CN115844821A - Desonide nanocrystal suspension, preparation method and application thereof - Google Patents

Abstract

The invention relates to the technical field of medicines, and provides a donepezil nanocrystal suspension, a preparation method and application thereof. The donepezil nanocrystal suspension comprises a stabilizer solution and a donepezil nanocrystal; the particle size range of the donepezil nanocrystal is 100-1000nm, and the potential is-10 mv to-50 mv; the stabilizer solution is an aqueous solution of Sodium Dodecyl Sulfate (SDS), and the mass fraction (g/g) of the sodium dodecyl sulfate is 10-20%. The invention overcomes the defects of the prior art and solves the technical problems of low solubility of the desonide and low skin permeation amount in the prior external preparation.

Description

Desonide nanocrystal suspension, preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a donepezil nanocrystal suspension, a preparation method and application thereof.

Background

Desonide is a synthetic, low-potency, non-fluorinated topical corticosteroid effective in a wide variety of dermatological conditions for which corticosteroid therapy is effective, and has been widely used for many years for the topical treatment of mild to moderate atopic dermatitis (eczema, psoriasis, contact dermatitis, neurodermatitis, seborrheic dermatitis, etc. resulting in skin inflammation and redness, swelling, itching, discomfort, etc. of the skin). Multiple clinical trial studies have confirmed the safety and efficacy of this drug, and desonide has a critical position as a topical corticosteroid hormone.

However, the solubility of the desonide is poor due to the chemical structure of the desonide, after the desonide is prepared into an external preparation, such as cream, gel, ointment and lotion, the desonide is suspended in a system, and due to the characteristic of poor solubility, the release speed of the desonide is slow, so that the desonide cannot be rapidly released to permeate through the stratum corneum in a short time, the skin permeation amount of the desonide is low, the effect is slow, and the disease can be effectively treated by using the desonide for many times, for example, the external use of the desonide lotion needs to be carried out 2-4 times a day clinically. However, because the donepezil is a glucocorticoid drug, multiple side effects, such as fungal infection, epidermal atrophy and the like, can be caused by long-term use of the donepezil for a high frequency, and even the risk of systemic adverse reaction is caused. Therefore, the physical and chemical properties of the desonide are improved, the transdermal permeation quantity of the desonide is improved, the local curative effect of the medicine is increased, and the clinical advantage of the product can be obviously improved by shortening the use frequency of the medicine.

The external preparation of desonide is administered transdermally, and its permeation route is the epidermal route, whereas for trans-membrane transport of the epidermal route, it occurs on the premise that the pharmaceutically active ingredient (API) is present in the form of a molecule (dissolved state). Therefore, the solubility of the desonide is improved, and the active effects of improving the transdermal permeation quantity of the desonide, increasing the local curative effect of the medicine and shortening the use frequency of the medicine are achieved.

The nanocrystalline technology is a novel pharmaceutical technology for increasing the solubility of insoluble drugs. It is currently believed that the mechanism of action of nanocrystals includes: 1. the release speed of the medicine is improved: according to the famous pharmacy Noyes-Whitney equation dC/dt = kD A (Cs-Ct) (wherein dC/dt is dissolution rate, kD is dissolution rate constant, A is specific surface area, cs is drug saturation solubility, and Ct is drug concentration), the dissolution rate of the drug is in positive correlation with the specific surface area of the drug. The nanocrystalline increases the specific surface area of the medicine by nanocrystallization, and improves the dissolution rate of the insoluble medicine. Data show that under the same dissolution condition, when the particle size of cilostazol is reduced from 13 μm to 220nm, the dissolution speed of the drug is increased to 5100 times of the original speed; 2. improving the solubility of the drug: according to another well-known pharmaceutical Ostwald-Freundlich equation (lgS 2/S1=2M σ (1/R2-1/R1)/ρ RT) (where S2 and S1 are solubilities of drugs at different sizes, R2 and R1 are sizes of drugs, M denotes a relative molecular mass of drugs, σ is an interfacial tension between solid and liquid, ρ is a density of drugs, R is a molar gas constant, and T is a thermodynamic temperature), the greater the difference in solubility is, the greater the difference in particle size is. After the medicine is prepared into the nano-crystal, the size of the medicine is greatly reduced, so that the solubility of the medicine in a system is directly improved, and the slightly soluble medicine is more easily dissolved in the system.

Therefore, a donepezil nanocrystal suspension, a preparation method and application thereof are provided.

