil and propylene glycol, the humectant is glycerin, the plasticizer is EG-03P,
the pH regulator is tartaric acid, and the crosslinking agent is aluminum glycinate; the method comprises the following steps:
2% of glucosamine sulfate, 20% of a mixture of polyacrylic acid and sodium polyacrylate, 10% of talcum powder and titanium dioxide, 0.5% of sodium carboxymethyl cellulose, 800.5% of polysorbate, 0.5% of peppermint oil and propylene glycol, 25% of glycerol, 25% of EG-03P5%, 1.5% of tartaric acid, 0.1% of aluminum glycyrrhetate and 34.9% of water.
Example 2
The glucosamine gel patch comprises the following raw materials in percentage by mass:
the skeleton material is polyacrylate, the filler is talcum powder, the thickener is carboxymethyl cellulose, the solubilizer is polysorbate 80, and the transdermal enhancer is a mixture of azone, glycerol and crotamiton; the humectant is glycerin, the plasticizer is EG-05P, the pH regulator is edetate disodium, and the cross-linking agent is aluminum hydroxide; the method comprises the following steps:
0.5% of glucosamine sulfate, 25% of polyacrylate, 5% of talcum powder, 0.6% of carboxymethyl cellulose, 801% of polysorbate, 1% of azone, glycerol and crotamiton, 28% of glycerol, 28% of EG-05P2.5%, 0.5% of disodium edentate, 0.15% of aluminum hydroxide and 35.75% of water.
Example 3
The glucosamine gel patch comprises the following raw materials in percentage by mass:
the skeleton material is sodium polyacrylate, the filler is titanium dioxide, the thickener is carboxymethyl cellulose, the solubilizer is polysorbate 80, and the transdermal enhancer is a mixture of azone, glycerol and dimethylformamide; the humectant is sorbitol, the plasticizer is EG-05PW, the pH regulator is citric acid, and the crosslinking agent is aluminum hydroxide; the method comprises the following steps:
3% of glucosamine sulfate, 22% of sodium polyacrylate, 8% of titanium dioxide, 0.7% of carboxymethyl cellulose, 800.1% of polysorbate, 2.5% of azone, glycerol and dimethylformamide, 35% of sorbitol, 0.8% of EG-05PW7.5%, 0.2% of citric acid, 0.2% of aluminum hydroxide and 20.2% of water.
Example 4
The glucosamine gel patch comprises the following raw materials in percentage by mass:
the skeleton material is polyacrylic acid, the filler is titanium dioxide, the thickener is carboxymethyl cellulose, the solubilizer is polysorbate 80, and the transdermal enhancer is a mixture of dimethyl sulfoxide, glycerol and urea; the humectant is sorbitol, the plasticizer is GL05, the pH regulator is malic acid, and the crosslinking agent is aluminum glycinate; the method comprises the following steps:
5% of glucosamine sulfate, 16% of polyacrylic acid, 5% of titanium dioxide, 0.8% of carboxymethyl cellulose, 800.3% of polysorbate, 1.5% of dimethyl sulfoxide, glycerol and urea, 32% of sorbitol, 0510% of GL, 0.9% of malic acid, 0.3% of aluminum glycyrrhizate and 28.2% of water.
Example 5
The glucosamine gel patch comprises the following raw materials in percentage by mass:
the skeleton material is polyacrylic acid and polyacrylate, the filler is titanium dioxide, the thickener is sodium carboxymethyl cellulose, the solubilizer is polysorbate 80, and the transdermal enhancer is mixture of eucalyptol, glycerol, urea and azone; the humectant is propylene glycol, the plasticizer is GL05, the pH regulator is lactic acid, and the crosslinking agent is aluminum glycinate; the method comprises the following steps:
5% of glucosamine sulfate, 15% of polyacrylic acid and polyacrylate, 9% of titanium dioxide, 1% of sodium carboxymethyl cellulose, 800.7% of polysorbate, 3.5% of eucalyptol, glycerol, urea and azone, 30% of propylene glycol, 053.5% of GL, 2% of lactic acid, 0.5% of aluminum glycollate and 29.8% of water.
