CN116687840B - Gel preparation for treating eye symptoms and preparation method thereof - Google Patents
Gel preparation for treating eye symptoms and preparation method thereof Download PDFInfo
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- CN116687840B CN116687840B CN202310972469.0A CN202310972469A CN116687840B CN 116687840 B CN116687840 B CN 116687840B CN 202310972469 A CN202310972469 A CN 202310972469A CN 116687840 B CN116687840 B CN 116687840B
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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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- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- 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
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- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本申请涉及治疗眼部疾病的药物制剂技术领域，具体提供了一种用于治疗眼部病状的凝胶制剂及其制备方法，所述凝胶制剂包括药物载体、药物成分和赋形成分；药物载体优选为丝素蛋白，对药物成分提供结合位点和/或包埋作用，载药载体和药物成分的质量比为1：（0.3‑2），赋形成分包括海藻酸钠和钙离子，实现药物成分的缓释作用，进一步优化凝胶制剂制备中药物载体、药物成分和赋形成分的相对用量，使本申请的凝胶制剂同时具有根源性治疗、药物短期释放和缓释效果好、保水性高、延展性好、结构稳定性优异、粘度稳定性强且与眼部环境生物相容性好的特点，有效减少了眼部的施药次数。
This application relates to the technical field of pharmaceutical preparations for treating eye diseases, and specifically provides a gel preparation for treating eye conditions and a preparation method thereof. The gel preparation includes a pharmaceutical carrier, pharmaceutical ingredients and excipients; pharmaceuticals The carrier is preferably silk fibroin, which provides binding sites and/or entrapment effects for drug ingredients. The mass ratio of drug carrier and drug ingredients is 1: (0.3-2). The excipient ingredients include sodium alginate and calcium ions. Realize the sustained release effect of drug ingredients, and further optimize the relative dosage of drug carriers, drug ingredients and excipients in the preparation of gel preparations, so that the gel preparation of the present application has root treatment, short-term drug release and sustained release effects, It has the characteristics of high water retention, good ductility, excellent structural stability, strong viscosity stability and good biocompatibility with the eye environment, which effectively reduces the number of eye applications.
Description
Technical Field
The application relates to the technical field of pharmaceutical preparations for treating eye diseases, in particular to a gel preparation for treating eye symptoms and a preparation method thereof.
Background
According to epidemiological reports, the incidence rate of eye diseases such as xerophthalmia, photophobia, glaucoma, keratitis, retinitis and the like in China is increased, wherein the dry eye disease is more remarkable. Dry eye is caused by mismatch in tear production, drainage and evaporation rates, and is caused by a number of factors, such as: complications after eye treatment, irritation of the eye by the external environment, overexposure and use before electronic products, and the like. At present, the medicine for treating xerophthalmia is mainly artificial tears, but the artificial tears have short retention time in eyes, can maintain the medicine effect after repeated use, and lack continuous lubrication. In addition, the artificial tears can only play a role in lubrication, can not treat the eye focus environment in pathology, and have the defect of treating both symptoms and root causes.
Chinese patent CN100340233C discloses an ophthalmic composition comprising a synergistic combination of three polymers, which adopts the technical scheme that the combination of hydroxypropyl methylcellulose and other two polymers is used as a carrier for ophthalmic drugs, and optimizes the relative amount to improve the viscosity stability of the composition; however, the technical solution does not describe the rapid release and slow release effect of the composition on the drug. Chinese patent CN100463681C discloses an artificial tear for treating dry eye, which comprises hydroxypropyl methylcellulose, dextran-70 and l-carnitine as main components, and in embodiments discloses the composition as a solution, emulsion and gel, but for the latter two existing forms, it does not disclose how the problems of structural stability and flowability of the gel-like substance are solved.
Therefore, the prepared material which has the advantages of radical treatment, good short-term release and sustained release effects of the drug, high water retention, good ductility, excellent structural stability, strong viscosity stability and good biocompatibility with the ocular environment has very important significance in treating ocular diseases (especially dry eye).
Disclosure of Invention
In order to solve the technical problems, the application firstly provides a gel preparation for treating eye symptoms, which comprises a drug carrier, a drug component and a forming component.
Further, the pharmaceutical ingredient is a medicament for treating ocular diseases, which is commercially available; such as, for example, glaucoma treating, such as, for example, subtilisin, sha Bide, timolol, levobetaxolol, ciprofloxacin, tobramycin, etc., such as, for example, rapamycin for the treatment of macular edema of the retina, such as, for example, antagonists for the treatment of dry eye, such as, for example, pirenzepine, oxyphenium, etc., for the treatment of myopia.
