CN117462492A - Preparation method of pimecrolimus external nano preparation with high stability and bioavailability - Google Patents
Preparation method of pimecrolimus external nano preparation with high stability and bioavailability Download PDFInfo
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- CN117462492A CN117462492A CN202311644409.2A CN202311644409A CN117462492A CN 117462492 A CN117462492 A CN 117462492A CN 202311644409 A CN202311644409 A CN 202311644409A CN 117462492 A CN117462492 A CN 117462492A
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- 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
- A61K31/435—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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- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
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- Organic Chemistry (AREA)
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- Biophysics (AREA)
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Abstract
The invention relates to a preparation method of a pimecrolimus external-use nanometer preparation with high stability and bioavailability, which can improve the stability of pimecrolimus, keep 18 months stable at normal temperature, and is convenient for daily use. On the premise of not changing the molecular structure of pimecrolimus and not changing the specification of the product, the release speed of pimecrolimus is improved by utilizing the characteristics of pharmaceutics, the accumulated permeation quantity of pimecrolimus on skin and the retention quantity of skin layers are obviously improved, the bioavailability is improved, the clinical effectiveness of the external preparation of pimecrolimus is enhanced, and the curative effect of the product is improved. The stability of the pimecrolimus nano preparation is improved by optimizing the prescription, so that the product can be sold for a long time at normal temperature and used, and the daily use of consumers is facilitated.
Description
Technical Field
The invention relates to a preparation method of a pimecrolimus external-use nano-preparation for improving stability and bioavailability, in particular to a preparation method of a pimecrolimus external-use nano-preparation for improving accumulated permeation quantity of pimecrolimus in skin and retention quantity of a skin layer.
Background
Atopic Dermatitis (AD) is a chronic, recurrent, inflammatory skin disease. Patients often have allergic rhinitis, asthma, and other atopic diseases, and are therefore considered to be systemic diseases. AD patients often have severe itching, which severely affects quality of life.
The chinese guidelines for diagnosis and treatment of atopic dermatitis (2020 edition) recommend the use of 1% pimecrolimus cream for the treatment of AD. Pimecrolimus is a lipophilic anti-inflammatory derivative of ascomycin macrolactam and its immunosuppressive activity is through specific binding to intracellular FK506 binding protein as a complex which inhibits intracellular smart-regulated nervonic acid smart activity, thereby inhibiting the transcriptional expression of mRNA of downstream multiple inflammatory factors. However, the water solubility of the medicine is low, so that the medicine is difficult to quickly and effectively permeate into the skin, and the clinical curative effect of the medicine is limited.
The current pimecrolimus preparation on the market is pimecrolimus Mo Siru ointment, the pimecrolimus emulsifiable ointment is approved by the FDA to be marketed for the first time in 12 months of 2001, the evidence-holding manufacturer is BAUSCH HEALTH US LLC, the pimecrolimus preparation is introduced into China from Novartis Pharma GmbH in 2003, the manufacturer is changed to French MEDA Manufacturing from 2013, and the evidence-holding manufacturer is MEDA Pharma GmbH & Co.KG. The API in pimecrolimus cream from the original mill was suspended in the matrix due to its low water solubility. However, according to the prior art, it is reported that a suspension-type drug must be dissolved and then penetrate through the stratum corneum to exert its drug effect.
Emulsion refers to a heterogeneous dispersion of liquid formulations formed by mixing two mutually immiscible liquids, the liquids being dispersed in the form of droplets in the other phase. One phase forming the droplets is a dispersed phase, such as oil; the other phase of liquid is then referred to as a dispersion medium, for example water. The dispersed phase is also referred to as the internal phase or discontinuous phase and the dispersion medium is also referred to as the external phase or continuous phase. The emulsion has high dispersion degree of liquid drops, large total surface area and high surface free energy, is a thermodynamically unstable system, and needs to be added with an emulsifier to keep stable in two phases. Emulsifiers are generally surfactants with amphiphilicity (hydrophilic and lipophilic) capable of concentrating at the interface between the emulsion droplets and the continuous phase, with the hydrophilic polar end facing the aqueous phase and the lipophilic nonpolar end facing the oil phase, in such a way as to reduce the interfacial tension between the phases and prevent the aggregation and fusion of the droplets into larger emulsion droplets.
