CN112023056B - Fluconazole pharmaceutical composition and preparation method thereof - Google Patents
Fluconazole pharmaceutical composition and preparation method thereof Download PDFInfo
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- 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 relates to a fluconazole pharmaceutical composition, which consists of fluconazole and microcrystalline cellulose compound in the weight ratio: fluconazole: microcrystalline cellulose complex= (1:4) - (2:1). By selecting a proper microcrystalline cellulose compound, the invention can increase the powder fluidity, improve the medicine uniformity and dissolution rate and obviously improve the stability of the fluconazole capsule.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a fluconazole pharmaceutical composition and a preparation method thereof.
Background
Fluconazole is a pyrrole broad-spectrum antifungal agent developed by the company of the best pharmacy (Pfizer Pharmaceuticals Ltd), and highly selectively interferes with the activity of cytochrome P-450 of fungi, thereby inhibiting the biosynthesis of ergosterol on the fungal cell membrane and leading intracellular substances to leak and die. The composition is mainly used for treating vaginal candidiasis, thrush, atrophic oral candidiasis, fungal meningitis, pulmonary fungal infection, abdominal infection, urinary tract infection, dermatomycosis and the like in clinic. The molecular action targets are as follows: lansterol 14-alpha demethylase.
The chemical name of fluconazole is alpha- (2, 4-difluorophenyl) -alpha- (1H-1, 2, 4-triazole-1-methyl) -1H-1,2, 4-triazole-1-yl ethanol. The structural formula is shown in formula I, and the molecular formula C 13 H 12 F 2 N 6 O, molecular weight 306.28, CAS number 86386-73-4, fluconazole is white crystalline powder, odorless, melting point 137-141 ℃, soluble in methanol, soluble in ethanol, slightly soluble in dichloromethane, water or acetic acid, insoluble in diethyl ether.
I. Fluconazole structural formula
According to reports (Yan Xiaogong, et al, polycrystals of fluconazole and transformation researches; 8 th phase of volume 29 of 8 of the modern applied pharmaceutical of China, 2012), fluconazole has four crystal forms of I crystal form, II crystal form, III crystal form and monohydrate crystal form, the I crystal form and the II crystal form have good thermal stability, and the monohydrate crystal form is transformed into the II crystal form at 60-160 ℃.
The fluconazole capsules published by the fei pharmaceutical in the french medical administration network (trade name:
) In the specification, the auxiliary materials comprise lactose, corn starch, sodium dodecyl sulfate, silicon dioxide, magnesium stearate, gelatin, titanium dioxide (E171) and blue No. 5 (E131). While inquiring fluconazole capsules (trade name:. For:. Sub.>
Specification of: 50 mg) of lactose 49.708 mg/granule, corn starch 16.500 mg/granule, sodium dodecyl sulfate 0.117 mg/granule, and a mixture of silica and magnesium stearate (ratio of 1: 9) 1.175 mg/grain. Fluconazole capsule->
The auxiliary materials are various, the dosage of the sodium dodecyl sulfate is low, and the sodium dodecyl sulfate is easy to mix unevenly, so that the stability of the medicine is affected.
The Chinese patent publication No. CN 108578377A discloses a fluconazole tablet and a preparation method thereof, and the fluconazole quick-release tablet is prepared, and the pharmaceutical excipients comprise a filler, a disintegrating agent, an adhesive and a lubricant; the preparation process comprises the steps of raw and auxiliary material crushing, mixing, wet granulation, drying, mixing and tabletting. The invention has the advantages of multiple prescription components, complex preparation process and low production efficiency.
In chinese patent publication No. CN 1812783a there is provided a fluconazole capsule with improved release, wherein fluconazole is mixed with an agent providing hydrophilic surface properties to the particles and optionally a surfactant to form particles, and the resulting particles are mixed with a filler, a disintegrant, a lubricant and a glidant and filled into the capsule. However, the technical scheme has the following defects: in the process of forming particles by fluconazole and hydrophilic surfactant, the surfactant is unevenly distributed in the particles easily to influence dissolution and in-vivo absorption due to small dosage of the surfactant, and the bioavailability is not high.