In one embodiment, the pharmaceutical composition is an antagonist, such as an NK1R antagonist, for the treatment of dry eye.
Further, the drug carrier is capable of providing binding sites and/or entrapment for the drug component.
Further, the drug carrier structurally comprises both hydrophilic and hydrophobic portions.
Further, the drug carrier has excellent biocompatibility.
Further, the drug carrier is selected from any one or a combination of several of silk fibroin, fibrin and globulin.
Preferably, the drug carrier is a silk fibroin, and is at least one selected from spider silk fibroin, silk fibroin and insect silk protein. Silk fibroin contains a large number of hydrophobic amino acid residues such as glycine, alanine and the like in the primary structural sequence, and contains some hydrophilic amino acid residues such as tyrosine, serine and the like. From the aspect of the hydrophobicity of the side chains, the hydrophobic side chains and the hydrophilic side chains of amino acids in the silk fibroin molecular chains are irregularly arranged alternately; the amino acid residues rich in hydrophobicity enable the silk fibroin molecules to easily form beta-sheet in aqueous solution to precipitate, and the amino acid residues with long side chain hydrophilicity also endow the silk fibroin with better water solubility under specific conditions. The hydrophobic and hydrophilic chain blocks in the amino acid sequence of silk fibroin are arranged so that they form micelle-like structures in aqueous solution. The medicine can be combined with the silk fibroin through non-covalent interactions such as electrostatic attraction, hydrogen bond, conjugation and the like, and meanwhile, the micelle embedding effect of the silk fibroin also plays a good slow release role on the medicine, so that the administration frequency of the gel preparation is effectively reduced.
Further preferably, the silk fibroin is silk fibroin.
Furthermore, the fibroin is liquid or solid, can be self-made or purchased, and the application does not strictly require the fibroin.
Further, the preparation method of the fibroin comprises the steps of silk degumming and protein purification.
In one embodiment, the silk fibroin is prepared by the process of:
(1) Degumming silk: the silk is peeled into small pieces according to 1g: (30-80 mL of the silk flakes are put into a sodium carbonate solution according to the mass-volume ratio and boiled for 20-60min; and taking out the silk, pressing and dewatering, and repeatedly flushing with deionized water until the water quality is clear. Repeating the boiling and washing steps for at least 2 times, and drying silk to obtain crude silk fibroin;
(2) Protein purification: preparing a mixed solution of calcium chloride, ethanol and water, and mixing the crude silk fibroin according to 1g: (10-40) placing the mixture into the mixed solution according to the mass-volume ratio, heating to 70-90 ℃ and keeping stirring for 1-5h, and dissolving to obtain the mixed solution of silk fibroin; cooling to room temperature, dialyzing the mixed solution of silk fibroin for 48-96h; centrifuging at low temperature and high speed after dialysis is completed, discarding insoluble matters to collect liquid, and lyophilizing the liquid to obtain silk fibroin.
Further, the mass fraction of the sodium carbonate solution is 0.3-0.8%, and the solvent is water.
Further, in the mixed solution of calcium chloride, ethanol and water, the mass concentration of the calcium chloride is 38-45g/mL; the molar mass ratio of the ethanol to the water is 1: (3-5).
Further, the specification of the dialysis bag used in the dialysis in the step (2) is 10000Da-18000Da; preferably 14000Da.
Further, the high-speed centrifugal speed in the step (2) is 8000-10000rpm, and the centrifugal speed is 10-30min.
Further, the low temperature at the time of high-speed centrifugation in the step (2) is 2-6 ℃.
Further, the mass ratio of the silk fibroin to the medicine is 1: (0.3-2), preferably 1: (0.5-1.2).
Further, after the drug carrier has a distribution, fixation or embedding effect on the drug, the drug-carrier composite component is mixed with the excipient to prepare the gel preparation.
Further, the excipient includes, but is not limited to, at least one of chitosan and its derivatives, cellulose and its derivatives, gelatin, sodium hyaluronate, polyvinylpyrrolidone, cyclodextrin, sodium alginate.
Further, the excipient comprises sodium alginate.
Further, the forming component further comprises a positive divalent cation selected from Ca 2+ 、Zn 2+ 、Ba 2+ 。
Further, the source of the positive divalent cations is not critical, and there may be selected gluconate, halide, sulfate, acetate and the like.
In one embodiment, the positive divalent cation is Ca 2+ The method comprises the steps of carrying out a first treatment on the surface of the The Ca is 2+ Derived from calcium chloride and/or calcium gluconate, preferably calcium gluconate.
