CN116650400A - Oleogel, and preparation method and application thereof - Google Patents

Oleogel, and preparation method and application thereof Download PDF

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CN116650400A
CN116650400A CN202310408342.6A CN202310408342A CN116650400A CN 116650400 A CN116650400 A CN 116650400A CN 202310408342 A CN202310408342 A CN 202310408342A CN 116650400 A CN116650400 A CN 116650400A
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oil
oleogel
gel
stirring
csd
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易军
刘易文
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Guangdong Pharmaceutical University
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Guangdong Pharmaceutical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses an oleogel and a preparation method and application thereof, wherein the oleogel comprises an oiling agent and a gelling agent, and the gelling agent accounts for 6.5-11% of the mass fraction of the oleogel; wherein the oiling agent is selected from vegetable oil or mineral oil; the vegetable oil is preferably camellia oil and/or soybean oil, and the mineral oil is preferably liquid paraffin; the gelling agent is selected from colloidal silica, ethylcellulose, magnesium stearate. The oil gel has good stability, and particularly, the oil gel is prepared into the medicine oil gel after the medicine is added, has good product stability and has better medicine holding and releasing capacity.

Description

Oleogel, and preparation method and application thereof
Technical Field
The invention relates to the field of medicine carriers, in particular to an oleogel and a preparation method and application thereof.
Background
The gel can be added with medicine to play a corresponding role in medicine treatment, is often used as an external application preparation in application, can be used for local skin treatment, and can also play a role in whole body after percutaneous absorption. The whole percutaneous absorption process of the medicine is divided into three stages, namely release, permeation and absorption. Release means that the drug is liberated from the carrier and then dispersed onto the skin surface; permeation refers to the passage of drug molecules into the skin through the skin's existing channels, depending on their own characteristics; absorption refers to the absorption of a drug into the blood or lymph circulation, through which it is absorbed by tissues or cells, thereby effecting therapeutic action.
Piroxicam (piroxicam) is an anti-inflammatory agent, has a strong prostaglandin synthetase inhibition effect, can reduce chemotaxis of leucocytes and inhibit release of lysosomal enzymes from cells, has remarkable anti-inflammatory, antipyretic, analgesic and repercussive effects, has a half-life period of 36-86h in human body, has an anti-inflammatory effect which is 2 times of that of indomethacin and 14 times of that of phenylbutazone, and is mainly used for treating rheumatic and rheumatoid arthritis clinically. Most of the related dosage forms on the market at home and abroad at present are tablets and capsules, however, the piroxicam tablets have great irritation to gastrointestinal tracts, so that gastrointestinal bleeding and ulcers are caused, toxic and side effects are great, and the exertion of the efficacy of the drugs is severely limited; the prepared piroxicam external preparation can effectively avoid adverse reactions of medicines, satisfies clinical application, and has a plurality of advantages compared with piroxicam tablets: no gastrointestinal pain stimulus; can avoid liver first pass effect and gastrointestinal tract degradation, and reduce toxic and side effects; the fluctuation range of the blood concentration is small; the difference between individuals is reduced; the acting time of the medicine is prolonged, and the medicine use times are reduced; convenient to use, and is particularly suitable for infants, the elderly and patients who are not suitable for oral administration and certain special patients.
The currently available external preparation is piroxicam (water) gel. Because most hydrogels have significant evaporation of the continuous phase in their network structure, they are not durable under dry conditions and are only suitable for use in a wet environment or for a short period of time. Therefore, the research and development of the oil gel by taking piroxicam as a model drug have good practical application significance.
Disclosure of Invention
The invention aims to solve the technical problem of providing an oleogel, a preparation method and application thereof, wherein medicines (such as piroxicam) are added into the oleogel to prepare medicine-containing oleogel, so that the product has good stability and better medicine holding and releasing capacity.
In order to solve the technical problems, the invention is realized by adopting the following technical scheme:
an oleogel, comprising an oil agent and a gelling agent, wherein the gelling agent accounts for 6.5-11% of the mass fraction of the oleogel; wherein, the liquid crystal display device comprises a liquid crystal display device,
the oil agent is selected from vegetable oil or mineral oil, the vegetable oil is selected from camellia oil and soybean oil, and the mineral oil is selected from liquid paraffin; the gelling agent is selected from colloidal silica, ethylcellulose, magnesium stearate.
Optionally, the oleogel comprises colloidal silica and liquid paraffin, the mass fraction of the colloidal silica being 8-10%. Correspondingly, the preparation method comprises the following steps: adding colloidal silica into liquid paraffin for several times, and stirring at 25-65deg.C for 0.5-1.5 hr to obtain oleogel.
Optionally, the oleogel comprises magnesium stearate and liquid paraffin, wherein the mass fraction of the magnesium stearate is 7-9%. Correspondingly, the preparation method comprises the following steps: the magnesium stearate is dispersed in liquid paraffin, the beaker is placed on a constant temperature magnetic stirrer for heating and stirring, the temperature is heated to 110 ℃ at the speed of 10 ℃/min, stirring is maintained for 1.5 hours, and the beaker is naturally cooled and then kept stand at normal temperature until oil gel is formed.