According to the search, the prior art for improving the stability of the fluconazole capsules mostly adopts an improved mode of auxiliary materials or technology, and the common defects are that: the prepared fluconazole medicinal composition has the risks of poor flowability, large difference in batches, low dissolution rate, poor stability and the like. The use of the complex to improve the stability of fluconazole capsules has not been reported in the literature.
A complex, which is an excipient mixture prepared by co-processing at least one water-soluble excipient and at least one water-insoluble excipient. For example, in the specification of chinese patent publication No. CN 101460150a, a directly compressible compound for orally disintegrating tablets is described, wherein the compound is a combination of a water-soluble excipient and a water-insoluble excipient, but the listed drugs in the patent scheme are numerous and widely varied, and it is not shown that the specific drug (e.g. fluconazole) can be targeted; from examples 1 to 10 listed in this patent specification, only the application of a complex of mannitol combined with at least one water-insoluble excipient to aspartame tablets is known; therefore, how to select a proper compound component has an improving effect on the stability of the fluconazole capsule, and the technical teaching cannot be known from the patent.
For another example, the chinese patent of publication No. CN 105520918A discloses a pregabalin capsule, which is composed of pregabalin, lactose complex and pharmaceutically acceptable carrier, and lactose-microcrystalline cellulose complex is selected as lactose complex, so that the stability of pregabalin capsule is poor, but the technical scheme is not enough: (1) the patent adopts a direct mixing process, and as the prescription contains high proportion of starch, the fluidity of the starch is poor, so that the prepared total mixed powder has the risk of fluidity; (2) the starch has a plurality of varieties with different sources and different models, and the property difference among the different varieties is large, so the risk of large in-batch dissolution difference exists; (3) the physicochemical properties of pregabalin are quite different from fluconazole, so there is uncertainty whether lactose-microcrystalline cellulose complex can be applied to the development of fluconazole capsules.
In view of the above, how to select suitable compound components, and further develop a fluconazole capsule with good fluidity and high stability, is a technical problem that has not been solved by the person skilled in the art.
Disclosure of Invention
The invention aims to solve the technical problem of providing a fluconazole pharmaceutical composition and a preparation method thereof, wherein microcrystalline cellulose compound is adopted as an auxiliary material to be mixed with fluconazole to form the composition, and capsules are filled to improve the fluidity and stability of the fluconazole pharmaceutical composition.
In order to solve the technical problems, the invention adopts the following technical scheme:
the fluconazole pharmaceutical composition consists of fluconazole and microcrystalline cellulose compound, wherein the weight ratio of the fluconazole to the microcrystalline cellulose compound is as follows: fluconazole: microcrystalline cellulose complex= (1:4) - (2:1).
Preferably, the fluconazole has a particle size distribution D90 of 150 μm to 300 μm, D50 of 50 μm to 120 μm and D10 of 10 μm to 30 μm.
Preferably, the microcrystalline cellulose complex is one of the following: silicified microcrystalline cellulose, microcrystalline cellulose-lactose complex, microcrystalline cellulose-sodium carboxymethyl starch complex, and microcrystalline cellulose-mannitol complex.
Preferably, the microcrystalline cellulose complex is silicified microcrystalline cellulose or microcrystalline cellulose-carboxymethyl starch sodium complex.
Preferably, the fluorine Kangjing is one or more of form i, form ii, form iii or monohydrate, preferably form ii or form iii.
Preferably, the composition is filled in a gelatin hollow capsule selected from one of the following types: no. 2, no. 3 or No. 4.
Preferably, the composition consists of fluconazole and silicified microcrystalline cellulose complex, and the weight ratio of fluconazole to silicified microcrystalline cellulose complex is 2:3.
Preferably, the composition consists of fluconazole and microcrystalline cellulose-sodium carboxymethyl starch compound, and the weight ratio of fluconazole to microcrystalline cellulose-sodium carboxymethyl starch compound is 2:3.
A process for preparing a fluconazole pharmaceutical composition as hereinbefore described, comprising the steps of:
(1) Screening the compound of fluconazole and microcrystalline cellulose with a prescribed amount for standby;
(2) Adding the fluconazole and microcrystalline cellulose compound obtained in the step (1) into a mixer, and uniformly mixing;
(3) Filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule.
Preferably, the steps are as follows:
(1) Screening the compound of the fluconazole and the microcrystalline cellulose with a 40-mesh screen for standby;
(2) Adding the fluconazole and microcrystalline cellulose compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 15-25 min;
(3) Filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule.