The emulsion drops can be generally classified into common emulsion, microemulsion and nanoemulsion according to the particle size of the emulsion drops. The common emulsion refers to emulsion drop with particle size of 1-100 μm, and is milky opaque liquid; the microemulsion refers to the emulsion drop size of 0.1-1 μm, and the microemulsion gel (emulsion) is prepared by adding some high polymer gelatinizer into the external phase of the microemulsion to increase the viscosity, modulus, yield stress, etc. of the system. The microemulsion gel (emulsion) can store the insoluble medicine in the form of molecule in the medicine preparation, and has semi-solid rheological property, so that it is suitable for development and application of insoluble API preparation.
Pimecrolimus has poor solubility due to its own chemical structure. After the pimecrolimus is prepared into the emulsifiable paste, the pimecrolimus is suspended in the system, and the slow release speed of the pimecrolimus can not quickly release and penetrate through the stratum corneum in a short time due to the characteristic of indissolvable property, so that the skin permeation quantity of the pimecrolimus is low, the effect is slow, and the pimecrolimus can be used for multiple times to effectively treat diseases.
The stratum corneum is the outermost layer of the skin, which hardens due to the keratinization process, forming a hydrophobic barrier, impeding the transport of exogenous chemicals, including drugs, and the main skin barrier is located in the stratum corneum, since it has a unique stratum corneum structure, surrounded by a lipid bilayer composed of ceramides. It is arranged in 10 to 15 layers, approximately 10-20 μm thick, consisting of highly keratinized keratinocytes. Keratinocytes and intercellular lipids together constitute the stratum corneum, constituting a dense barrier. There are three possible transmembrane transport routes for drugs applied to the skin: the transcellular and intercellular and the accessory osmotic pathways (through hair follicles, associated sebaceous glands and sweat ducts). The transcellular pathway is a pathway that distributes and diffuses, respectively, to alternating hydrophilic and lipophilic domains in the extracellular matrix. In the intercellular pathway, the permeate passes through pathways within the extracellular matrix, but not through the cells. The transcellular and intercellular pathways constitute the epidermal pathways. The penetration of most topically applied compounds occurs through the epidermal pathway, which occurs on the premise that the API exists in molecular form for trans-membrane transport of the epidermal pathway. Although hair follicles (and associated sebaceous glands) and sweat glands account for only about 0.1% of the total skin surface area, these appendages are potential routes into the skin and may be important to the nanosystem.
Pimecrolimus is white to off-white odorless powder, is easy to dissolve in methanol and is difficult to dissolve in water. Pimecrolimus is in a suspension state in the current commercial products due to the poor solubility of pimecrolimus. As described above, the transdermal process needs to exist in molecular form as an API to occur. For APIs suspended in a formulation system, the solubility of the API in the system and the dissolution rate are dependent if it is to be converted to a molecular state. For pimecrolimus suspended in the system, the solubility is low and the dissolution rate is slow due to the physical and chemical properties of the pimecrolimus. This directly results in slow transdermal penetration rates and low penetration rates of pimecrolimus, resulting in slow and non-sustained clinical efficacy of the prior art pimecrolimus cream. This is also why clinical pimecrolimus cream is required to be used at a high frequency (2-3 times a day).
Aiming at the problems of slow and non-durable clinical curative effect of the pimecrolimus external preparation product in the prior art, firstly, the transdermal permeation rate and the permeation quantity of the pimecrolimus preparation are increased. The common means for improving the transdermal absorption in pharmacy are two, namely, the content of pimecrolimus is increased, the specification of the medicine is improved, but the medicine is obviously unsuitable in the aspect of medicine economy, and a series of problems such as the improvement of the occurrence rate of adverse reaction, skin drug resistance and the like can be brought when the specification of the medicine is increased; and secondly, changing the physicochemical property of pimecrolimus by means of pharmaceutics.