Disclosure of Invention

Technical problem to be solved

Aiming at the defects of the prior art, the invention provides a donepezil nanocrystal suspension, a preparation method and application thereof, and solves the technical problems of low solubility of the donepezil and low skin permeation in the prior external preparation.

(II) technical scheme

In order to achieve the purpose, the invention is realized by the following technical scheme:

a donepezil nanocrystal suspension is characterized in that:

the suspension comprises a stabilizer solution and a donepezil nanocrystal suspended in the stabilizer solution;

the particle size range of the donepezil nanocrystal is 100-1000nm, and the potential is-10 mv to-50 mv;

the stabilizer solution is an aqueous solution of Sodium Dodecyl Sulfate (SDS), and the mass fraction (g/g) of the sodium dodecyl sulfate is 10-20%.

Furthermore, the light scattering average particle size of the desonide nanocrystal is 354.7nm, the PDI of the particle size distribution is 0.204, and the average potential is-26.9 mv.

A preparation method of a donepezil nanocrystal suspension is characterized by comprising the following steps: the method comprises the following steps of mixing aqueous solution of the desonide and the sodium dodecyl sulfate according to a ratio of 1:20 (g/ml) and grinding, and obtaining suspension, namely the suspension of the desonide nanocrystal after grinding.

Further, the budesonide is pre-pulverized to a particle size D90 of 5 to 10 μm before being pulverized.

Furthermore, the grinding adopts a medium grinding method, the grinding equipment is a ball mill, and the grinding medium is zirconia beads.

Further, the particle size of the zirconia beads is 0.4mm, and the ratio of the zirconia beads to the aqueous solution of sodium dodecyl sulfate is 1:5 (g/ml), and the milling parameters were 2000rpm,12h.

The invention also provides application of the donepezil nanocrystal suspension in a donepezil external preparation.

Further, the external preparation comprises cream, gel, ointment, lotion.

Furthermore, the cream is prepared from a donepezil nanocrystal suspension, an oil phase, a water phase and a surfactant;

the oily matrix of the oil phase is one or more selected from light liquid paraffin, cetostearyl alcohol, white vaseline and beeswax;

the surfactant is a polyoxyethylene ether emulsifier, and the polyoxyethylene ether emulsifier is selected from one or more of castor oil polyoxyethylene ether, nonylphenol polyoxyethylene ether, octylphenol polyoxyethylene ether, oleyl alcohol polyoxyethylene ether, fatty alcohol polyoxyethylene ether and methyl stearate polyoxyethylene ether.

Furthermore, the gel is prepared from a donepezil nanocrystal suspension, a thickening agent, a cellulose derivative, chitosan, polyvinylpyrrolidone and polyvinyl alcohol;

the thickening agent is carbomer, and the carbomer is selected from one or more of carbomer 940, carbomer 941, carbomer 934, carbomer 1342, carbomer 980, carbomer ETD 2020, carbomer SF-1 and carbomer Ultrez;

the cellulose derivative is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and carboxymethyl cellulose.

(III) advantageous effects

The scheme provided by the invention has the following beneficial effects:

1. according to the invention, on the premise of not changing the molecular structure of the drug, the physical and chemical properties of the desonide are improved by pretreating the desonide, and the solubility and dissolution speed of the drug are increased, so that the transdermal rate and transdermal absorption amount of the desonide when being externally used are further improved, the curative effect of the drug is enhanced, the use frequency of the drug is reduced, the effectiveness and safety of the drug are improved, the basic theory of the drug economy is met, and the clinical value of the product is improved.

2. The prepared donepezil nanocrystal suspension has good stability and is not easy to generate obvious aggregation; the external reagent prepared by the donepezil nanocrystal suspension is also the same, so that the donepezil nanocrystals in the reagent do not obviously aggregate within at least one month, and the stability and the effectiveness are controllable.

3. The method adopts a medium grinding method to obtain the donepezil nanocrystal suspension, belongs to a common crushing mode in domestic industry, has no special requirements on equipment compared with methods such as a high-pressure homogenization method, a precipitation method, a solvent evaporation method, a spray drying method and the like introduced abroad, and is easier to popularize and apply in process.