Further, the preparation method of the gel preparation comprises the following steps:
(1) Assembling of drug-carrier composite components: firstly, weighing a drug carrier, and adding MES solution to prepare carrier solution of 2-6 mg/mL; heating the carrier solution to 100-130 ℃ and preserving heat for 1-3h, cooling, and adding 0.5-3mg/mL of solution containing the drug component into the carrier solution; then the mixed solution is placed at 35-37 ℃ for oscillation, frozen and thawed at low temperature, and finally dialyzed; obtaining the drug-carrier nanoparticle solution;
(2) Preparation of gel preparation: and (3) ultrasonically mixing the drug-carrier nano particle solution in the step (1) and the solution containing the excipient according to a certain volume ratio.
Further, the pH value of the MES solution is 4.8-7; preferably 5.
Further, in the mixed solution in the step (1), the mass ratio of the drug carrier to the drug ingredient is 1: (0.3-2); preferably 1: (0.5-1.2); more preferably 1:0.75. the application needs to strictly control the relative dosage of the carrier and the drug component so as to improve the encapsulation effect and the sustained release effect of the carrier on the drug, and also needs to ensure the viscosity stability of the gel preparation. Because when the content of the pharmaceutical ingredient is too high, on the one hand, the interaction between the pharmaceutical ingredient, particularly the NK1R antagonist, and the pharmaceutical carrier such as silk fibroin is very strong, and the concentration is too high, the coagulation phenomenon is caused, on the other hand, the combination amount of the silk fibroin and the pharmaceutical ingredient is too high, sufficient combination sites are not reserved for the silk fibroin and the excipient, and the intermolecular action for stabilizing the viscosity of the system is lacking, so that the viscosity of the gel system is mostly and even completely maintained by the excipient, and the viscosity stability is low. When the concentration of the drug carrier is too high, the particle size of the drug-carrier nano particles is obviously increased, which is not beneficial to slow release of the drug and easy coagulation, and when the concentration is too low, the particle size of the drug-carrier nano particles is too small, which is not beneficial to short-term release of the drug. Only the mass ratio of the drug carrier to the drug component is 1: (0.3-2), the carrier contains specific and proper active site, and the active site, the medicine component and the excipient have intermolecular effect, so that the medicine component has good encapsulation and sustained release effects, and the viscosity stability of the gel system reaches the optimal value.
Further, in the step (1), the oscillation speed is 120-200r/min, and the oscillation time is 1-2 days.
Further, in the step (1), the low temperature is-85 to-70 ℃, and the low temperature freezing time is 6-10 hours. The movement of the silk fibroin is limited at low temperature, the particle size of the formed nano particles is uniform, but the particle size is obviously increased and even coagulation is generated after the time is too long.
Further, in the step (1), the dialysis time is 12-24 hours.
In a preferred embodiment, the step (1) is: firstly, weighing silk fibroin, and adding MES solution with the pH value of 4.8-7 to prepare silk fibroin solution with the concentration of 2-6 mg/mL; heating silk fibroin solution to 100-130 ℃ and preserving heat for 1-3h, cooling, and adding a certain volume of 0.5-2mg/mL of antagonist solution into the silk fibroin solution; then placing the mixed solution in a temperature of 35-37 ℃ for shaking for 1-2 days, freezing and thawing at low temperature, and finally dialyzing for 12-24 hours; thus obtaining the solution of the antagonist-silk fibroin nano particles.
Further, the volume of the antagonist solution is 1-10 times of the volume of the silk fibroin solution; further preferably 2 to 5 times, more preferably 3 times.
Further, the excipient comprises sodium alginate and calcium ions.
In a preferred embodiment, the step (2) specifically includes: mixing the drug-carrier nanoparticle solution in (1), 0.5-2wt% sodium alginate aqueous solution and 0.25-1wt% calcium ion-containing solution according to the following formula 1:1: (0.18-0.72) by volume ratio. The application uses sodium alginate and calcium ions to form a crosslinking system, but when the concentration of sodium alginate or calcium ions is too high, the gel forming speed is too high, and the gel forming is uneven. The gel preparation has excellent fluidity, structural uniformity, gel state and easy dripping performance only when being matched with a specific volume ratio under a specific mass concentration.
Preferably, the volume ratio of the drug-carrier nanoparticle solution, the 0.5-2wt% sodium alginate aqueous solution and the 0.25-1wt% calcium ion-containing solution is 1:1:0.36.
further, the mass concentration of the drug-carrier nano particles in the drug-carrier nano particle solution is 1-2mg/mL, the mass fraction of sodium alginate in the sodium alginate aqueous solution is 0.8-1.5%, and the mass fraction of calcium ions in the calcium ion-containing solution is 0.3-0.7%.