Disclosure of Invention
The invention provides a preparation method of a pimecrolimus external nano preparation with high stability and bioavailability, which aims to overcome the defects in the prior art, changes the physicochemical properties of pimecrolimus by means of pharmaceutics, realizes the improvement of the accumulated permeation quantity of pimecrolimus on skin and the retention quantity of skin layers, improves the bioavailability, improves the stability of the pimecrolimus nano preparation at normal temperature by optimizing a prescription, and is convenient for daily use.
The technical solution of the invention is as follows: a preparation method of a pimecrolimus external nanometer preparation with high stability and bioavailability utilizes the characteristics of water-insoluble and oil-soluble pimecrolimus, uses a micro-emulsion gel (emulsion) technology, and prepares the pimecrolimus emulsion after the pimecrolimus is dissolved by medium-long chain fatty acid oil ester. On the premise of not changing the molecular structure of pimecrolimus and not changing the specification of the product, the release speed of pimecrolimus is improved by utilizing the characteristics of pharmaceutics, the accumulated permeation quantity of pimecrolimus on skin and the retention quantity of skin layers are obviously improved, the bioavailability is improved, the clinical effectiveness of the external preparation of pimecrolimus is enhanced, the curative effect of the product is improved, and the stability of pimecrolimus is improved.
Specifically, the characteristics of the lipophilic property of pimecrolimus are utilized to dissolve the pimecrolimus in mixed medium-long chain fatty acid oil (including but not limited to the mixture of a plurality of medium chain triglycerides, oleyl alcohol, oleic acid and isopropyl myristate) to prepare the micro-emulsion gel (emulsion). So that the pimecrolimus can be stored in the oil phase in a molecular form, and the dissolution and release speed of the pimecrolimus is improved.
The method specifically comprises the following steps:
1) Preparing pimecrolimus colostrum by using a pimecrolimus raw material drug, wherein the particle size of the pimecrolimus colostrum is about 1-100 mu m;
2) Homogenizing pimecrolimus colostrum by using a high-pressure homogenizer to prepare pimecrolimus Mo Siwei emulsion, wherein the particle size of the pimecrolimus Mo Siwei emulsion is 100-1000nm, and the electric potential is-10-50 mv;
3) Adding the high molecular gel into the pimecrolimus microemulsion, and slowly stirring until the solution is complete. Obtaining pimecrolimus emulsion.
Preferably, the step 1) specifically includes:
(1) adding pimecrolimus raw material medicine into the mixed medium-long chain fatty acid oil, and stirring until the mixture is clear;
(2) adding an emulsifying agent, stirring uniformly, and adding purified water;
(3) high-speed shearing and dispersing to prepare the colostrum.
Preferably, in the step (1), the pimecrolimus crude drug is added into the mixed oil of ethanol, medium chain triglyceride and isopropyl myristate.
Preferably, the emulsifying agent in the step (2) is tween 60 and span 60.
Preferably, the pimecrolimus bulk drug is 1% by weight, the mixed oil of ethanol, medium-chain triglyceride and isopropyl myristate is 20%, wherein the volume ratio of the ethanol, the medium-chain triglyceride and the isopropyl myristate is 1:1:2, tween 60 is 6%, span 60 is 2%, and the balance is purified water.
Preferably, the stirring speed of the step (1) is 500-1000rpm.
Preferably, the high-speed shearing dispersion in the step (3) is 10000rpm for 30min.
Preferably, in the step 2), the homogenizing pressure of the high-pressure homogenizer is 800bar, and the homogenizing is carried out for 3 times.
Preferably, the polymer gel in the step 3) is 0.5% of hydroxyethyl cellulose by weight.
The invention has the advantages that: the method is reasonable, the physical and chemical properties of pimecrolimus are improved by adopting a pharmaceutical method on the premise of not changing the molecular structure of the medicine and utilizing the characteristics of water-insoluble and oil-soluble pimecrolimus, the pimecrolimus is stored in a medicine preparation in a molecular form, the transdermal rate and the transdermal absorption of the pimecrolimus during external use are improved, namely the bioavailability is improved, the curative effect of the medicine is enhanced, the use frequency of the medicine is reduced, the effectiveness and the safety of the medicine are improved, the basic theory of medicine economy is met, and the clinical value of the product is improved. The stability of pimecrolimus is improved by optimizing the prescription, and the pimecrolimus can be kept stable for 18 months at normal temperature, so that the product can be sold for a long time at normal temperature and used, and the daily use of consumers is facilitated.