Drawings

FIG. 1 is a graph showing the distribution of the diameter of the nano-sized particles of the donepezil prepared in example 1;

FIG. 2 is a graph showing the potential distribution of the nano-crystals of desonide prepared in example 1;

FIG. 3 is an electron microscope scanning image of the nano-crystalline desonide prepared in example 1, wherein the scale on the left is 1 μm and the scale on the right is 200nm;

figure 4 is an electron micrograph of the nano-sized suspension of budesonide ofcontrol 1 in example 1 taken 12h after preparation.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1: preparation and transdermal absorption of desonide nanocrystalline cream

(1) Preparation of nano-crystalline of desonide

In this example, a dielectric grinding method is used to prepare the nano-crystalline of the desonide. Firstly, grinding a desonide raw material drug to a particle size D90 of about 5-10 mu m by using an airflow grinder, weighing 5g of the ground desonide raw material drug, adding the 5g of the ground desonide raw material drug into 100ml of aqueous solution of sodium dodecyl sulfate, uniformly dispersing the mixture by using a high-shear emulsifying machine (the shear speed is 10000 rpm) for 10min, transferring the mixture into a medium grinding machine, adding 20g of zirconia beads with the diameter of 0.4mm serving as grinding media, grinding the mixture at 2000rpm for 12h, and separating the zirconia beads to obtain a desonide nanocrystal suspension. The grain size and potential of the prepared nanocrystals, and scanning electron microscopy are shown in fig. 1, fig. 2, and fig. 3, respectively. The results show that the nano-crystalline of the desonide prepared by the embodiment is columnar crystal, the grain diameter ranges from 100 nm to 500nm, the light scattering average grain diameter is 354.7nm, the PDI of the grain diameter distribution is 0.204, the electric potential ranges from-10 mv to 50mv, and the average electric potential is-26.9 mv.

The mass fractions (g/g) of the aqueous solution of sodium dodecyl sulfate in the above preparation methods were adjusted to 5%, 10%, 15%, and 25%, to obtain four sets of donepezil nanocrystal suspension controls,control 1,control 2, control 3, andcontrol 4, respectively. Incontrast 4, the mass fraction of sodium dodecyl sulfate is 25%, the medium foams seriously, and the lubrication effect is large, which affects the impact force and the collision strength of zirconia beads in the grinding machine, so that the donepezil nanocrystals meeting the particle size requirement (100-1000 nm) cannot be prepared, and the subsequent observation of the donepezil nanocrystal suspension is not performed. In the present example and the first three groups of controls, nano-scale suspension of the desonide nanocrystals can be prepared, and scanning is performed every hour to observe the condition of the desonide nanocrystals in the suspension, incontrast 1, see fig. 4, at room temperature, in 12 hours, a significant aggregation phenomenon occurs, and incontrast 2, 3 and in example 12 hours, a significant aggregation phenomenon occurs, wherein 40-50 μm particles of the desonide are observed.

(2) Preparation of Desonide nanocrystalline cream

Weighing the raw and auxiliary materials according to the prescription in the table for later use. Heating white vaseline, liquid paraffin, cetostearyl alcohol, tween 80 and span 60 to 70-80 ℃ for dissolving to obtain an oil phase for later use; heating purified water, propylene glycol and methyl paraben to 70-80 ℃ for later use. Then mixing the oil phase and the water phase, and mixing for 30min at 80 ℃ to obtain an intermediate. And then cooling the intermediate by using cooling water. When the temperature of the paste body is reduced to 60 ℃, the nano-crystalline of the desonide is added, and the paste body is cut at 2000rpm for 30min and then is continuously cooled to obtain a finished product. And according to the same prescription process, the same specification of the desonide cream is prepared by using the desonide with the grain diameter of micron grade (D90 is between 5 and 10 mu m).

(3) Transdermal absorption of the Desonide nanocrystal cream

Comparing the nano-crystalline cream of desonide prepared in (2)' with common nano-crystalline cream of desonide by transdermal absorption, and adopting the area of the medicine applied to the cream of 1.77cm² Franz diffusion cell with 8mL receiving cell volume, and Bama miniature pig skin as permeation barrier (one month old) at 10mg/cm² And (3) applying the medicine, wherein the medicine applying amount is about 17.7mg, the receiving solution is normal saline, and an in-vitro transdermal test is carried out, wherein the temperature is set to be 32 ℃, the rotating speed is 600rpm, n =6, and the sampling time points are 4, 8, 12 and 24 hours. The results obtained are shown in the following table. From the results of tables 1 and 2, it is understood that the transdermal permeation amount and the skin retention amount (p < 0.05) of the donepezil are significantly improved when the donepezil is prepared into the nanocrystal, as compared to the micron-sized donepezil.

TABLE 1 cumulative transdermal amounts of Desonide nanocrystalline cream and Desonide cream

TABLE 2 skin Retention of Desonide nanocrystalline cream and Desonide cream

(4) Storage of a Desonide nanocrystalline cream

The storage conditions were: at room temperature (30 deg.C), in the shade.