Optionally, the oleogel comprises ethyl cellulose and soybean oil, and further comprises a surfactant, wherein the surfactant is preferably glycerin monostearate, the mass fraction of the ethyl cellulose is 7-9%, and the mass ratio of the glycerin monostearate to the ethyl cellulose is 1:10. correspondingly, the preparation method comprises the following steps: measuring corresponding amounts of soybean oil, ethyl cellulose and glyceryl monostearate in a beaker, uniformly stirring by a magnetic stirrer at a rotating speed of 500rpm, stirring and heating the ethyl cellulose/soybean oil/glyceryl monostearate mixture, stirring and heating until the mixture is clear and transparent, and keeping stirring at the temperature for 30min to enable EC to be fully swelled and dissolved. Naturally cooling to room temperature to form the oleogel.
Optionally, the oleogel comprises colloidal silica and soybean oil, the mass fraction of the colloidal silica being 8-11%. Correspondingly, the preparation method comprises the following steps: and (3) putting the soybean oil into a beaker, adding a small amount of colloidal silicon dioxide accounting for 8-11% of the total mass percent into the soybean oil for multiple times, and stirring for 1-2h at room temperature to obtain the soybean oil.
Optionally, the oleogel comprises colloidal silica and camellia oil, the mass fraction of the colloidal silica being 8-11%. Correspondingly, the preparation method comprises the following steps: adding oleum Camelliae Japonicae into beaker, adding colloidal silicon dioxide 8-11% by weight into oleum Camelliae Japonicae, and stirring at room temperature for 1-2 hr.
The use of the above oil gel as a carrier for a transdermally absorbed topical medicament, preferably piroxicam.
A medicine gel comprises the oil gel and a percutaneous absorption external medicine, wherein the external medicine is preferably piroxicam, and after Cheng Biluo oxicam oil gel medicine is prepared, the medicine is thoroughly released, and the sustained release time is ideal.
Drawings
FIG. 1 is a schematic diagram of a simplified apparatus for determining the adhesion of an oleogel matrix;
FIG. 2 is an external view of the oleogel matrix of example 1;
FIG. 3 is a graph showing the results of the oil gel matrix centrifugation test of example 1;
fig. 4 is an external view of an oil gel containing piroxicam in example 1;
fig. 5 is a graph showing the release profile (x±s, n=3) of three dosage forms of piroxicam in example 1;
FIG. 6 is a graph showing the cumulative release profile of piroxicam hydrogel, single ointment, and oleogel of example 2;
FIG. 7 is a graph showing the oil holding force measurement effect of the oleogel of example 3;
FIGS. 8-11 are microscopic images of CSD powder, LP+CSD (blank), CO+CSD (blank), SO+CSD (blank), respectively, of example 3;
FIG. 12 is a graph of static rheological property results for example 3;
FIG. 13 is a graph showing the strain sweep result in example 3;
FIG. 14 shows the results of the frequency sweep of the vegetable oil gel in example 3;
FIG. 15 is a graph showing the result of LP+CSD frequency scanning in example 3
FIG. 16 is a graph showing the apparent viscosity of SO+CSD, CO+CSD, LP+CSD as a function of temperature in example 3;
fig. 17 is a diagram of example 3: a, in vitro release results of the CO+CSD medicine; b, in vitro release result of SO+CSD drug; c, in vitro release results of the LP+CSD drugs; d, a drug in vitro release comparison graph of the three;
FIG. 18 is an appearance of the oleogel prepared under the optimal conditions of example 4;
fig. 19 is an external view of an oil gel sample containing piroxicam in example 4.
Detailed Description
EXAMPLE 1 colloidal silica-liquid paraffin oil gel
Taking 20ml of liquid paraffin in a 50ml beaker, weighing colloidal silicon dioxide according to the mass fraction of each prescription, adding a small amount of colloidal silicon dioxide into the liquid paraffin for multiple times, and stirring under corresponding preparation conditions, namely stirring time and preparation temperature to obtain the oleogel matrix. The quality of the prepared oil gel matrix is examined by examining three factors of the mass fraction of the colloidal silica, the preparation temperature T and the stirring time T, and the test is carried out according to the table 1, so that 9 groups of formulas are formed, and the total amount of liquid paraffin in each prescription is 20ml.
Table 1: experimental design of silica-liquid paraffin oil gel prescription
After the oil gel matrix is prepared, properties of the oil gel matrix are examined and scored (table 2), wherein the properties comprise fluidity, granular feel, transparency, oil holding power and adhesion.