Example 6
With reference to example 1, experimental groups 1 to 6 and comparative examples 1 to 5 were set up, and they differ from example 1 only in the kind of the transdermal enhancer, specifically, table 1 below (other auxiliary materials in the table refer to other auxiliary materials except for glucosamine sulfate and the transdermal enhancer in example 1).
TABLE 1
Simultaneously setting experiment groups 7-12, and respectively setting the components and the ratio in table 2;
TABLE 2
Comparative example 6 preparation the procedure was the same as in example 1, adjusting the amount of EG-03 in the formulation to 2%.
Comparative example 7 and comparative example 8 are gel formulations prepared according to the preparation methods of examples 5 and 9 in chinese patent CN 102614111.
The preparation method and process of the formulas of comparative example 9 and comparative example 10 are the same as that of example 2, and the coating thickness is adjusted to be 1.5mm and 2.0mm after paste formation.
Meanwhile, real experiment groups 13 to 16, comparative examples 11 to 15 are set; see table 3 below;
TABLE 3 Table 3
The gel patches prepared in the above examples, experimental groups and comparative examples were subjected to performance tests, specifically as follows:
stability test
The gel patches prepared in example 1 and comparative example 6 were placed under the same storage conditions (30±2 ℃,60±10%rh), and the surface condition of the patch matrix was observed by electron microscopy at regular intervals, and the observation results are shown in fig. 1, and it can be seen that the high drug loading rate of example 1 cannot be achieved by using the conventional amount of EG-03 in comparative example 6, and that the typical drug crystallization phenomenon occurs in comparative example 6 after storage for 1 month, which mainly involves the transition from the high thermodynamic activity of the drug to the low thermodynamic activity of the fixed crystal form, and causes a significant decrease in the transdermal release rate of the drug. In contrast, example 1, no change in the crystalline type of the drug occurred, indicating a good effect of stabilizing the drug in the PVA gel plaster matrix.
Meanwhile, in the experimental groups 13 to 16, no precipitation was observed in 1 month, 3 months and 6 months, and in comparative example 11,
no precipitation is generated in 1 month, and precipitation is generated in 3 months; in comparative example 12, no precipitation was observed for 1 month or 3 months, and precipitation was observed for 6 months; in comparative example 13, no precipitation was performed for 1 month and 3 months, in comparative example 14, no precipitation was performed for 1 month and 3 months, in comparative example 15, and no precipitation was performed for 6 months.
Continuous observation results of gel plaster preparations prepared by different prescriptions show that the examined examples 1, 2, 5 and 2 can be stably stored for 3 months under the placing condition, and no sample crystallization is caused. The stability samples all meet the standard.
In vitro Release test
According to the method for measuring the dissolution and release rates of the glucosamine sulfate plaster preparation containing different permeation enhancers in phosphate buffer medium with pH value of 7.4 by using a dissolution instrument, the method is examined according to the fourth rule 0931 of the fourth rule of Chinese pharmacopoeia 2020, and comprises the following specific steps:
the dissolution method comprises the following steps: a paddle-disc method; instrument device: tianjin Tiantian Fang RC806D star; dissolution medium: phosphate buffer pH7.4 (3% NaCl content to prevent over-swelling of the patch); dissolution volume: 900ml; rotor speed: 50 revolutions per minute; sampling time: 1h, 3h, 6h, 8h and 12h; sampling volume: 5ml; after sampling, the sample solution was centrifuged through a 0.45 μm filter membrane, and the filtrate was measured by HPLC.
Chromatographic conditions: the results of liquid phase analysis using a column (C8250 mm. Times.4.6mm5 μm or performance column) with octaalkylsilane-bonded silica gel as the filler in a mobile phase composed of phosphate buffer solution at pH3.0 and acetonitrile are shown in FIG. 2, and as can be seen from FIG. 2, the results of the dissolution release test for different samples are similar, indicating that the release behavior of the overall structure after the introduction of PVA is not affected by the different permeation enhancers.