In a preferred embodiment, in the gel preparation, the mass concentration of the drug-carrier nano particles in the drug-carrier nano particle solution is 1.75mg/mL, the mass fraction of sodium alginate in the sodium alginate aqueous solution is 1%, and the mass fraction of calcium ions in the calcium ion-containing solution is 0.5%.
Further, the gel formulations of the present application may be applied to the eye using a drip coating method.
Advantageous effects
1. According to the application, the silk fibroin with a special molecular structure and biocompatibility is used for fixing and/or embedding and packaging the medicinal components, and the relative dosage of the silk fibroin and the medicinal components is optimized, so that the short-term release and long-term slow release effects of the medicament are improved, the medicament persistence can be maintained for 12 hours, the use requirement of once-a-day administration can be met, the viscosity stability of a gel system can be improved, and the storage performance of the gel system can be improved;
2. the application adopts special shaping components, improves the water retention effect of the gel material, further optimizes and adjusts the usage amount of the shaping components, and ensures that the gel system has excellent fluidity, structural uniformity, gel state and easy dripping performance by designing a unique gel pore structure;
3. the gel preparation prepared by the application has excellent gel state, can ensure the effective residence time and the water retention effect of the medicine, has excellent ductility and fluidity, has the effects of good comfort, no greasy feeling, easy washing and removal, and can absorb tissue exudates, and the like, and has very obvious advantages in treating eye diseases.
Drawings
Fig. 1: DLS map of SF@CP group;
fig. 2: TEM images of SF@CP groups;
fig. 3: particle size change graphs of SF@CP groups in different time periods;
fig. 4: ultraviolet spectrum test graphs of different groups;
fig. 5: an encapsulation rate and a load rate result histogram of the SF@CP group to the CPs, wherein EE in the graph refers to the encapsulation rate and LE refers to the load rate;
fig. 6: g 'and G "for different groups of graphs of the trend of increasing shear strain (room temperature, fixed frequency 1Hz condition, G' for storage modulus, G" for loss modulus);
fig. 7: a plot of viscosity versus time for different groups at a particular frequency and shear force;
fig. 8: a graph of the release effect of sf@cp@gel group of example 1 on drug CP;
fig. 9: CKK-8 test result diagram; wherein a is the comparison result of the SF group and the blank control group, b is the comparison result of the Gel group and the blank control group, and c is a comparison result graph of different Gel concentrations; CKK-8 test cells are ocular corneal epithelial cells;
fig. 10: ROS fluorescence profiles in corneal epithelial cells within different groups;
fig. 11: cell mobility histogram at 24h for different groups of cells in cell scratch experiments;
fig. 12: SEM images of different example gel formulations; wherein the three left panels are the gel formulation of example 4, the three middle panels are the gel formulation of example 1, and the three right panels are the gel formulation of example 5;
fig. 13: example 8 SEM images of sf@cp prepared in step (1);
fig. 14: SEM image of sf@cp prepared in example 9 step (1).
Detailed Description
Examples
Example 1
The present embodiments provide a gel formulation for treating an ocular condition, the gel formulation comprising a drug carrier, a drug ingredient, and a excipient ingredient;
the drug carrier is silk fibroin; the medicine component is an antagonist CP99994; the forming component comprises sodium alginate and a solution containing calcium ions;
the preparation method of the gel preparation comprises the following steps:
(1) Firstly, weighing silk fibroin, and adding MES solution with pH value of 5 to prepare silk fibroin solution with concentration of 4 mg/mL; heating the silk fibroin solution to 120 ℃ and preserving heat for 1.5h, and adding an antagonist CP99994 aqueous solution which is 3 times of the volume of the silk fibroin solution and is 1mg/mL after cooling; then placing the mixed solution at 37 ℃ and 150r/min, vibrating for 1 day, freezing at-80 ℃ for 8 hours, thawing, and finally dialyzing for 12 hours; a blue transparent solution of silk fibroin-antagonist nanoparticles (marked as SF@CP NPs) can be obtained, wherein the mass concentration of the silk fibroin-antagonist nanoparticles is 1.75mg/mL, and the mass ratio of the silk fibroin to the drug is 1:0.75.
(2) The SF@CP NPs solution, 1wt% sodium alginate aqueous solution and 0.5wt% calcium gluconate solution in the step (1) are prepared according to the following steps: 1: and (3) carrying out ultrasonic mixing according to the volume ratio of 0.36.