Sampling every 24h to observe the transformation condition of the nano-crystalline of the desonide in the cream, and no obvious aggregation occurs within 30 days.

In addition, when the donepezil nanocrystal cream prepared from the donepezil nanocrystal suspension obtained incontrol 1 was used, it was found that aggregation occurred in a short time after the cream was prepared.

Example 2: preparation and transdermal absorption of desonide nanocrystalline gel

(1) Preparation of the Desonide nanocrystal

Preparation of the nano-crystalline forms of the desonide is referred to the preparation method of the nano-crystalline forms of the desonide in "example 1". The preparation process is the same as that in "example 1", and the nano-crystalline of the desonide is prepared by a medium grinding method.

(2) Preparation of desonide nanocrystalline gel

Weighing the raw and auxiliary materials according to the prescription in the table for later use. 10g of purified water was added to the sodium hydroxide to dissolve the sodium hydroxide to prepare an aqueous solution of sodium hydroxide. Adding the prescribed amount of water into a container, adding ethyl p-hydroxybenzoate, heating, stirring to dissolve, cooling, adding carbomer 940, and standing overnight to allow it to swell sufficiently. And adding the propylene glycol according to the prescription amount, stirring uniformly, then adding the donepezil nanocrystal or the donepezil, continuing stirring uniformly, then adding the aqueous solution of the sodium hydroxide, and stirring uniformly to obtain the donepezil nanocrystal gel and the donepezil gel.

(3) Transdermal absorption of a gel of nano crystals of desonide

Comparing the nano-crystalline gel of the desonide prepared in the step (2) with the common gel of the desonide in a percutaneous absorption way, and adopting the medicine application area of 1.77cm² Franz diffusion cell with 8mL receiving cell volume, and Bama miniature pig skin as permeation barrier (one month old) at 10mg/cm² And (3) applying the medicine, wherein the medicine applying amount is about 17.7mg, the receiving solution is normal saline, and an in-vitro transdermal test is carried out, wherein the temperature is set to be 32 ℃, the rotating speed is 600rpm, n =6, and the sampling time points are 4, 8, 12 and 24 hours. The results obtained are shown in the following table. The results show that nano-crystalline desonide can also significantly increase the transdermal penetration and skin retention (p < 0.05) of desonide when the dosage form of desonide is changed to gel, which is consistent with the results of the cream of "example 1".

TABLE 3 cumulative transdermal amounts of desonide nanocrystal gels and desonide gels

TABLE 4 Denide nanocrystalline gels and skin retentions of the Denide gels

(4) Storage of desonide nanocrystalline gels

The storage conditions were: no more than 20 deg.C, and shade.

Sampling every 24h to observe the transformation condition of the nano-crystalline of the desonide in the cream, and no obvious aggregation occurs within 30 days.

Example 3: preparation and transdermal absorption of desonide nanocrystalline lotion

(1) Preparation of the Desonide nanocrystal

Preparation of the nano-crystalline forms of the desonide is referred to the preparation method of the nano-crystalline forms of the desonide in "example 1". The preparation process is the same as that in "example 1", and the nano-crystalline of the donepezil is prepared by a medium grinding method.

(2) Preparation of nano-crystalline detergent of desonide

Weighing the raw and auxiliary materials according to the prescription in the table for later use. Preparation of an aqueous phase: weighing purified water with a general prescription amount at 80 ℃, adding hydroxypropyl methylcellulose, stirring and dispersing, adding purified water with a general prescription amount, and stirring and dissolving; then adding glycerol, disodium ethylene diamine tetraacetate, phenoxyethanol, citric acid and sodium citrate, heating at 80 ℃, stirring and dissolving completely, preserving heat, adding the nano-crystalline of the budesonide or the budesonide, stirring and dispersing uniformly; preparation of oil phase: weighingspan 8, liquid paraffin and cetostearyl alcohol according to the prescription amount, heating and melting completely at 80 ℃, and preserving heat; emulsification: and (3) adding the water phase into the oil phase at the temperature of 80 ℃, stirring and emulsifying for 10min at 40rpm, and gradually cooling to room temperature to obtain the donepezil nanocrystal/donepezil lotion.