Drawings
FIG. 1 is an electron micrograph of pimecrolimus colostrum prepared in example 1 of the present invention.
FIG. 2 is a graph of particle size of pimecrolimus microemulsion prepared in example 1 of the present invention.
Fig. 3 is a potential diagram of pimecrolimus microemulsion prepared in example 1 of the present invention.
Fig. 4 is an electron microscopic image of pimecrolimus microemulsion prepared in example 1 of the present invention.
Fig. 5 is a rheological profile of a piramide Mo Siwei emulsion gel prepared in example 2 of the present invention.
Description of the embodiments
The present invention will be described in further detail with reference to examples and embodiments.
A preparation method of a pimecrolimus external-use nanometer preparation with high stability and bioavailability utilizes the lipophilicity of pimecrolimus, adopts a pharmacological means to dissolve the pimecrolimus in an oil solution, and stores the pimecrolimus in a medicine preparation in a molecular form so as to increase the release and transdermal speed of the medicine.
Specifically, pimecrolimus is dissolved in mixed medium-long chain fatty acid oil (including but not limited to a mixture of a plurality of medium chain triglycerides, oleyl alcohol, oleic acid and isopropyl myristate), and purified water, an emulsifier and the like are added to prepare the colostrum.
Pimecrolimus preparation pimecrolimus colostrum in addition to the above methods, the pimecrolimus can be stored in a pharmaceutical preparation in the form of molecules, such as: pretreating pimecrolimus to prepare a pimecrolimus inclusion compound; preparing a phospholipid complex of pimecrolimus by utilizing the lipophilic characteristic of pimecrolimus; solubilization of pimecrolimus by eutectic action; pretreating pimecrolimus to prepare solid dispersion and the like.
And then using a high-pressure homogenizer to crush and homogenize the emulsion drops to finally obtain the piramide Mo Siwei emulsion with the particle size ranging from 100 nm to 1000nm, wherein the potential of the microemulsion is-10 to 50mv, and the emulsion drops are stable and controllable. And then adding a high molecular gel including but not limited to hydroxyethyl cellulose, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. into the outer aqueous phase.
The high pressure homogenizing process is adopted to prepare piramate Mo Siwei emulsion gel (emulsion) and the particle size of the colostrum is further reduced to hundreds of nanometers. The main parameters of high pressure homogenization are the homogenization pressure, which is typically 600-1500bar, and the number of homogenization, which is selected according to the particle size of the milk particles.
The forces of the homogenizer are mainly shear forces and pressure forces. In the homogenizing process, the plunger pump sucks materials into the valve group through continuous reciprocating motion, and the plunger can adjust the pressure. When the material flows through the gap under high pressure, the liquid drop is firstly extended, and then the extended part is sheared and broken due to the turbulence effect when passing through the valve body. The liquid flow rushing out from the valve gap at high speed collides with the check ring, and the high-speed collision effect is generated. Simultaneously, the pressure is rapidly and greatly reduced, a great blasting force is generated, cavitation is instantaneously caused, and particles or liquid drops are crushed by strong released energy and strong high-frequency vibration, so that the effects of homogenizing, crushing and emulsifying liquid samples are achieved. The liquid drops carry extremely high static pressure energy at the feed liquid inlet, and in the homogenizing process, the static pressure energy is converted into kinetic energy to break the liquid drops.
Pimecrolimus colostrum to prepare pimecrolimus Mo Siwei emulsion gel (emulsion) includes, but is not limited to, drip method, micro-jet, etc., in addition to high pressure homogenization.