Compared with the prior art, the fluconazole pharmaceutical composition and the preparation method thereof provided by the invention have the following beneficial effects:
by selecting a proper microcrystalline cellulose compound, the invention can increase the powder fluidity, improve the medicine uniformity and dissolution rate and obviously improve the stability of the fluconazole capsule.
Detailed Description
The following are specific examples of the present invention, and the technical solutions of the present invention are further described, but the scope of the present invention is not limited to these examples. All changes and equivalents that do not depart from the gist of the invention are intended to be within the scope of the invention.
Example 1: prescription and process of fluconazole pharmaceutical composition
The prescription is shown below, and the dosage (unit: g) of each component in the capsule is as follows, calculated by the fluconazole with the specification of 50 mg/granule and the prescription amount of 1000 granules:
| fluconazole | 50.00g |
| Silicified microcrystalline cellulose | 75.00g |
| Gelatin hollow capsule No. 3 | 1000 sets |
Example 1 the formulation had a fluconazole to silicified microcrystalline cellulose content ratio of 2:3, fluconazole as form ii, fluconazole with a particle size distribution of D 90 ＝215.28μm，D 50 ＝94.39μm，D 10 =15.14 μm; the bulk density of silicified microcrystalline cellulose was 0.25g/ml and tap density was 0.42g/ml.
The preparation method is as follows:
(1) Screening prescription amount of fluconazole and silicified microcrystalline cellulose with 40 mesh sieve respectively for standby;
(2) Adding the fluconazole and the silicified microcrystalline cellulose obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 15min;
(3) And (3) filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule of No. 3.
Example 2: prescription and process of fluconazole pharmaceutical composition
The prescription is shown below, and the dosage (unit: g) of each component in the capsule is as follows, calculated by the fluconazole with the specification of 50 mg/granule and the prescription amount of 1000 granules:
| fluconazole | 50.00g |
| Microcrystalline cellulose-lactose complexes | 200.00g |
| Gelatin hollow capsule No. 2 | 1000 sets |
EXAMPLE 2 the formulation has a fluconazole to microcrystalline cellulose-lactose composite content ratio of 1:4, fluconazole as monohydrate crystalline form and fluconazole with particle size distribution D 90 ＝169.40μm，D 50 ＝55.91μm，D 10 =12.83 μm; the bulk density of the microcrystalline cellulose-lactose complex was 0.39g/ml and the tap density was 0.57g/ml.
The preparation method is as follows:
(1) The prescription amount of fluconazole and microcrystalline cellulose-lactose compound are respectively screened by a 40-mesh screen for standby;
(2) Adding the fluconazole and microcrystalline cellulose-lactose compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 15min;
(3) And (3) filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule of size 2.
Example 3: prescription and process of fluconazole pharmaceutical composition
The prescription is shown below, and the dosage (unit: g) of each component in the capsule is as follows, calculated by the fluconazole with the specification of 50 mg/granule and the prescription amount of 1000 granules:
| fluconazole | 50.00g |
| Microcrystalline cellulose-mannitol complexes | 25.00g |
| Gelatin hollow capsule No. 4 | 1000 sets |
Example 3 the formulation had a fluconazole to microcrystalline cellulose-mannitol ratio of 2:1, fluconazole in form III, and fluconazole with a particle size distribution of D 90 ＝296.39μm，D 50 ＝118.70μm，D 10 = 28.98 μm; the bulk density of the microcrystalline cellulose-lactose complex was 0.30g/ml and the tap density was 0.49g/ml.
The preparation method is as follows:
(1) Screening the prescription amount of fluconazole and microcrystalline cellulose-mannitol compound with a 40-mesh screen for standby;
(2) Adding the fluconazole and microcrystalline cellulose-mannitol compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 20min;
(3) And (3) filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule of No. 4.