Table 2: oil gel matrix appearance property scoring criteria
Oil retention measurement
About 2g of the prepared oleogel was weighed, placed in the center of quantitative filter paper (diameter 18 cm) for 2 hours, then the oleogel sample was scraped off, the mass of the filter paper was measured, and the mass of the oleogel after measurement was calculated by the difference before and after the mass to calculate the loss amount, and the measurement results are shown in Table 3.
Table 3: measurement of oil holding force of oleogel matrix
Adhesion measurement
A simple apparatus for measuring the adhesion of an oleogel matrix was prepared as shown in FIG. 1. About 2g of the prepared oleogel substrate sample was weighed, placed on 7cm×7cm plastic plate A, 2.5cm×2.5cm plastic plate B was pressed against the sample, and a 500g weight was pressed against plastic plate B for 5min, allowing the sample to spread between the plastic plates. The plastic plates B are connected with the left end of the lever through wires, water is slowly dripped into the water bag at the right end of the lever until the two plastic plates are just pulled apart, and water addition is stopped. The quality of water in the water bag is measured, the adhesion force of each group of oil gel is obtained according to the lever principle, and the same steps are repeated once. The oil gel matrix adhesion measurements for each group are as follows (Table 4).
Table 4: measurement of oleogel matrix adhesion
Scoring of experimental results
The test is carried out according to the table 1, 9 groups of formulas are formed, the appearance characteristics including fluidity, transparency, granular feel, oil holding force and adhesion force are scored after the silicon dioxide-liquid paraffin oil gel matrix of the corresponding formula is prepared, the appearance characteristic average is calculated according to the proportion of fifty percent of fluidity, forty percent of granular feel and ten percent of transparency, and the total weighted average is calculated according to the proportion of sixty percent of characteristic average, thirty percent of oil holding force and ten percent of adhesion force.
Table 5: silica-liquid paraffin oil gel test results
As can be seen from Table 5, the oleogels were prepared in the proportions of Table 1, with numbers 2, 3, 5 and 9 being the most preferred.
Stability test: the optimal prescription for preparing the oleogel matrix (fig. 2) was selected based on the results of the orthogonal experiments, and the gel matrix was prepared according to the optimal prescription, followed by stability determination. Comprises a centrifugal test (the rotation speed is 2500r/min for 30 min), a heat and cold resistant test (the water bath is carried out at 55 ℃ for 2h under the condition of avoiding light, and the oil gel is placed in a refrigerator at minus 15 ℃ for 24 h), and whether the color of the oil gel after the stability test is changed or not is observed, and the phenomena of layering, coagulation and solid precipitation are caused.
Centrifugal test: taking 3 batches of colloidal silica-liquid paraffin oil gel prepared by the optimal prescription, respectively placing the 3 batches of colloidal silica-liquid paraffin oil gel into 10ml centrifuge tubes, placing the centrifuge tubes into a table centrifuge, regulating the rotating speed (2500 r/min) and the centrifuging time (30 min), taking out the centrifuge tubes after the centrifuging is completed, and observing the change of the oil gel. A small amount of oily dye is added into a centrifuge tube, and after the centrifugal test (2500 r/min for 30 min), the oil gel in the centrifuge tube is partially layered. As shown in fig. 3.
Heat resistance test: and (3) putting 20ml of colloidal silica-liquid paraffin oil gel prepared by 3 batches of optimal prescription into 50ml beakers, sealing, adjusting the set temperature of a constant-temperature water bath kettle to 55 ℃, putting the beakers into the beakers, carrying out water bath for 2 hours, taking out the beakers, and after the beakers reach the room temperature, observing whether the color of the oil gel subjected to the heat resistance test changes or not, and judging whether layering, coagulation and solid precipitation occur or not. The test sample was taken out of the 55 ℃ thermostat water bath, and it was observed that the freshly taken-out oleogel test sample became clear and transparent as compared with the oleogel sample placed at room temperature. After leaving to stand at room temperature, visual inspection revealed no significant change, except after becoming more clear and transparent. Taking out the test sample from the constant temperature water bath kettle at 55 ℃ through a heat resistance test (light-resistant water bath at 55 ℃ for 2 h), and observing that the oil gel test sample just taken out becomes clearer and more transparent than the oil gel sample placed at room temperature. The original hydrogen bond pattern of the colloidal silica-liquid paraffin oil gel system which depends on hydrogen bonding between groups such as siloxane groups is changed with the increase of temperature, so that the oil gel matrix becomes clearer and more transparent after heat resistance test.
Cold resistance test: taking 3 batches of colloidal silica-liquid paraffin oil gel prepared by the optimal prescription, respectively filling 20ml into 50ml beaker, sealing, placing the beaker in a refrigerator-15 ℃ part, standing for 24 hours, taking out after reaching the time, and observing whether the color of the oil gel after cold resistance test changes or not after the temperature is reached, and whether layering, coagulation and solid precipitation occur or not. The test sample was taken out of the-15 ℃ refrigerator frozen layer and left to stand at room temperature, and visual inspection revealed no significant change compared with the oil gel sample obtained without the heat resistance test.