In vitro transdermal experiments
In vitro transdermal experiments were performed according to U.S. FDA in vitro transdermal technical guidelines in vitro permeation test studies for topical drug products submitted in ANDAs, and evaluated using the modified Franz diffusion cell method, with the skin being the skin of the back portion of Bama miniature pig. The specific operation method is that a full-automatic percutaneous dissolution and diffusion instrument (FDC-6 type, LOGAN System 914-12) is used for carrying out the test, and the pigskin is placed between a supply chamber and a receiving chamber, wherein the inner diameter of the receiving chamber is 9mm, and the volume of the receiving chamber is 12ml. The gel patch preparation to be inspected is cut into a round patch with the inner diameter of 9mm and is applied to the surface of the skin to be inspected. The stirring speed of the inner rotor in the diffusion tank was set at 500rpm/min, and the solution temperature was set at 32.0.+ -. 0.5 ℃. Sampling begins after 15 minutes of equilibration, general sampling points: 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 20h, 24h, part of the sample detected only 12h. Fresh medium was replenished after each sampling and the supernatant was injected into the HPLC system, with HPLC analysis method identical to the in vitro release assay method.
The in vitro transdermal curves of the examples obtained are shown in figures 3-5 for the combination of different penetration enhancers, different scalp accelerators and different medicines and EG-03 contents. As can be seen from fig. 3, when the transdermal enhancer is a mixture of peppermint oil and propylene glycol, and the transdermal enhancers of experimental groups 1 to 6, the effect of the transdermal enhancer is good, and comparative examples 1 to 5 are the contrary, showing that the addition of different enhancers affects the transdermal efficiency; as can be seen from fig. 4, the effect on the final transdermal effect is different when the combination of different scalp promoters is combined with glucosamine and auxiliary materials, which indicates that there is a difference between the combinations of different scalp promoters; as can be seen from FIG. 5, the transdermal results were similar when the drug loading was the same, and the transdermal results were similar in experimental group 16 and comparative example 13 (3-month precipitation), and experimental group 15 and comparative example 15 (6-month precipitation). High drug loading can enhance transdermal efficacy, as demonstrated in experimental group 15 and experimental group 16. However, the transdermal effect was affected by the increase in drug loading but the stability was not maintained, as in comparative example 14 (precipitation for 1 month). Since the transdermal experiments were performed after 1 month of placement of the patches, the results of comparative examples 13 and 15 were still acceptable, but the results were predicted for 3 months and 6 months. The results show that when the gel patch formulation contains the same content (0.5 wt%) of dimethylformamide, crotamiton, azone, glycerol, propylene glycol and peppermint oil (0.4% and 0.1%), eucalyptol and dimethyl sulfoxide, the in vitro transdermal rate is obviously higher than that of the gel patch formulation containing lauric acid, oleic acid, sodium laurylsulfate, N-2-methyl-pyrrolidone and phospholipids, and the statistics are significant. Although oleic acid and phospholipids are commonly used in gel patch formulations as transdermal penetration enhancers in vitro, the effect of the penetration enhancers is not apparent in the transdermal behavior of glucosamine sulfate formulations in vitro. The above results further demonstrate that the complete permeation of the drug in the skin is not sufficient as judged by the results of in vitro release experiments, and the penetration ability in the skin after the drug is released from the matrix is more important. According to Japanese "drug bioequivalence test-correspondence (Japanese guidelines)" it is known that the disappearance of a drug from the stratum corneum in a topically-active skin preparation follows a first order kinetics process, and that the release rate of the drug from the matrix of the preparation is almost constant and follows a zero order kinetics process. Thus, after a drug reaches steady state over 4-5 half-lives, the concentration of the drug in the stratum corneum remains constant, and the time to reach steady state depends on the half-life of the drug metabolizing in the stratum corneum and not on the rate of drug release from the matrix. In combination with the experimental results, we only examined the in vitro transdermal release conditions of different prescriptions.