Example 4: prescription and process of fluconazole pharmaceutical composition
The prescription is shown below, and the dosage (unit: g) of each component in the capsule is as follows, calculated by the fluconazole with the specification of 50 mg/granule and the prescription amount of 1000 granules:
| fluconazole | 50.00g |
| Microcrystalline cellulose-carboxymethyl starch sodium complex | 75.00g |
| Gelatin hollow capsule No. 3 | 1000 sets |
EXAMPLE 4 the formulation had a fluconazole to microcrystalline cellulose-sodium carboxymethyl starch complex content ratio of 2:3, fluconazole in form III, and fluconazole with particle size distribution D 90 ＝221.37μm，D 50 ＝99.48μm，D 10 =19.73 μm; the bulk density of the microcrystalline cellulose-lactose complex was 0.28g/ml and tap density was 0.49g/ml.
The preparation method is as follows:
(1) Screening the prescription amount of fluconazole and microcrystalline cellulose-carboxymethyl starch sodium compound with a 40-mesh screen for standby;
(2) Adding the fluconazole and microcrystalline cellulose-carboxymethyl starch sodium compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 20min;
(3) And (3) filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule of No. 3.
Example 5: comparative formulations and related test experiments
To facilitate the explanation of the formulation screening of the present invention, this example summarizes comparative formulation formulations based on examples 1-4 (the process is the same as example 1), and test experiments for formulation-related properties.
Comparative formulation 1: the components of the formulation were the same as in example 2, except that the content ratio of fluconazole to the compound was changed to 4:1.
| Fluconazole | 50.00g |
| Microcrystalline cellulose-lactose complexes | 12.50g |
| Gelatin hollow capsule No. 4 | 1000 sets |
Comparative formulation 2: the dosage (unit: g) of each component in the capsule is as follows, calculated by the fluconazole with the specification of 50 mg/granule and the prescription amount of 1000 granules:
| fluconazole | 50.00g |
| Lactose and lactose | 50.00g |
| Corn starch | 16.70g |
| Silica dioxide | 0.12g |
| Magnesium stearate | 1.18g |
| Gelatin hollow capsule No. 3 | 1000 sets |
Comparative formulation 3: the components of the formulation were the same as in example 1, except that the content ratio of fluconazole to the compound was changed to 1:5.
| Fluconazole | 50.00g |
| Microcrystalline cellulose-silicified microcrystalline cellulose composite | 250.00g |
| Gelatin hollow capsule No. 2 | 1000 sets |
Comparative formulation 4: the components of the formulation were the same as in example 1, except that the fluconazole to compound content ratio was changed to 5:2.
| Fluconazole | 50.00g |
| Microcrystalline cellulose-silicified microcrystalline cellulose composite | 20.00g |
| Gelatin hollow capsule No. 4 | 1000 sets |
Reference formulation: fluconazole capsules of the psicose pharmaceutical (trade name:
specification of: 50 mg).
1. Powder particle flowability test
In the invention, the evaluation index of the powder flowability test is the repose angle and the compression index.
Determination of the compression index: charging a certain amount of powder into a measuring cylinder under vibration-free condition, and measuring apparent volume V 1 Tapping volume V to final volume unchanged 2 . The method for calculating the compression index is as follows: compression index= (V 1－ V 2 )/V 1 ×100％。 USP<1174>The criteria for medium flowability and compression index are as follows:
| fluidity of the product | Compression index (%) |
| Excellent in | ≤10 |
| Good (good) | 11～15 |
| In general | 16～20 |
| Can pass through | 21～25 |
| Difference of difference | 26～31 |
| Very poor | 32～37 |
| Very poor | ＞38 |
Measurement of angle of repose: referring to the powder flowability measurement of USP <1174>, the funnel was fixed to a horizontally placed coordinate paper at a suitable height by a fixed funnel method such that the lower opening of the funnel was spaced from the coordinate paper by a distance H, and the powder particles were carefully poured into the funnel until the tip of the cone formed under the funnel contacted the outlet of the funnel, and the radius r of the cone was measured from the coordinate paper.