Preparation of medicated gel and measurement of drug content and release
Preparation of medicated gel: the non-steroidal anti-inflammatory drug piroxicam is selected as a model drug, raw materials are weighed according to the content proportion of the commercial piroxicam hydrogel (20 g:100mg of piroxicam gel), and in the process of preparing the oil gel matrix, the weighed piroxicam raw materials are added during matrix pregelatinization, and stirring is continued for a preset time to obtain yellow-green oil gel (figure 4).
Preparation of a medicated ointment: prescription beeswax 6.6g vegetable oil 15ml. Heating Cera flava in the amount of prescription in evaporating dish in water bath, melting, slowly adding vegetable oil, stirring, taking off from the water bath, and continuously stirring to condense to form single ointment. The raw material medicines are weighed according to the content proportion of the commercial piroxicam hydrogel (20 g:100 mg), and are added into the raw material medicines, and the mixture is stirred and dispersed uniformly to obtain the piroxicam-containing ointment.
Determination of the oil gel content: the method has the advantages that the model drug piroxicam is added in the process of preparing the silica-liquid paraffin oil gel, the prepared yellowish green gel is detected, and the content of the model drug piroxicam can be judged whether to be destroyed and decomposed or not under the method for preparing the gel, so that the content of the model drug piroxicam is obviously different from the content of the model drug added in the process of preparing the gel.
According to the related medicine content measuring method of pharmacopoeia, 2g of medicine-containing oil gel (about equivalent to 10mg of piroxicam) is taken, placed in a 100ml beaker, 30ml of hydrochloric acid methanol solution is added, stirred in a constant temperature water bath kettle at 70 ℃ for water bath, extracted for 10 minutes, taken out of the water bath kettle, cooled, filtered, placed in a 100ml measuring flask for filtrate, the residue is treated for 2 times according to the method, the extract is combined, diluted to scale by 0.1mol/L hydrochloric acid methanol solution, shaken uniformly, precisely measured by 1ml, placed in a 100ml measuring flask, diluted to scale by 0.1mol/L hydrochloric acid methanol solution, and shaken uniformly. After the preparation of the solution, the absorbance was measured at 343nm by ultraviolet-visible spectrophotometry, and the absorbance was measured according to the absorbance coefficient (E 1％ 1cm ) Calculated for 856. The measurement results are as follows: the piroxicam content of the three groups of medicine-containing oil gel samples is 97.34%, 96.59% and 97.66% of theoretical content. In general, piroxicam added during gel preparation is hardly destroyed in the presence of errors in the formulation of the solution.
Determination and comparison of in vitro release rates of three dosage forms: in a topical formulation, the drug is released from the matrix onto the skin surface and then transdermally absorbed into the body to act, and thus the release rate of the drug is closely related to the permeation rate of the transdermal formulation. In vitro drug release studies are the simplest and effective methods to examine the effectiveness of transdermal drug delivery systems.
The release degree of the medicine is measured by the modified paddle method and the ultraviolet-visible spectrophotometry, and the comparison of the release degrees of the two gel agents is carried out to judge whether the silica-liquid paraffin oil gel has a slow release effect and how the slow release effect is.
Investigation of drug release: improved paddle method: adding the oleogel solution into a penicillin bottle, and adjusting the temperature to about 37 ℃. Placing penicillin bottle at the bottom of the dissolution cup, slowly adding 300ml of release medium (PBS) along the wall of the dissolution cup; regulating the rotation speed to 100 r.min -1 A temperature of 37 ℃ (±0.5); absorbing 5ml of the dissolution liquid in 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours respectively, supplementing 4ml of fresh constant-temperature release medium, immediately filtering with a 0.45 mu m microporous filter membrane, taking clear filtrate, measuring the content according to a sample solution content measuring method (visible light-ultraviolet spectrophotometry), and calculating the accumulated permeation quantity (Q), wherein the calculation formula is as follows:
wherein: c (C) n Drug concentration (μg/ml) measured for the nth sampling point, V 0 To release the total volume of the medium, C i Drug concentration (μg/ml) was measured for the ith sampling point, V was the volume of PBS taken each time, and m was the total amount of drug contained in piroxicam oleogel.
The in vitro release degree of piroxicam hydrogel and ointment is consistent with that of oleogel, and the results are as follows:
table 6: cumulative 60 hour release rate (Q) for three dosage forms of hydrogel, oleogel, and ointment
And (3) calculating the accumulated release amount of the piroxicam according to a standard curve, drawing a release curve by taking a time point as an abscissa and the accumulated release percentage of the piroxicam as an ordinate, and analyzing three dosage forms of hydrogel, oleogel and ointment according to the release curve, wherein the hydrogel release is the fastest, the oleogel is the next time, and the self-made piroxicam ointment in a laboratory is the slowest to release. The integrated release rate of piroxicam hydrogel reaches (99.09+/-1.36)%, the integrated release rate of oleogel reaches (98.02+/-0.27)% in 48 hours, and the integrated release rate of self-made ointment in laboratory reaches half (48.60 +/-1.60)% after 60 hours. In the drug release within 24 hours, the hydrogel release was the fastest, the cumulative release rate was (89.87.+ -. 1.46)%, the oleogel was (73.14.+ -. 0.27)%, and the ointment was the slowest (20.51.+ -. 1.02)%.