The preparation method of the silk fibroin comprises the following steps:
(1) Degumming silk:
the silk is peeled into small pieces according to 1g:50mL of the flaky silk is put into a sodium carbonate aqueous solution with the mass fraction of 0.5% and boiled for 30min; stirring the obtained silk with a clean glass rod to form a mass, and pressing to remove water; and adding deionized water, and repeatedly washing for 3 times until the water quality is clear after washing. Repeating the boiling-washing steps for 2 times, draining excessive water from the degummed silk for 3 times, putting the degummed silk into an 80 ℃ oven for 3 hours, and drying to obtain crude silk fibroin;
(2) Protein purification:
130mL of a mixed solution of calcium chloride, ethanol and water is prepared, wherein the mass concentration of the calcium chloride in the mixed solution is 42.7g/mL, and the molar mass ratio of the ethanol to the water is 1:4, a step of;
crude silk fibroin was purified according to 1g: placing 20mL of the silk fibroin into the mixed solution according to the mass-volume ratio, heating to 90 ℃ and keeping stirring for 2 hours, and dissolving to obtain the mixed solution of silk fibroin; naturally cooling to room temperature, dialyzing with 14000Da dialysis bag (which is boiled in boiling water for 10min, sterilized in advance with clip, and should not be filled with mixed solution too much, and should leave 1/3 space) for 72 hr (water surface should cover dialysis bag, changing water every 4 hr, and collecting silk fibroin solution after dialysis is completed); centrifuging at 9000rpm for 15min at 4deg.C after dialysis, discarding insoluble substances to collect liquid, and lyophilizing to obtain silk fibroin.
Example 2
The present embodiments provide a gel formulation for treating an ocular condition, the gel formulation comprising a drug carrier, a drug ingredient, and a excipient ingredient;
the drug carrier is silk fibroin; the medicine component is an antagonist CP99994; the forming component comprises sodium alginate and a solution containing calcium ions;
the preparation method of the gel preparation comprises the following steps:
(1) Firstly, weighing silk fibroin, and adding MES solution with pH value of 6 to prepare silk fibroin solution with concentration of 2 mg/mL; heating the silk fibroin solution to 130 ℃ and preserving heat for 1h, and adding an antagonist aqueous solution with the volume of 0.5mg/mL which is 2 times that of the silk fibroin solution after cooling; then placing the mixed solution at 37 ℃ and 120r/min, vibrating for 2 days, freezing at-80 ℃ for 6 hours, thawing, and finally dialyzing for 24 hours; a solution of the silk fibroin-antagonist nanoparticles (marked as SF@CP NPs) can be obtained, wherein the mass concentration of the silk fibroin-antagonist nanoparticles is 1.0mg/mL, and the mass ratio of the silk fibroin to the drug is 1:0.5;
(2) The SF@CP NPs solution in (1), 1.5wt% sodium alginate aqueous solution and 0.7wt% calcium gluconate solution were mixed according to a ratio of 1:1: and (3) carrying out ultrasonic mixing according to the volume ratio of 0.36.
The preparation method of the silk fibroin comprises the following steps:
(1) Degumming silk:
the silk is peeled into small pieces according to 1g: the flaky silk is put into a sodium carbonate aqueous solution with the mass fraction of 0.5% according to the mass-volume ratio of 30mL and boiled for 20min; stirring the obtained silk with a clean glass rod to form a mass, and pressing to remove water; and adding deionized water, and repeatedly washing for 3 times until the water quality is clear after washing. Repeating the boiling-washing steps for 2 times, draining excessive water from the degummed silk for 3 times, putting the degummed silk into an 80 ℃ oven for 3 hours, and drying to obtain crude silk fibroin;
(2) Protein purification:
130mL of a mixed solution of calcium chloride, ethanol and water is prepared, wherein the mass concentration of the calcium chloride in the mixed solution is 45g/mL, and the molar mass ratio of the ethanol to the water is 1:3, a step of;
crude silk fibroin was purified according to 1g: placing 10mL of the silk fibroin into the mixed solution according to the mass-volume ratio, heating to 70 ℃, keeping stirring for 5 hours, and dissolving to obtain the mixed solution of silk fibroin; naturally cooling to room temperature, dialyzing with 10000Da dialysis bag (which is boiled in boiling water for 10min, sterilized in advance with clip, and should not be filled with mixed solution too much and should leave 1/3 space) for 72 hr (water surface should cover dialysis bag, changing water every 4 hr, and collecting silk fibroin solution after dialysis is completed); centrifuging at 8000rpm at 4deg.C for 30min after dialysis, discarding insoluble substances to collect liquid, and lyophilizing to obtain silk fibroin.