The calculation method of the repose angle alpha is as follows: alpha=tan -1 (H/r)
The criteria for fluidity and angle of repose determination in USP <1174> are as follows:
| fluidity of the product | Angle of repose (°) |
| Very good | 25～30 |
| Very good | 31～35 |
| Good-no need of adding auxiliary material | 36～40 |
| Acceptable-requiring the addition of auxiliary substances | 41～45 |
| Difference of difference | 46～55 |
| Very poor | 55～65 |
| Very poor | >66 |
2. In vitro dissolution test
In the invention, the in vitro dissolution rate is determined by the following method: taking dissolution rate and release rate measurement method (first method of China pharmacopoeia 2015 edition general rule 0931), taking 0.1mol/L hydrochloric acid solution (9 ml of hydrochloric acid is measured and diluted to 1000ml by adding water), and taking 500ml of acetate buffer solution (18 g of sodium acetate, 9.8ml of glacial acetic acid and diluted to 1000ml by adding water) as dissolution medium, sampling at 100 revolutions per minute according to law operation at 5min, 10min, 15min, 30min and 45min respectively, taking a proper amount of solution, filtering, and taking the subsequent filtrate as sample solution; and precisely weighing a proper amount of fluconazole reference substance, adding a dissolution medium for dissolution, and quantitatively diluting to prepare a solution containing about 0.1mg of fluconazole reference substance per 1 ml. The dissolution rate of each pellet was calculated by measuring the content under the method of measurement.
3. Stability investigation test
Influence factors: samples of the examples and comparative examples of the present invention were taken, placed under conditions of high temperature (60.+ -. 2 ℃), high humidity (90%.+ -. 5% RH) and light irradiation (4500 Lx.+ -. 500 Lx) for 10 days, sampled on day 10, and the dissolution was examined and compared with the sample on day 0.
Accelerating sample retention: taking samples of the examples and the comparative examples, packaging the samples by aluminum plastic, coating a composite film bag (the reference preparation adopts commercial package), placing the samples at 40 ℃ and 75% RH for 6 months, ending the placing, sampling, detecting the dissolution, and comparing the dissolution with the 0-day sample.
Long-term sample retention: taking samples of the examples and the comparative examples, packaging the samples by aluminum plastic, sleeving a composite film bag (the reference preparation adopts commercial packaging), placing the samples for 12 months (or 24 months) at 25 ℃ and 60% RH, ending the placing, sampling, detecting the dissolution rate, and comparing the dissolution rate with the 0-day sample.
Example 6: investigation of the influence of the prescription on the flowability of the powder of the formulation
This example was intended to evaluate powder flowability of the formulations by testing the compression index and angle of repose of examples 1 to 4, comparative formulations 1 to 4, and reference formulations.
The powder flowability test method of this example is shown in example 5, and the test results are shown in table 1.
TABLE 1 test results of powder flowability
| Sample name | Compression index (%) | Angle of repose (°) |
| Example 1 | 18.7 | 37.5 |
| Example 2 | 16.2 | 36.2 |
| Example 3 | 18.9 | 39.3 |
| Example 4 | 16.1 | 34.3 |
| Comparative formulation 1 | 26.6 | 46.3 |
| Comparative formulation 2 | 28.3 | 47.4 |
| Comparative formulation 3 | 22.1 | 38.1 |
| Comparative formulation 4 | 24.5 | 44.2 |
| Reference formulation | 29.0 | 48.6 |
As can be seen from table 1, the compression index and the determination criterion of the angle of repose are combined:
1) The compression indexes of examples 1-4 are between 16% and 20%, and the repose angle is between 31-40 degrees, which indicates that the powder has better fluidity, and the content ratio of fluconazole to the compound is in the interval (1:4) - (2:1); in particular, in example 4, the powder flowability was optimal, and the content ratio of fluconazole to the compound was 2:3.
2) The compression indexes of the comparative preparations 1 and 2 and the reference preparation are between 26% and 31%, and the repose angle is between 46 and 55 degrees, which indicates that the powder has poor flowability.
3) The compression index of the comparative formulations 3 and 4 was between 21% and 25%, in the "passable" standard range, but the angle of repose was between 46 ° and 55 °, in the "good" or "acceptable" standard range, indicating that the powder flowability was better than the comparative formulations 1 and 2, at which time the fluconazole to complex content ratio was <1:4 or >2:1.
Example 7: investigation of the influence of the prescription on the in vitro dissolution of the formulation
This example was conducted to evaluate the dissolution rate and the intra-batch difference of the formulations by testing the in vitro dissolution rates of examples 1 to 4, comparative formulations 1 to 4, and reference formulations.