In this example, the oil gel matrix is prepared from colloidal silica and liquid paraffin, and the optimal formulation for preparing the gel matrix is selected by scoring the appearance properties (flowability, particle feel, transparency) and oil holding power and adhesion of the oil gel matrix, namely, the mass fraction of the colloidal silica is 8.5%, the stirring time is 1.5 hours, and the preparation temperature is 65 ℃. The preparation method comprises the steps of preparing an oil gel matrix according to an optimal prescription, preparing a yellow-green medicine-containing gel by taking piroxicam as a model medicine, and then measuring the release degree, wherein the release rate of the hydrogel is fastest in medicine release within 24 hours, the accumulated release rate is (89.87+/-1.46)%, the oil gel time is (73.14 +/-0.27)%, and the laboratory homemade ointment is slowest (20.51+/-1.02)%. Compared with hydrogel, the silica-liquid paraffin oil gel has obvious slow release effect, and compared with ointment, the medicine in the oil gel is released more completely.
EXAMPLE 2 magnesium stearate-liquid paraffin oil gel
The analysis method of the embodiment 1 is adopted in the embodiment, and the optimal preparation process of the gel matrix is screened by examining the influence of three factors of mass fraction, temperature and continuous stirring time on the gel matrix: 7% by mass, 110 ℃ and continuous stirring time of 1.5h. The stability experiment result shows that the sample shows a certain stability at high temperature and low temperature, but the centrifugal stability is still to be improved; the gel matrix is added with the model drug piroxicam to prepare the drug-containing oleogel, and the oleogel is yellow-green and semitransparent, has good stability and has certain drug holding and releasing capacity. See fig. 6. Similar to the silicon dioxide-liquid paraffin oil gel, the magnesium stearate-liquid paraffin oil gel has obvious slow release effect compared with the hydrogel, and the medicine release is more complete compared with the ointment.
EXAMPLE 3 preparation of different oil phase gels Using colloidal silica as the gelling agent
And selecting camellia oil and soybean oil as oiling agents to prepare the colloidal silicon dioxide-vegetable oil gel.
The mass fraction of the gelling agent (mass of the gelling agent/total mass), the stirring time T, and the preparation temperature T were taken as variables and are denoted as A, B, C, respectively. The levels of A were 10%, 10.5% and 11%, the levels of B were 1h, 1.5h and 2h, the levels of C were 25℃and 45℃and 65℃and the effect on the properties of the oleogel matrix was examined. Experiments were performed according to table 7, with camellia oil and soybean oil each constituting 9 formulations.
In each group of experiments, 50g of camellia oil/soybean oil is taken in a 250mL beaker, CSD is weighed according to the mass fraction of the set gelling agent, and a small amount of CSD is added into the oil phase for many times, and is stirred for corresponding time at a certain temperature.
Table 7: experimental design of CSD-camellia oil or soybean oil gel prescription
The evaluation index and the method are as follows: after the oleogel matrix is prepared in groups, the oleogel matrix is placed at 4 ℃ for 24 hours and then is subjected to property investigation and grading, wherein the investigation contents comprise fluidity, granular feel, transparency and oil holding capacity.
The method comprises the following steps:
fluidity: about 50g of oil gel is weighed into a 250mL beaker, the surface of the gel is smoothed, the beaker is inverted, and after the system is stable, the gel is measuredThe included angle between the surface and the inner wall of the beaker; granular feel: about 2g of oleogel is smeared on the skin of the back of the hand, and the mixture is kneaded for ten times to score the granular sensation; transparency: about 50g of the oleogel was weighed into a 250mL beaker and the gel surface was smoothed. Under the fluorescent lamp, the beaker is placed on a piece of printing paper with white background and small number Song Ti Chinese characters, and the definition of the fonts is observed. Oil holding force: taking a 5mL centrifuge tube, and recording the precise weighing as m 1 Placing about 2.5mL of oleogel into a centrifuge tube, and weighing the total mass of the oleogel and the centrifuge tube and recording as m 2 The method comprises the steps of carrying out a first treatment on the surface of the Centrifuging at 9000r/min for 15min, inverting the centrifuging tube for 10min, sucking the leached oil phase with filter paper, and weighing the total mass of the rest oil gel and the centrifuging tube as m 3 . The procedure was repeated 3 times and the average was taken. And calculating the oil holding force according to a formula. The oil retention measurement effect is shown in fig. 7.
Wherein: m is m 1 The mass of the centrifuge tube, g; m is m 2 The mass of the centrifuge tube and the oleogel before centrifugation, g; m is m 3 Centrifuging, draining oil, centrifuging the mass of the centrifuge tube and the oil gel, and g; omega, mass fraction of gellant in oleogel.