Example 3
The present embodiments provide a gel formulation for treating an ocular condition, the gel formulation comprising a drug carrier, a drug ingredient, and a excipient ingredient;
the drug carrier is silk fibroin; the medicine component is an antagonist CP99994; the forming component comprises sodium alginate and a solution containing calcium ions;
the preparation method of the gel preparation comprises the following steps:
(1) Firstly, weighing silk fibroin, and adding MES solution with pH value of 4.8 to prepare silk fibroin solution with concentration of 5 mg/mL; heating the silk fibroin solution to 100 ℃ and preserving heat for 3 hours, and adding an antagonist aqueous solution with the volume of 1.5mg/mL which is 5 times that of the silk fibroin solution after cooling; then placing the mixed solution at 37 ℃ and 200r/min, vibrating for 1 day, freezing at-80 ℃ for 10 hours, thawing, and finally dialyzing for 24 hours; a solution of the silk fibroin-antagonist nanoparticles (marked as SF@CP NPs) can be obtained, wherein the mass concentration of the silk fibroin-antagonist nanoparticles is 2.08mg/mL, and the mass ratio of the silk fibroin to the drug is 1:1.5;
(2) The SF@CP NPs solution in (1), 0.8wt% sodium alginate aqueous solution and 0.3wt% calcium ion-containing solution were prepared according to a ratio of 1:1: and (3) carrying out ultrasonic mixing at a volume ratio of 0.25.
The preparation method of the silk fibroin comprises the following steps:
(1) Degumming silk:
the silk is peeled into small pieces according to 1g:80mL of the flaky silk is put into a sodium carbonate aqueous solution with the mass fraction of 0.5% and boiled for 60min; stirring the obtained silk with a clean glass rod to form a mass, and pressing to remove water; and adding deionized water, and repeatedly washing for 3 times until the water quality is clear after washing. Repeating the boiling-washing steps for 2 times, draining excessive water from the degummed silk for 3 times, putting the degummed silk into an 80 ℃ oven for 3 hours, and drying to obtain crude silk fibroin;
(2) Protein purification:
130mL of a mixed solution of calcium chloride, ethanol and water is prepared, wherein the mass concentration of the calcium chloride in the mixed solution is 38g/mL, and the molar mass ratio of the ethanol to the water is 1:5, a step of;
crude silk fibroin was purified according to 1g: putting 40mL of the silk fibroin into the mixed solution according to the mass-volume ratio, heating to 90 ℃ and keeping stirring for 1h, and dissolving to obtain the mixed solution of silk fibroin; naturally cooling to room temperature, dialyzing with 18000Da dialysis bag (which is boiled in boiling water for 10min, sterilized in advance with clip, and should not be filled with mixed solution too much, and should leave 1/3 space) for 96 hr (water surface should cover dialysis bag, changing water every 4 hr, and collecting silk fibroin solution); centrifuging at 4deg.C and 10000rpm for 10min, discarding insoluble substances, collecting liquid, and lyophilizing to obtain silk fibroin.
Example 4
Substantially identical to example 1, except that: in the preparation process of the gel preparation, the volume ratio of SF@CP NPs solution, 1wt% sodium alginate aqueous solution and 0.5wt% calcium gluconate solution is 1:1:0.18.
example 5
Substantially identical to example 1, except that: in the preparation process of the gel preparation, the volume ratio of SF@CP NPs solution, 1wt% sodium alginate aqueous solution and 0.5wt% calcium gluconate solution is 1:1:0.72.
example 6
Substantially identical to example 1, except that: in the preparation process of the gel preparation, the mass fraction of sodium alginate in the sodium alginate aqueous solution is 2%.
Example 7
Substantially identical to example 1, except that: in the preparation process of the gel preparation, the mass fraction of calcium gluconate in the calcium gluconate solution is 1%.
Example 8
Substantially identical to example 1, except that: the mass concentration of the antagonist CP99994 aqueous solution is 3.33mg/mL.
Example 9
Substantially identical to example 1, except that: -80 ℃ in the step (1) is replaced by-20 ℃.
Performance test method and results:
the parallel experimental groups and the preparation of the application are respectively described below:
1. silk fibroin group (noted SF): weighing silk fibroin, and adding MES solution with pH value of 5 to prepare silk fibroin solution of 1 mg/mL; heating silk fibroin solution to 120deg.C, maintaining the temperature for 2 hr, cooling to room temperature, oscillating silk fibroin solution at 37deg.C and 150r/min for 1 day, freezing at-80deg.C for 8 hr, thawing, and dialyzing for 12 hr; thus obtaining the solution of the silk fibroin nano particles as silk fibroin groups. The preparation method of the silk fibroin is the same as that of the example 1.
2. Gel group (noted Gel): respectively preparing 1wt% sodium alginate aqueous solution and 0.5wt% calcium gluconate solution, and then according to the following steps: mixing sodium alginate aqueous solution and calcium gluconate solution in a volume ratio of 0.36, and performing ultrasonic mixing.