The in vitro dissolution test method described in this example is shown in example 5, and first, the in vitro cumulative dissolution amounts of examples 1 to 4, comparative preparations 1 to 4 and reference preparation in a hydrochloric acid solution with dissolution medium of 0.1mol/L are tested, and the cumulative dissolution amounts of all experimental groups at 15min are found to be greater than 85%. Next, examples 1 to 4, comparative preparations 1 to 4 and reference preparations were subjected to in vitro cumulative elution amounts in the presence of acetate buffer having a pH of 4.5 as the elution medium, and the test results are shown in Table 2.
TABLE 2 test results of cumulative elution amount of samples at 0 day of standing
Note that: "/" indicates room temperature without special conditioning.
According to the guidelines of the common oral solid preparation dissolution test technology of the 5 th day of the 2015 th year of the national food and drug administration, the following rules are provided: when the cumulative dissolution rate is less than or equal to 85% at 15min, the dissolution rate at the first sampling time point is more than 20% relative to the standard deviation, and the dissolution rate at the other sampling time points is more than 10% relative to the standard deviation, which is regarded as large in-batch dissolution difference.
As can be seen from table 2:
1) The cumulative dissolution rate of examples 1 to 4 in 15min is more than 85%, the dissolution rate RSD value in 5min is less than 10%, and the dissolution rate RSD value in 10 to 45min is less than 3%, which is rapid dissolution and has small in-batch dissolution difference.
2) The cumulative dissolution rate of the comparative preparations 1 to 4 in 15min is respectively 70.5%, 57.6%, 84.1% and 79.4%, which are all less than 85%; and the dissolution rate RSD values of 5min are all more than 20%, and the dissolution rate RSD values of 10min are all more than 10%, so that the dissolution differences in batches are large.
3) The cumulative dissolution rate of the reference preparation at 15min was 62.9%, the dissolution rate RSD value at 5min was 38.0%, and the dissolution rate RSD values at 10 to 15min were 24.8% and 17.0%, respectively, so that the difference in dissolution in the batch was large.
4) It can be seen that examples 1 to 4 have higher dissolution rates and less difference in dissolution lot than comparative formulations 1 to 4 and reference formulations.
Example 8: investigation of the Effect of prescriptions on formulation stability
This example was intended to evaluate the stability of the formulations by testing the cumulative dissolution amounts of examples 1 to 4, comparative formulations 1 to 4, and reference formulations under different standing conditions.
When stability is investigated, the placement conditions are selected as follows: high temperature, high humidity, light irradiation, acceleration (6 months), long term (12 months), and the selection of dissolution medium is: 0.1mol/L hydrochloric acid; the test method is shown in example 5, and the test results are shown in tables 3 to 11.
TABLE 3 test results for stability investigation of example 1 samples
Note that: "/" indicates room temperature without special conditioning.
As is clear from Table 3, the samples of example 1 all had a cumulative elution amount of more than 85% at 15min under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long term (12 months) and were not significantly different from the sample under the conditions of room temperature.
TABLE 4 test results for stability investigation of example 2 samples
Note that: "/" indicates room temperature without special conditioning.
As is clear from Table 4, the samples of example 2 all had a cumulative elution amount of more than 85% at 15min under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long term (12 months) and were not significantly different from the sample under the conditions of room temperature.
TABLE 5 test results for stability investigation of example 3 samples
Note that: "/" indicates room temperature without special conditioning.
As is clear from Table 5, the samples of example 3 all had a cumulative elution amount of more than 85% at 15min under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long term (12 months) and were not significantly different from the sample under the conditions of room temperature.
TABLE 6 test results for stability investigation of example 4 samples
Note that: "/" indicates room temperature without special conditioning.
As is clear from Table 6, the samples of example 4 all had a cumulative elution amount of more than 85% at 15min under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long term (12 months) and were not significantly different from the sample under the conditions of room temperature.
TABLE 7 test results for stability investigation of comparative formulation 1 samples
Note that: "/" indicates room temperature without special conditioning.
As can be seen from table 7, under the special conditions of high temperature, high humidity, light irradiation and long term (12 months), the cumulative dissolution rate of the comparative preparation 1 sample in 15min is more than 85%, and the sample is not significantly different from the sample in the room temperature; however, under the accelerated (6 month) special standing condition, the cumulative dissolution rate of the comparative preparation 1 sample at 15min was 72.5%, and the cumulative dissolution rate at 15min was reduced by about 17% as compared with the room temperature standing condition. Furthermore, the dissolution RSD values of 10min were all greater than 10%, indicating large differences in batch dissolution.