Table 8: oil gel matrix character scoring criteria
Results of oil holding force measurement
Table 9: measurement of oil holding force of CSD-camellia oil gel
Table 10: measurement of oil holding force of CSD-soybean oil oleogel
Table 11: CSD-camellia oil gel experiment result
As can be seen from Table 11, camellia oil gel was prepared according to the formulation ratio of Table 7, wherein the optimal preparation conditions were 25℃and 11% CSD was added to camellia oil and stirred for 2 hours.
Table 12: CSD-Soybean oil gel test results
As can be seen from Table 12, according to the formulation ratio of Table 7, soybean oil gel was prepared, wherein the optimal preparation condition was 25℃and 10.5% of CSD was added to soybean oil and stirred for 1.5 hours.
Sample preparation method
Blank oil gel
CSD-camellia oil gel: weighing about 30g of camellia oil in a 100mL beaker, adding a small amount of CSD accounting for 11% of the total mass into the camellia oil for multiple times, and stirring for 2 hours at 25 ℃; CSD-soybean oil gel: weighing about 30g of soybean oil in a 100mL beaker, adding a small amount of CSD accounting for 10.5% of the total mass into the soybean oil for multiple times, and stirring for 1.5h at 25 ℃; CSD-liquid paraffin oil gel: about 30g of liquid paraffin was weighed into a 100mL beaker, and a small amount of CSD accounting for 8.5% of the total mass was added to the liquid paraffin several times, followed by stirring at 65℃for 1.5 hours.
Gel containing medicine oil: when the blank oil gel matrix is prepared, the gel forming agent is in a semi-gel state when being added in half, at the moment, corresponding piroxicam raw material medicine is added according to the content of the piroxicam gel (20 g:100 mg) on the market, and after the medicine is uniformly stirred, the rest CSD is continuously added and stirred for the required time.
Microscopic observation: appropriate amounts of CSD powder and three blank oleogels were smeared onto slides, lightly pressed thereon with coverslips and carefully bubble removed, and observed under an optical microscope at 100-fold and 400-fold magnification. The results are shown in FIGS. 8-11. LP+CSD refers to CSD-liquid paraffin oil gel; CO+CSD refers to CSD-camellia oil gel; SO+CSD refers to CSD-soybean oil oleogel.
Observing CSD in a white flaky crystal sample under a microscope, wherein the CSD has obvious aggregation phenomenon due to the excessively small particle size; the dispersion of the oil gellant particles was observed in three blank oil gel matrices, with the difference that the particle dispersion in mineral oil was significantly denser than that in two vegetable oils, with a larger particle size.
Texture characteristics
Measurement conditions: in TPA mode, a cylindrical probe is used at room temperature, the pre-test speed is 2.0mm/s, the test speed is 1.0mm/min, the test depth is 15mm, the compression ratio is 60%, and the trigger force is 5g.
Table 13: TPA mode determination parameters and results
Rheological Properties
The method comprises the following steps: at 25 ℃, a proper amount of oleogel is taken and placed on a temperature control base of a rheometer, a gap is set to be 1mm, and a 35mm flat plate is used as a clamp.
Investigation of static rheological Properties: equilibrium time 60s, duration 180s, shear rate 10 -1 ～10 3 s -1 The method comprises the steps of carrying out a first treatment on the surface of the Strain scanning procedure: the frequency is 1Hz, and the strain range is 0.01-100%; frequency sweep procedure: strain 0.05% and frequency 0.1-50 Hz. Apparent viscosity as a function of temperature: placing proper amount of oil gel on a temperature control base of a rheometer, wherein a clamp is a 35mm flat plate, and the gap is set to be 1mm; the fixed oscillation frequency is 1Hz, and the constant shear rate is 1s -1 The apparent viscosity of the sample at 0-50 ℃ is measured at a heating rate of 1 ℃/min.
As in figure 12. The apparent viscosity of the three oil gels all show a decreasing trend along with the increase of the shear rate of the static rheological property results; the curves of the two vegetable oil-based oil gels are similar and have significant differences from the curves of the mineral oil-based oil gels; at a shear rate of 268s -1 When three curves are generated, the intersection points are generated. Before the intersection point, the apparent viscosity of the vegetable oil-based gel is obviously higher than that of the mineral oil-based gel, and the apparent viscosity of the mineral oil-based gel reaches 46s at a shearing rate -1 The gel starts to be stable, the apparent viscosity of the two vegetable oil-based gels continues to decrease, and the apparent viscosity of the gel is liquid paraffin oil gel > soybean oil gel > camellia oil gel after the intersection point.