Example 1: preparation of pime Mo Siwei milk (nanoemulsion):
the high-pressure homogenization method is adopted to prepare the piraMei Mo Siwei emulsion:
firstly, adding 1% pimecrolimus raw material drug into mixed oil of 20% ethanol, medium-chain triglyceride and isopropyl myristate (volume ratio is 1:1:2), and stirring at 500-1000rpm until the mixture is clear;
adding 6% Tween 60 and 2% span 60, stirring, and adding purified water to 100%;
high-speed shearing and dispersing (10000 rpm/30 min) to obtain colostrum with particle size of about 1-100 μm (see figure 1);
homogenizing the prepared colostrum for 3 times by using a high-pressure homogenizer (homogenizing pressure 800 bar) to obtain the microemulsion, wherein the particle size of the prepared microemulsion is shown in figure 2, the potential is shown in figure 3, and the electron microscope is shown in figure 4.
The result shows that the particle size of the prepared piramide Mo Siwei emulsion ranges from 100 nm to 1000nm, the light scattering average particle size is 251.7nm, the PDI of the particle size distribution is 0.214, the potential is between-10 mv and 50mv, and the average potential is-18.9 mv.
Example 2: preparation of pimecrolimus latex (microemulsion gel)
To the pimecrolimus microemulsion prepared in example 1, 0.5% of Hydroxyethylcellulose (HEC) was added and stirred slowly until completely dissolved.
The HEC model used was HEC 250M, sold under the trade name Natrosol ™, mitsubishi.
The final pimecrolimus emulsion was tested for rheological profile using a rheometer (Discovery HR-10), and the obtained rheological profile (as shown in fig. 5) showed that the emulsion was a pseudoplastic fluid with semi-solid rheological characteristics.
Example 3: comparison of transdermal absorption (bioavailability) of pimecrolimus latex
Transdermal absorption of pimecrolimus latex prepared in example 2 was compared with commercially available pimecrolimus cream using a loading area of 1.77cm 2 Franz diffusion cell with a receiving cell volume of 8mL was 10mg/cm with the skin of the pig of bar Ma Xiaoxiang as a permeation barrier (one month old) 2 The drug was applied at a dose of about 17.7mg, the receiving solution was physiological saline, and an in vitro transdermal test was performed, wherein the temperature was set at 32℃and the rotational speed was 600rpm, n=6, and the sampling time points were 4, 8, 12, 24 hours.
The results obtained are shown in the following table.
Table 1 example 2 cumulative transdermal amount comparison of pimecrolimus latex and commercially available pimecrolimus cream
Table 2 example 2 skin hold-up comparison of pimecrolimus latex with commercially available pimecrolimus cream
From the results in tables 1 and 2, it is apparent that the transdermal penetration amount and skin retention amount (p < 0.05) of pimecrolimus can be significantly improved when Cheng Nami crystals (pimecrolimus latex) are prepared from pimecrolimus, compared to the micro-sized pimecrolimus (commercially available pimecrolimus Mo Siru).
Example 4: stability test of pimecrolimus latex
The nanometer preparation of pimecrolimus is a common product, and the current pharmaceutics nanometer preparation comprises nanoemulsion, liposome, micelle, nanoparticle, nanocrystalline and the like. However, conventional nano-formulations are very unstable, nano-formulations are thermodynamically highly unstable, and the oshi ripening effect can destabilize particles, causing aggregation, incorporation, and the like. Instability of nanoformulations is currently a bottleneck limiting the application of nanoformulations.
For such problems, most of the strategies adopted by the nano-formulations currently on the market are to change the storage conditions and the use modes. The new corona vaccine of the psilon is a liposome of mRNA, in order to prevent aggregation, merger and the like of the liposome. The storage mode adopted by the mRNA vaccine of the pyroxene is low-temperature storage to ensure the stability of the medicament before use, and the medicament can be stored for 6 months at the temperature of-70 ℃.
For daily use, particularly topical, the cost of such harsh storage conditions is unacceptable. The invention adopts another idea and uses a gel method adopted in the external preparation. After the microemulsion (nanoemulsion) is prepared, carbomer, hydroxyethyl cellulose and other substances are used for increasing the viscosity of the system, preventing the collision between nanoemulsions and maintaining the stability of the system. And the gel materials such as hydroxyethyl cellulose, carbomer and the like are reported in the literature to be capable of increasing the negative potential of the system, and electrostatic repulsion is utilized to increase the stability of the system.