(3) Transdermal absorption of donepezil nanocrystalline lotion

Comparing the nano-crystalline lotion of the desonide prepared in the step (2) with the common lotion of the desonide in a percutaneous absorption way, and adopting the application area of 1.77cm² Franz diffusion cell with 8mL receiving cell volume, and Bama miniature pig skin as permeation barrier (one month old) at 10mg/cm² Applying the medicine, wherein the medicine applying amount is about 17.7mg, and the receiving liquid is physiological saline to carry out an in-vitro transdermal test, wherein the temperature is set to be 32 ℃, the rotating speed is 600rpm, n =6, and the sampling time points are 4, 8, 12 and 24h. The results obtained are shown in the following table. The result shows that after the dosage form of the desonide is changed into the lotion, the nano-crystallized desonide can also obviously improve the transdermal permeation quantity and the skin retention quantity (p is less than 0.05) of the desonide, and in addition, the transdermal result of the lotion shows that the transdermal cumulative permeation quantity and the skin retention quantity of the desonide are obviously higher than those of the cream and the gel after the desonide is prepared into the lotion. This is probably due to the low viscosity of the lotion, and the faster dissolution and transport of the desonide through the membrane in the system.

TABLE 5 cumulative transdermal amounts of DENEDEAD NANOCRYSTAL WASHING AGENT AND DENEDENDAD WASHING AGENT

TABLE 6 skin Retention of Desonide nanocrystal lotions and Desonide lotions

(4) Storage of a Desonide nanocrystal wash solution

The storage conditions were: at room temperature (30 deg.C), in the shade.

Sampling every 24h to observe the transformation condition of the desonide nanocrystals in the washing liquid, and no obvious aggregation occurs within 30 days.

It should be noted that, in this document, the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (10)

1. A donepezil nanocrystal suspension is characterized in that:

the suspension comprises a stabilizer solution and a donepezil nanocrystal suspended in the stabilizer solution;

the particle size range of the desonide nanocrystal is 100-1000nm, and the potential is-10 mv to 50mv;

the stabilizer solution is an aqueous solution of sodium dodecyl sulfate, and the mass fraction (g/g) of the sodium dodecyl sulfate is 10-20%.

2. The donepezil nanocrystal suspension of claim 1, wherein: the light scattering average particle size of the donepezil nanocrystal is 354.7nm, the PDI of the particle size distribution is 0.204, and the average potential is-26.9 mv.

3. The method of preparing a donepezil nanocrystal suspension according to claim 1 or 2, characterized in that: the method comprises the following steps of mixing aqueous solution of the desonide and the sodium dodecyl sulfate according to a ratio of 1:20 (g/ml) and grinding, and obtaining suspension, namely the suspension of the desonide nanocrystal after grinding.

4. The method of preparing a donepezil nanocrystal suspension of claim 3, wherein: the diniconide is pre-crushed to a particle size D90 of 5-10 mu m before being ground.

5. The method of preparing a donepezil nanocrystal suspension of claim 3, wherein: the grinding adopts a medium grinding method, the grinding equipment is a ball mill, and the grinding medium is zirconia beads.

6. The method of preparing a donepezil nanocrystal suspension of claim 5, wherein: the particle size of the zirconia beads is 0.4mm, and the ratio of the zirconia beads to the aqueous solution of sodium dodecyl sulfate is 1:5 (g/ml), and the milling parameters were 2000rpm,12h.

7. Use of the donepezil nanocrystal suspension of claim 1 or 2 in a topical formulation of donepezil.

8. Use of the donepezil nanocrystal suspension of claim 7 in a topical formulation of donepezil, characterized in that: the external preparation comprises cream, gel, ointment, and lotion.

9. The use of the donepezil nanocrystal suspension of claim 8 in a topical formulation of donepezil, wherein: the cream is prepared from a donepezil nanocrystal suspension, an oil phase, a water phase and a surfactant;

the oily matrix of the oil phase is one or more selected from light liquid paraffin, cetostearyl alcohol, white vaseline and beeswax;

the surfactant is a polyoxyethylene ether emulsifier, and the polyoxyethylene ether emulsifier is one or more selected from castor oil polyoxyethylene ether, nonylphenol polyoxyethylene ether, octylphenol polyoxyethylene ether, oleyl alcohol polyoxyethylene ether, fatty alcohol polyoxyethylene ether and methyl stearate polyoxyethylene ether.

10. The use of the donepezil nanocrystal suspension of claim 8 in a topical formulation of donepezil, wherein: the gel is prepared from a donepezil nanocrystal suspension, a thickening agent, a cellulose derivative, chitosan, polyvinylpyrrolidone and polyvinyl alcohol;

the thickening agent is carbomer, and the carbomer is selected from one or more of carbomer 940, carbomer 941, carbomer 934, carbomer 1342, carbomer 980, carbomer ETD 2020, carbomer SF-1 and carbomer Ultrez;

the cellulose derivative is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and carboxymethyl cellulose.

Images