Strain scan results: as shown in fig. 13, the linear viscoelastic regions of lp+csd, co+csd, so+csd are 0.01% -0.2%, 0.01% -3%, and 0.01% -3%, respectively, and the critical strain value of mineral oil is smaller, i.e., the linear viscoelastic region range is smaller, than that of two kinds of vegetable oil. Frequency sweep results: as shown in fig. 14, the elastic modulus (G') of both vegetable oil gels was always greater than the viscous modulus (G ") throughout the frequency sweep; as shown in FIG. 15, the elastic modulus (G ') of the LP+CSD system is substantially unchanged with increasing frequency, and the viscous modulus (G ") is gradually increasing, with G' and G" being closest at a frequency of 42 Hz. Apparent viscosity as a function of temperature measurement: as shown in fig. 16, the apparent viscosity of the co+csd and lp+csd systems overall decreases with increasing temperature; the apparent viscosity of the SO+CSD system is in an ascending trend within the range of 0-10 ℃, and the apparent viscosity is in a descending trend after the temperature is higher than 10 ℃; the apparent viscosity of the three oil gels after 25 ℃ is close to and tends to be stable.
In vitro Release test
The method comprises the following steps: 2g of gel containing medicine oil is taken and placed in a penicillin bottle, and the whole gel is ensured to be uniformly positioned at the bottom of the penicillin bottle; after the penicillin bottle is put into a dissolution cup, 300mL PBS buffer solution with pH of 7.4 is slowly added, the temperature is controlled to be 37+/-1 ℃, and the rotating speed is 100r/min; 4ml of the dissolution liquid is sucked up for 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48 and 60 hours, and the dissolution liquid is filtered and stored by a microporous filter membrane with the size of 0.22 mu m to be detected, and meanwhile, the fresh constant temperature release medium with the same amount is supplemented.
And (3) data processing: measuring absorbance values of the solutions taken out at different time intervals at 354nm, calculating the concentration of the drug, and further calculating the cumulative release (Q) according to a formula:
wherein: cn, drug concentration at nth sampling point, μg/ml; v0, releasing the total volume of the medium, mL; ci, drug concentration at the ith sample site, μg/ml; v, the volume of the buffer solution taken each time is mL; m, total piroxicam medicine contained in the oleogel, μg.
Results: the in vitro drug release of the three oleogels (co+csd, so+csd, lp+csd) remained consistent with the following results:
table 14: results of in vitro drug release
Note that: q (Q) CO 、Q SO 、Q LP The accumulated release rates of the medicines respectively refer to camellia oil gel, soybean oil gel and mineral oil gel
The results as shown in table 14 and fig. 17 show that: the drug may be released in the oleogel. The cumulative release rate of the drug reaches (81.44 +/-0.49)% at 12 hours of CO+CSD, and the measurement result is basically stable; the cumulative release rate of the SO+CSD reaches (82.70 +/-0.81)% at 12h, reaches (86.66 +/-0.75)% at 24h, and the measurement result is basically stable; in vitro release test of the drug from lp+csd was performed in the same manner as in example 1. The results were compared with the results of co+csd and so+csd obtained in the study of this example: in the first 3h, the drug release rate is SO+CSD > LP+CSD > CO+CSD; 3-30 h, wherein the release rate is SO+CSD > CO+CSD > LP+CSD; 30-36 h, wherein the release rate is SO+CSD > LP+CSD > CO+CSD; after 36h, the release rate is LP+CSD > SO+CSD > CO+CSD; the drug release states of the two plant oil-based oil gels are basically consistent, the accumulated release rate is more than 70% at 6 hours, more than 80% at 8 hours, more than 40% at 6 hours, and more than 80% at 30 hours; the accumulated release rate of the CO+CSD medicine can reach 83.54%, the SO+CSD can reach 3.50%, and the LP+CSD can reach 98.02%.
The curve fitting equation for the change of the cumulative drug release rate (Q) over time (t) for three oleogels, co+csd, so+csd, lp+csd, results were: q=17.93×ln (t) +26.281, q=16.72×ln (t) +36.438, q=17.51×ln (t) +16.092.
In the embodiment, the optimal prescription of CSD-camellia oil and CSD-soybean oil gel is screened, and meanwhile, CSD-liquid paraffin oil gel is prepared according to the prescription in the embodiment 1, and microscopic observation and oil holding force measurement are carried out on a hollow Bai Jizhi; and taking the three gel matrixes as carriers and taking piroxicam raw material medicines as model medicines, investigating the texture characteristics, rheological properties and in-vitro release state of the medicines,
the results of the texture characteristics show that the three oleogels do not exhibit brittleness and have good ductility. The cohesion of the adhesive is larger than the cohesiveness of the adhesive, so that the adhesive is beneficial to extrusion and easy to prepare and produce. Rheological properties show that all three oleogels increase with shear rate, and the apparent viscosity decreases, which is a shear-thinning pseudoplastic fluid, facilitating spreading on the skin surface. At the same time, they have suitable elastic modulus and viscous modulus, and the stability degree meets the requirement of being used as a percutaneous administration carrier. The apparent viscosity of the three oil gels tends to be stable under the condition that the temperature is more than or equal to the room temperature, and the three oil gels are suitable for production and storage under the condition of room temperature. The medicine can be completely released in three kinds of oil gel matrixes, and the release effect is achieved.