3. Silk fibroin drug-loaded nanoparticle (i.e., antagonist-loaded silk fibroin) group (denoted sf@cp): in the same manner as in step (1) of example 1.
4. Silk fibroin gel set (noted sf@gel): a solution of silk fibroin nanoparticles (i.e. SF group), 1wt% sodium alginate aqueous solution and 0.5wt% calcium gluconate solution were mixed according to 1:1: and (3) carrying out ultrasonic mixing according to the volume ratio of 0.36.
The gel preparation prepared in example 1 above was designated as SF@CP@gel group (experimental group).
(II) test method and results
1. Dimensional stability of silk fibroin drug-loaded nanoparticles: and analyzing the particle size change of the silk fibroin drug-loaded nano particles within 72 hours at the beginning by adopting a transmission diagram, and judging the dimensional stability of the silk fibroin drug-loaded nano particles.
Test results: from the DLS (see fig. 1) and TEM (see fig. 2) images of sf@cp: the particle size of SF@CP in DLS is 122 nm; the transmission result shows that the shape of the drug-loaded silk fibroin is spherical, the size is 120 nm, and the particle size results are consistent. As can be seen from the graph of the particle size change of sf@cp over 72h (see fig. 3), the drug-loaded particles have good dimensional stability and are easy to deliver in vivo.
Fig. 13 is an SEM image of sf@cp prepared in step (1) of example 8, and the particle size distribution of the nanoparticles is seen to be uneven and the particles are seriously aggregated in the right image.
FIG. 14 is an SEM image of SF@CP prepared in step (1) of example 9, which shows that the SF@CP prepared by the method is basically random flocculent and has few nanoparticles; the silk fibroin carrier cannot generate good fixing and encapsulating effects on the medicine CP, and is unfavorable for slow release performance.
2. Encapsulation and drug loading rate of silk fibroin drug-loaded nanoparticles: and (5) ultraviolet spectrum testing.
Test results: according to the ultraviolet spectrum test curve (see fig. 4), compared with the single silk fibroin group, the drug-loaded nanoparticle group has a characteristic absorption peak of the drug CP at 275 nm, which indicates successful combination or encapsulation of the drug CP by the silk fibroin nanoparticle (Zeta potential test and nuclear magnetic hydrogen spectrum test confirm the above results); the drug loading rate and the encapsulation efficiency of the drug are tested by utilizing an ultraviolet spectrum, and the test result (see figure 5) shows that the encapsulation efficiency and the loading rate of the drug CP in the drug-loaded nanoparticle group are 71.7 percent and 15.2 percent respectively; the application is illustrated that by selecting a specific drug carrier, namely silk fibroin, and optimizing the relative content of the silk fibroin and the carrier, the carrier has good encapsulation and loading effects on the drug CP, and is beneficial to the residence of the drug in the ocular environment and the continuous exertion of the drug effect.
3. Gel state analysis: when the storage modulus G ' is far greater than the loss modulus G ' ', the material is mainly elastically deformed, so the material is solid; when G ' ' is far greater than G ', the material is mainly subjected to viscous deformation, so that the material is in a liquid state; when G ' and G ' ' are the same, the material is semi-solid, and the hydrogel is a typical semi-solid substance, and has both solid and liquid properties.
Test results: from the gel state graphs (see fig. 6) of each group, it can be seen that: the gel has G ' and G ' ' distributed between 0.5-10 and Pa, and has comparable modulus, which indicates that the sample has both solid and liquid properties. Whereas from another aspect, G' < G "indicates that the sample is predominantly liquid in character, with a relatively high flowability; with increasing shear strain (γ), G' drops rapidly when γ >1%, and the post curve tends to stabilize, indicating initial presence of colloid in the sample, followed by partial or global collapse, and complete conversion to liquid. In summary, gels can be demonstrated to be semi-solid materials, but liquid properties predominate.
4. Viscosity stability: the viscosity of each set of gels was observed as a function of time at room temperature at a fixed frequency and shear strain.
Test results: referring to FIG. 7, the Gel viscosity of the Gel group, SF@gel group, SF@CP@gel group remained stable for 120 s; the viscosity increases significantly when silk fibroin and drug-loaded silk fibroin are added to Gel group, because a large number of hydroxyl groups and amino groups on silk fibroin can be combined with carboxyl groups and hydroxyl groups on sodium alginate side chains through hydrogen bonding, and thus the viscosity increases. The viscosity of the drug-loaded silk fibroin nanoparticle gel was slightly reduced compared to the silk fibroin gel, probably due to the binding of a portion of the silk fibroin to the drug, thus reducing the binding to sodium alginate, resulting in a reduced viscosity (consistent nuclear magnetic results).