The results of the stability test performed on the pimecrolimus latex of example 2 are shown in the following table.
Table 3 example 2 pimecrolimus latex stability test
As can be seen from the above table, the pimecrolimus latex of example 2 was stable for 18 months at normal temperature. The stability of the nano system is maintained, and the nano system is the basis for increasing the drug permeation. The water-based paint has the capability of being stable under normal temperature, and can effectively meet the daily use requirements of consumers.
The results of comparing the particle size and potential of the pimecrolimus latex of example 2 with those of pimecrolimus latex without gel and with carbomer 980 replaced by hydroxyethyl cellulose are shown in the following table.
TABLE 4 pimecrolimus latex comparison with different matrices
As can be seen from the above table, the hydroxyethyl cellulose matrix and the carbomer matrix can meet the requirements of particle size and potential, and the invention combines the microemulsion (nanoemulsion) technology and the gel technology, thereby creatively obtaining a nanoemulsion preparation which can be stable for a long time.
In conclusion, the external nano preparation provided by the invention not only can increase the permeation quantity of pimecrolimus in skin and improve the bioavailability, but also can be stable for 18 months under the condition of normal temperature, thereby meeting the daily use requirements of consumers.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (9)
1. The preparation method of the pimecrolimus external nano preparation with high stability and bioavailability is characterized by comprising the following steps:
1) Preparing pimecrolimus colostrum with the particle size of 1-100 mu m by using the pimecrolimus raw material drug;
2) Homogenizing pimecrolimus colostrum by using a high-pressure homogenizer to prepare pimecrolimus Mo Siwei emulsion, wherein the particle size of the pimecrolimus Mo Siwei emulsion is 100-1000nm, and the electric potential is-10-50 mv;
3) And adding the high molecular gel into the pimecrolimus microemulsion, and slowly stirring until the solution is completely dissolved to obtain the pimecrolimus emulsion.
2. The method for preparing a highly stable and bioavailable pimecrolimus topical nano-formulation according to claim 1, wherein said step 1) comprises:
(1) adding pimecrolimus raw material medicine into the mixed medium-long chain fatty acid oil, and stirring until the mixture is clear;
(2) adding an emulsifying agent, stirring uniformly, and adding purified water;
(3) and (5) shearing and dispersing at high speed to prepare pimecrolimus colostrum.
3. The method for preparing a highly stable and bioavailable pimecrolimus topical nano-formulation according to claim 2, wherein in step (1), the pimecrolimus drug substance is added to a mixture of ethanol, medium chain triglycerides and isopropyl myristate.
4. The method for preparing a highly stable and bioavailable pimecrolimus external preparation according to claim 3, wherein the emulsifying agent in step (2) is tween 60 and span 60.
5. The method for preparing the external-use nano-preparation of pimecrolimus with high stability and bioavailability according to claim 4, wherein the raw material medicine of pimecrolimus is 1% by weight, the mixed oil of ethanol, medium-chain triglyceride and isopropyl myristate is 20%, and the volume ratio of ethanol, medium-chain triglyceride and isopropyl myristate is 1:1:2, tween 60 is 6%, span 60 is 2%, and the balance is purified water.
6. The method for preparing a highly stable and bioavailable pimecrolimus topical nano-formulation according to any of claims 2-5, wherein the stirring speed in step (1) is 500-1000rpm.
7. The method for preparing a pimecrolimus external preparation with high stability and bioavailability according to any one of claims 2-5, wherein the high-speed shearing dispersion in the step (3) is 10000rpm for 30min.
8. The method for preparing a pimecrolimus external preparation with high stability and bioavailability according to any one of claims 2-5, wherein the homogenizing pressure of the high-pressure homogenizer in step 2) is 800bar and the homogenizing is performed 3 times.
9. The method for preparing a highly stable and bioavailable pimecrolimus topical nano-formulation according to claim 5, wherein the polymer gel in step 3) is 0.5% by weight of hydroxyethylcellulose.
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