All three oleogels meet the requirements as a transdermal drug delivery matrix as a whole.
EXAMPLE 4 Ethylcellulose (EC) -Soybean oil oleogel
This example uses the procedure of example 1 to prepare an EC oil gel as shown in fig. 18. The optimal prescription is selected as EC100, the mass fraction is 8% and the ratio of Glyceryl Monostearate (GMS) to EC mass is 1:10, verifying that the prescription is viable. Piroxicam was used as a model drug and added to EC oil gel, the appearance of which is shown in figure 19. The fluidity, granular feel, transparency, oil holding power, adhesion and content measurement are inspected to be in proper ranges; the in vitro release degree of the piroxicam gel and the piroxicam ointment is inspected by adopting an improved paddle method, and the initial verification shows that the piroxicam oil gel has better drug release performance compared with the piroxicam ointment, can release the drug in a shorter time which is close to 100 percent, and has a certain slow release effect compared with the piroxicam hydrogel. The EC oil gel has simple preparation process and controllable quality, can be used as a local transdermal drug delivery carrier, and can be subjected to more comprehensive and systematic quality evaluation in subsequent researches, so that the EC oil gel still has great development space.

Claims (10)

1. The oil gel is characterized by comprising an oil agent and a gelling agent, wherein the gelling agent accounts for 6.5-11% of the mass of the oil gel; wherein, the liquid crystal display device comprises a liquid crystal display device,
the oil agent is selected from vegetable oil or mineral oil; the vegetable oil is preferably camellia oil and/or soybean oil, and the mineral oil is preferably liquid paraffin;
the gelling agent is selected from colloidal silica, ethylcellulose, magnesium stearate.
2. The oleogel as claimed in claim 1, wherein the oleogel comprises colloidal silica and liquid paraffin, the mass fraction of colloidal silica being 8-10%.
3. A method of preparing an oleogel as claimed in claim 2, including the steps of: adding colloidal silica into liquid paraffin for several times, and stirring at 25-65deg.C for 0.5-1.5 hr to obtain oleogel.
4. The oleogel of claim 1, comprising magnesium stearate and liquid paraffin, the mass fraction of magnesium stearate being 7-9%, the preparation method comprising the steps of: the magnesium stearate is dispersed in liquid paraffin, the beaker is placed on a constant temperature magnetic stirrer for heating and stirring, the temperature is heated to 110 ℃ at the speed of 10 ℃/min, stirring is maintained for 1.5 hours, and the beaker is naturally cooled and then kept stand at normal temperature until oil gel is formed.
5. The oleogel of claim 1, which comprises ethylcellulose and soybean oil, and in addition surfactants, preferably glycerol monostearate, the mass fraction of said ethylcellulose being 7-9%, the mass ratio of glycerol monostearate to ethylcellulose being 1:10.
6. the method for preparing the oleogel as claimed in claim 5, comprising the steps of: measuring corresponding amounts of soybean oil, ethyl cellulose and glyceryl monostearate in a beaker, uniformly stirring by a magnetic stirrer at a rotating speed of 500rpm, stirring and heating the ethyl cellulose/soybean oil/glyceryl monostearate mixture, stirring and heating until the mixture is clear and transparent, and keeping stirring at the temperature for 30min to enable the ethyl cellulose to fully swell and dissolve; naturally cooling to room temperature to form the oleogel.
7. The oleogel of claim 1, wherein the oleogel comprises colloidal silica, soybean oil or camellia oil, the mass fraction of colloidal silica being 8-11%.
8. The method for preparing the oleogel as claimed in claim 7, comprising the steps of: and (3) putting soybean oil or camellia oil into a beaker, adding a small amount of colloidal silicon dioxide into the oil phase for many times, and stirring for 1-2 hours at room temperature to obtain the product.
9. Use of an oleogel as claimed in any one of claims 1 to 8 as a carrier for a transdermally absorbed topical medicament, preferably the topical medicament is piroxicam.
10. A pharmaceutical gel comprising an oleogel as claimed in any one of claims 1 to 8 and a transdermally absorbed topical medicament, preferably piroxicam.
CN202310408342.6A 2023-04-17 2023-04-17 Oleogel, and preparation method and application thereof Pending CN116650400A (en)

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CN102510725A (en) * 2009-06-12 2012-06-20 玛尔斯有限公司 Polymer gelation of oils
US20190167749A1 (en) * 2016-04-13 2019-06-06 Uab Satimed The oleo gel composition and delivery system with active compounds from cannabis sativa and mentha arvensis for reduction of inflammation and pain in deep tissues
CN107897531A (en) * 2017-11-13 2018-04-13 江南大学 A kind of oily gel composition containing glycerol monobutyralte and phosphatide
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