TABLE 8 test results for stability investigation of comparative formulation 2 samples
Note that: "/" indicates room temperature without special conditioning.
As can be seen from table 8, under the special conditions of high temperature, high humidity, light irradiation and long term (12 months), the cumulative dissolution rate of the comparative preparation 2 sample in 15min is more than 85%, and the comparative preparation 2 sample has no significant difference from the comparative preparation 2 sample in the room temperature conditions; however, under the accelerated (6 month) special standing condition, the cumulative dissolution rate of the comparative preparation 2 sample at 15min was 65.6%, and the cumulative dissolution rate at 15min was reduced by about 20% as compared with the room temperature standing condition. Furthermore, the dissolution RSD values of 10min were all greater than 10%, indicating large differences in batch dissolution.
TABLE 9 test results for stability investigation of comparative formulation 3 samples
Note that: "/" indicates room temperature without special conditioning.
As can be seen from table 9, under the special conditions of high temperature, high humidity, light irradiation and long term (12 months), the cumulative dissolution rate of the comparative preparation 3 sample in 15min is more than 85%, and there is no significant difference compared with the room temperature conditions; however, under the accelerated (6 month) special standing condition, the cumulative dissolution rate of the comparative preparation 3 sample at 15min was 84.5%, and the cumulative dissolution rate at 15min was reduced by about 5% as compared with the room temperature standing condition. Furthermore, the dissolution RSD values of 10min were all greater than 10%, indicating large differences in batch dissolution.
TABLE 10 test results comparing stability studies for sample of preparation 4
Note that: "/" indicates room temperature without special conditioning.
As can be seen from table 10, under the special conditions of high temperature, high humidity, light irradiation and long term (12 months), the cumulative dissolution rate of the comparative preparation 4 sample in 15min is more than 85%, and the comparative preparation 4 sample has no significant difference from the comparative preparation under the room temperature conditions; however, under the accelerated (6 month) special standing condition, the cumulative dissolution rate of the comparative preparation 4 sample at 15min was 73.5%, and the cumulative dissolution rate at 15min was reduced by about 16% as compared with the room temperature standing condition. Furthermore, the dissolution RSD values of 10min were all greater than 10%, indicating large differences in batch dissolution.
TABLE 11 test results of stability investigation of reference formulation samples
Note that: "/" indicates room temperature without special conditioning.
As can be seen from table 11, under the special conditions of high temperature, high humidity, light irradiation and long term (12 months), the cumulative dissolution rate of the reference preparation sample in 15min is more than 85%, and the reference preparation sample has no significant difference compared with the room temperature conditions; however, under the accelerated (6 month) special standing condition, the cumulative dissolution rate of the reference formulation sample at 15min was 72.3%, and the cumulative dissolution rate at 15min was reduced by about 27% as compared with the room temperature standing condition. Furthermore, the dissolution RSD values of 10min were all greater than 10%, indicating large differences in batch dissolution.
In summary, the fluconazole pharmaceutical compositions (examples 1-4) provided by the invention have better stability than the comparative formulations 1-4 and the reference formulation.
Example 9: investigation of the Effect of the formulation on the Long-term stability of the formulation
On the basis of example 8, examples 1 to 4 of the present invention were subjected to long-term (24 months) stability studies to screen out the optimal prescription.
When stability is investigated, 0.1mol/L hydrochloric acid is selected as a dissolution medium; the test method is shown in the example 5 of the invention, and the test result is shown in Table 12.
TABLE 12 test results of stability investigation of samples of examples 1 to 4 of the present invention
Note that: "/" indicates room temperature without special conditioning.
As can be seen from the table 12,
1) After long-term (24 months) standing, the cumulative dissolution amounts of the example 1 and the example 4 in 15min are respectively 94.9% and 96.8%, and are respectively more than 85%, and the cumulative dissolution amounts are not significantly different from the cumulative dissolution amounts in the room temperature standing condition; and the dissolution rate RSD values in 5min are all smaller than 10%, and the dissolution rate RSD values in 10-45 min are all smaller than 3%, so that the dissolution difference in batch is small.