Adhesion performance test
The adhesion and peel strength measurements were performed on the present example 1 and comparative example 10 according to the rule 0952 adhesion measurement method of the fourth edition of the chinese pharmacopoeia of 2020 edition, with the exception that the coating thickness was doubled for comparative example 10, which was the same recipe as for example 1, and the results are shown in table 4:
TABLE 4 Table 4
In the present specification, each embodiment is described in a progressive manner, and each embodiment is mainly described in a different point from other embodiments, and identical and similar parts between the embodiments are all enough to refer to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A composition for promoting sustained release of glucosamine comprising: transdermal enhancers and PVA; wherein the dosage of PVA is 2.5-10%, and the mass ratio of the transdermal enhancer to PVA is 1:20-2:1; the PVA includes: EG-03P, EG-05P, EG-05PW or GL05.
2. A composition for enhancing sustained release of glucosamine according to claim 1, wherein the transdermal enhancer comprises: any one or a combination of a plurality of polyols, terpenes, sulfoxides, azones, amines and amides.
3. A composition for promoting sustained release of glucosamine according to claim 2, wherein the polyhydric alcohol comprises: propylene glycol or glycerol; the terpenes include eucalyptol, d-limonene or nerolidol; the sulfoxides include dimethyl sulfoxide or decyl methyl sulfoxide; the azones include azone, 5-methyl-2-pyrrolidone or 1, 5-dimethyl-2-pyrrolidone; the amine and amide include urea, dodecyl-N, N-dimethylaminoethyl ester, dimethylformamide, dimethylacetamide or crotamiton.
4. Use of a composition for promoting sustained release of glucosamine according to any one of claims 1-3 for the preparation of a glucosamine gel patch.
5. The glucosamine gel patch is characterized by comprising the following raw materials in percentage by mass: comprises 0.5-5% of glucosamine, 2.5-10% of plasticizer, 15-25% of framework material, 5-10% of filler, 0.1-1% of solubilizer, 0.5-1% of thickener, 25-35% of humectant, 0.5-2% of pH regulator, 1-5% of transdermal enhancer, 0.1-0.5% of cross-linking agent and the balance of water.
6. The glucosamine gel patch of claim 5, wherein the glucosamine is glucosamine sulfate.
7. The glucosamine gel patch of claim 5, wherein the matrix material is any one or a combination of sodium polyacrylate, polyacrylic acid and polyacrylate; the filler is titanium dioxide or talcum powder or a combination of the titanium dioxide and talcum powder; the solubilizer is polysorbate 80; the thickener is carboxymethyl cellulose or sodium carboxymethyl cellulose; the humectant is glycerin, propylene glycol or sorbitol; the pH regulator is disodium edentate, tartaric acid, citric acid, malic acid or lactic acid; the cross-linking agent is aluminum hydroxide or aluminum glycollate.
8. A method of preparing a glucosamine gel patch as in any one of claims 5-7, wherein the process comprises:
1) Weighing the glucosamine with the formula amount, dissolving the solubilizer in water, and stirring at the rotating speed of 200-500 rpm until the glucosamine is completely dissolved;
2) Weighing framework materials, filling agents, thickening agents and transdermal promoters according to the formula amount, putting the framework materials, the filling agents, the thickening agents and the transdermal promoters into a reaction kettle, stirring for 10-50 min, adding the humectant while stirring until uniform paste is formed, slowly adding the main medicine solution, stirring for 10-30 min, and finally adding the cross-linking agents, the PVA aqueous solution and the pH regulator under the stirring condition, and stirring for 10-30 min until white to white-like uniform paste is formed.
3) Uniformly coating the paste between a backing layer and a protective layer, cutting into proper size and shape according to the requirement, putting into proper package, and standing for 14d to obtain the glucosamine gel paste.
9. The method for preparing the glucosamine gel paste as set forth in claim 8, wherein in the step 2), the stirring speed is based on the principle of first being fast and then being slow, the initial stirring speed is 400-600 RPM, and the later stirring speed is 100-300 RPM.