The SF@CP@gel groups of examples 6 and 7 showed higher instability in the viscosity change during the test time.
5. Drug release test: the release of the drug in the drug-loaded silk fibroin gel was tested using ultraviolet light.
Test results: as can be seen from fig. 8, the gel preparation prepared in example 1 can release 60% of the CP antagonist at 6 hours, and can reach a release balance at 12 hours, and the cumulative release amount reaches 80%, which demonstrates that the gel preparation prepared in the application has an excellent drug release effect, and also proves that the gel preparation can meet the requirement of once-a-day administration.
The slow release effect on CP of the sf@cp@gel group gel formulations of example 6 and example 7 is far less than that of the gel formulation of example 1, wherein the sf@cp@gel group gel formulation of example 6 achieves 80% CP release at 9h and the sf@cp@gel group gel formulation of example 7 achieves 80% CP release at 11 h.
6. Cell viability test: the biocompatibility of the material was evaluated by testing the cell viability of ocular corneal epithelial cells in each group using CCK-8.
Test results: the results are shown in FIG. 9, where the OD values of the blank and silk fibroin nanoparticle groups in FIG. 9a are substantially identical, indicating that silk fibroin nanoparticles have no effect on cell viability. The results in fig. 9b, 9c show that cells of the blank and gel groups proliferate steadily over time, there is no significant difference, and cells proliferate steadily over time in different gel leach concentrations, there is no significant drop compared to the blank, thus indicating that the nano-and gel materials have no toxic side effects on cells.
7. Antioxidant capacity: the DCF probe and the active oxygen can be combined to form green fluorescence under a confocal microscope, and the larger the green fluorescence intensity is, the more the active oxygen content is.
Test results: in fig. 10, the leftmost blank is the normal cell group of hDPCs, and the blank under LSP is the oxidative damage model group in which the hDPCs cells were stimulated with LPS to undergo oxidative damage. As can be seen from fig. 10, the ROS fluorescence levels of the CP group and sf@cp@gel group were significantly reduced compared to the blank control (i.e., the oxidative damage model group) under the LSP, indicating that the sf@cp@gel group has excellent antioxidant activity.
8. Cell migration ability test: cell scratch experiments;
test results: in fig. 11, the leftmost blank is a normal cell group, and the LSP group is an oxidative damage model group in which oxidative damage is performed by using LPS-stimulated cells. As can be seen from fig. 11, the cell migration ability was significantly increased in the lps+cp group, lps+sf@cp@gel group, compared to the simple LPS group (i.e., the oxidative damage model group), indicating that the silk fibroin nanoparticles and gel material were not cytotoxic, and were able to promote cell migration and proliferation.
9. Gel morphology and structural uniformity: SEM image.
Test results: fig. 12 shows the morphology of the gel preparation of example 4 on the left, fig. 12 shows the morphology of the gel preparation of example 1 on the right, and fig. 12 shows the morphology of the gel preparation of example 5 on the right; comparing the above results, it can be seen that: the gel preparation prepared in example 1 has a more uniform pore structure, and the pore size structure is more suitable; thus, the gel formulation prepared in example 1 also had optimal flowability, drop-coating properties and sustained release properties.
Claims (3)
1. A method of preparing a gel formulation for treating an ocular condition, comprising the steps of:
(1) Assembling of drug-carrier composite components: firstly, weighing a drug carrier, and adding MES solution to prepare carrier solution of 2-6 mg/mL; heating the carrier solution to 100-130 ℃ and preserving heat for 1-3h, cooling, and adding 0.5-3mg/mL of solution containing the drug component into the carrier solution; then the mixed solution is placed at 35-37 ℃ for oscillation, frozen and thawed at-85 to-70 ℃ and finally dialyzed; obtaining the drug-carrier nanoparticle solution;
(2) Preparation of gel preparation: mixing the drug-carrier nanoparticle solution in (1), 0.8-1.5wt% sodium alginate aqueous solution and 0.3-0.7wt% calcium ion-containing solution according to the following formula 1:1: (0.18-0.72) by volume ratio;
the drug carrier is silk fibroin;
in the mixed solution in the step (1), the mass ratio of the drug carrier to the drug ingredient is 1: (0.3-2);
the mass concentration of the drug-carrier nano particles in the drug-carrier nano particle solution is 1-2mg/mL.
2. The method of preparing a gel formulation according to claim 1, wherein the volume ratio of drug-carrier nanoparticle solution, 1wt% sodium alginate aqueous solution, and 0.5wt% calcium ion-containing solution is 1:1:0.36.
3. a gel formulation for treating an ocular condition prepared by the preparation method of claim 1 or 2.
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