2) After long-term (24 months) standing, the dissolution rate RSD values of the example 2 and the example 3 are less than 20% in 5min, the dissolution rate RSD values of the example 10-45 min are less than 10%, and the difference of batch dissolution is small; however, the cumulative elution amounts for 15min were 83.5% and 84.2%, respectively, and were less than 85%, respectively, and the elution was not similar to that under the room temperature standing condition.
In summary, the microcrystalline cellulose compound in the optimal prescription of the fluconazole composition provided by the invention can be selected from silicified microcrystalline cellulose and microcrystalline cellulose-carboxymethyl starch sodium compound.
Claims (10)
1. The fluconazole pharmaceutical composition is characterized by comprising fluconazole and microcrystalline cellulose in the following weight ratio: fluconazole: microcrystalline cellulose complex= (1:4) to (2:1);
the microcrystalline cellulose complex is one of the following: silicified microcrystalline cellulose, microcrystalline cellulose-lactose complex, microcrystalline cellulose-sodium carboxymethyl starch complex, microcrystalline cellulose-mannitol complex;
the pharmaceutical composition is a capsule.
2. The fluconazole pharmaceutical composition according to claim 1, wherein said fluconazole has a particle size distribution D 90 150-300 μm, D 50 50-120 μm, D 10 Is 10-30 μm.
3. The fluconazole pharmaceutical composition according to claim 1, wherein said microcrystalline cellulose complex is silicified microcrystalline cellulose or microcrystalline cellulose-carboxymethyl starch sodium complex.
4. The fluconazole pharmaceutical composition according to claim 1, wherein said form Kangjing is one or more of form i, form ii, form iii or monohydrate.
5. The fluconazole pharmaceutical composition according to claim 4, wherein said form Kangjing is form II or form III.
6. The fluconazole pharmaceutical composition according to claim 1, wherein said composition is filled in a gelatin hollow capsule selected from one of the following types: no. 2, no. 3 or No. 4.
7. The fluconazole pharmaceutical composition according to any one of claims 1-6, wherein said composition comprises fluconazole and silicified microcrystalline cellulose complex, and the weight ratio of fluconazole to silicified microcrystalline cellulose complex is 2:3.
8. The fluconazole pharmaceutical composition according to any one of claims 1-6, wherein said composition comprises fluconazole and microcrystalline cellulose-sodium carboxymethyl starch compound, and the weight ratio of fluconazole to microcrystalline cellulose-sodium carboxymethyl starch compound is 2:3.
9. A process for the preparation of a fluconazole pharmaceutical composition according to claim 1, characterized by the steps of:
(1) Screening the compound of fluconazole and microcrystalline cellulose with a prescribed amount for standby;
(2) Adding the fluconazole and microcrystalline cellulose compound obtained in the step (1) into a mixer, and uniformly mixing;
(3) Filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule.
10. The method for preparing a fluconazole pharmaceutical composition according to claim 9, comprising the steps of:
(1) Screening the compound of the fluconazole and the microcrystalline cellulose with a 40-mesh screen for standby;
(2) Adding the fluconazole and microcrystalline cellulose compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 15-25 min;
(3) Filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule.
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| CN1593405A (en) * | 2004-07-09 | 2005-03-16 | 沈阳药科大学 | Prescription for liquid status of fluconazole and its preparation |
| WO2011101862A1 (en) * | 2010-02-17 | 2011-08-25 | Fdc Limited | Stabilized fluconazole polymorph iii formulation |
| CN107737112A (en) * | 2017-11-07 | 2018-02-27 | 海南锦瑞制药有限公司 | A kind of Letrozole piece and preparation method thereof |
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|---|---|---|---|---|
| CN1593405A (en) * | 2004-07-09 | 2005-03-16 | 沈阳药科大学 | Prescription for liquid status of fluconazole and its preparation |
| WO2011101862A1 (en) * | 2010-02-17 | 2011-08-25 | Fdc Limited | Stabilized fluconazole polymorph iii formulation |
| CN107737112A (en) * | 2017-11-07 | 2018-02-27 | 海南锦瑞制药有限公司 | A kind of Letrozole piece and preparation method thereof |
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| Co-proccessed excipients with enhanced direct compression functionality for improved tableting performance;John Rojas et al;《Drug Development and Industrial Pharmacy》;20120912;第38卷(第10期);第1161页右栏最后一段，第1164页右栏第4段，第1159页摘要，第1162页表1，第1163页表2 * |
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