10. The method of claim 8, wherein in step 3), the coating is applied to a clear thickness of 1mm.
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08774B1 (en) * | 1990-11-09 | 1996-01-10 | ||
| CN1634088A (en) * | 2004-10-25 | 2005-07-06 | 苏波 | Novel method for externally applied glucosamine for the treatment of arthritis and externally applied formulation of glucosamine |
| KR20080066253A (en) * | 2007-01-11 | 2008-07-16 | 주식회사 티디에스팜 | Transdermal preparation comprising glucosamine for treating arthritis |
| CN102614111A (en) * | 2012-04-05 | 2012-08-01 | 苏州豫源生物医药有限公司 | Glucosamine gel and preparation method thereof |
| CN102626401A (en) * | 2012-04-28 | 2012-08-08 | 佛山拜澳生物科技有限公司 | Hydrogel paste and preparation method thereof |
| US20170189443A1 (en) * | 2014-02-24 | 2017-07-06 | C. Lowell Parsons | Compositions and methods for treatment of diseases and conditions employing oral administration of sodium pentosan polysulfate and other pentosan polysulfate salts |
| CN111372551A (en) * | 2017-12-27 | 2020-07-03 | 株式会社高丝 | Gel sheet for skin adhesion |
| CN111565720A (en) * | 2017-11-16 | 2020-08-21 | 日本新药株式会社 | Controlled release formulations |
| CN111773201A (en) * | 2020-08-19 | 2020-10-16 | 扬州中宝药业股份有限公司 | Etamsylate gel patch and preparation method thereof |
| CN113648297A (en) * | 2021-08-16 | 2021-11-16 | 乐明药业(苏州)有限公司 | Pharmaceutical composition and patch containing flurbiprofen |
| CN115554276A (en) * | 2021-12-31 | 2023-01-03 | 上海达铸健康科技有限公司 | Joint maintenance patch composition and preparation method thereof |
-
2023
- 2023-05-08 CN CN202310509966.7A patent/CN116459238B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08774B1 (en) * | 1990-11-09 | 1996-01-10 | ||
| CN1634088A (en) * | 2004-10-25 | 2005-07-06 | 苏波 | Novel method for externally applied glucosamine for the treatment of arthritis and externally applied formulation of glucosamine |
| KR20080066253A (en) * | 2007-01-11 | 2008-07-16 | 주식회사 티디에스팜 | Transdermal preparation comprising glucosamine for treating arthritis |
| CN102614111A (en) * | 2012-04-05 | 2012-08-01 | 苏州豫源生物医药有限公司 | Glucosamine gel and preparation method thereof |
| CN102626401A (en) * | 2012-04-28 | 2012-08-08 | 佛山拜澳生物科技有限公司 | Hydrogel paste and preparation method thereof |
| US20170189443A1 (en) * | 2014-02-24 | 2017-07-06 | C. Lowell Parsons | Compositions and methods for treatment of diseases and conditions employing oral administration of sodium pentosan polysulfate and other pentosan polysulfate salts |
| CN111565720A (en) * | 2017-11-16 | 2020-08-21 | 日本新药株式会社 | Controlled release formulations |
| CN111372551A (en) * | 2017-12-27 | 2020-07-03 | 株式会社高丝 | Gel sheet for skin adhesion |
| CN111773201A (en) * | 2020-08-19 | 2020-10-16 | 扬州中宝药业股份有限公司 | Etamsylate gel patch and preparation method thereof |
| CN113648297A (en) * | 2021-08-16 | 2021-11-16 | 乐明药业(苏州)有限公司 | Pharmaceutical composition and patch containing flurbiprofen |
| CN115554276A (en) * | 2021-12-31 | 2023-01-03 | 上海达铸健康科技有限公司 | Joint maintenance patch composition and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| MUHAMMAD SHAHZAD RASHEED，等: "Formulation, characterization of glucosamine loaded transfersomes and in vivo evaluation using papain induced arthritis model", SCIENTIFIC REPORTS, vol. 12, pages 1 - 13 * |
| 刘萍;: "羧甲基壳聚糖对雌二醇凝胶透皮吸收促进作用的研究", 中国药师, vol. 12, no. 08, pages 1025 - 1028 * |
| 郭香琴: "盐酸氨基葡萄糖巴布剂的制备与质量研究", 中国优秀硕士学位论文全文数据库 医药卫生科技辑, no. 5, pages 079 - 18 * |
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