CN112023056A - Fluconazole pharmaceutical composition and preparation method thereof - Google Patents
Fluconazole pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN112023056A CN112023056A CN202010930894.XA CN202010930894A CN112023056A CN 112023056 A CN112023056 A CN 112023056A CN 202010930894 A CN202010930894 A CN 202010930894A CN 112023056 A CN112023056 A CN 112023056A
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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 a microcrystalline cellulose compound in a weight ratio of: fluconazole-microcrystalline cellulose complex (1:4) - (2: 1). According to the invention, by selecting a proper microcrystalline cellulose compound, the powder flowability can be increased, the medicine uniformity and dissolution rate can be improved, and the stability of the fluconazole capsule can be obviously improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a fluconazole pharmaceutical composition and a preparation method thereof.
Background
Fluconazole is a pyrrole broad-spectrum antifungal agent developed by Pfizer Pharmaceuticals Ltd (Pfizer Pharmaceuticals Ltd), and interferes with the activity of cytochrome P-450 of fungi highly selectively, thereby inhibiting the biosynthesis of ergosterol on the cell membrane of fungi and leading the intracellular substances to leak out and die. The medicine is mainly used for treating vaginal candidiasis, thrush, atrophic oral candidiasis, fungal meningitis, pulmonary fungal infection, abdominal infection, urinary tract infection, dermatophyte infection and the like in clinic. The molecular action targets are as follows: lanosterol 14-alpha demethylase.
The chemical name of fluconazole is alpha- (2, 4-difluorophenyl) -alpha- (1H-1,2, 4-triazol-1-ylmethyl) -1H-1,2, 4-triazol-1-ylethanol. The structural formula is shown as the following formula I, and the molecular formula C13H12F2N6O, molecular weight 306.28, CAS number 86386-73-4, fluconazole is white crystalline powder, odorless, melting point 137-141 ℃, soluble in methanol, slightly soluble in dichloromethane, water or acetic acid, and insoluble in ether.
I. Fluconazole structure
According to reports (such as Selenmex, the research on the polymorphism and the transformation of fluconazole; China modern application pharmacy, 8 th volume at 8.8.2012), fluconazole has four crystal forms, namely a crystal form I, a crystal form II, a crystal form III and a crystal form monohydrate, the crystal forms I and II have better thermal stability, and the crystal form monohydrate is transformed into the crystal form II at 60-160 ℃.
The pharmaceutical preparation of Peprozil in FranceFluconazole capsules published by the official network of the drug administration (trade name:
) The auxiliary materials comprise lactose, corn starch, sodium dodecyl sulfate, silicon dioxide, magnesium stearate, gelatin, titanium dioxide (E171) and blue No. 5 (E131). Meanwhile, consider fluconazole capsules marketed by argentina (trade name:
specification: 50mg) of lactose 49.708 mg/capsule, corn starch 16.500 mg/capsule, sodium lauryl sulfate 0.117 mg/capsule, a mixture of silicon dioxide and magnesium stearate (ratio 1: 9)1.175 mg/pellet. Fluconazole capsule
The auxiliary materials are various in types, the dosage of the sodium dodecyl sulfate is low, the mixing is easy to be uneven, and the stability of the medicine is influenced.
The Chinese patent with publication number CN 108578377A discloses a fluconazole tablet and a preparation method thereof, the fluconazole quick-release tablet is prepared, and the pharmaceutic adjuvant comprises a filler, a disintegrant, an adhesive and a lubricant; the preparation process comprises the steps of raw material and auxiliary material crushing, mixing, wet granulation, drying, mixing and tabletting. The formula of the invention has various components, complex preparation process and low production efficiency.
Chinese patent publication No. CN 1812783a discloses a fluconazole capsule with improved release, which is prepared by granulating fluconazole with a reagent capable of providing hydrophilic surface characteristics to the granules and optionally a surfactant, mixing the obtained granules with a filler, a disintegrant, a lubricant and a glidant, and filling the mixture into capsules. But the technical scheme has the following defects: in the process of forming the particles by the fluconazole and the hydrophilic surfactant, the surfactant is not uniformly distributed in the particles easily because of less dosage of the surfactant, so that the dissolution and the in-vivo absorption are influenced, and the bioavailability is not high.
Through retrieval, aiming at the prior art for improving the stability of the fluconazole capsules, the prior art mostly adopts an improvement mode of auxiliary materials or process, and the common defects of the prior art are as follows: the prepared fluconazole medicine composition has the risks of poor fluidity, large difference in batches, low dissolution rate, poor stability and the like. No literature report on the use of complexes to improve the stability of fluconazole capsules has been found.
A complex 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, which is a combination of a water-soluble excipient and a water-insoluble excipient, but the drugs listed in the patent scheme are numerous and wide in variety, and there is no indication that the compound can be directed to a specific drug (e.g., fluconazole); from examples 1 to 10 listed in this patent specification, only the application of mannitol in combination with at least one water-insoluble excipient as a composite to aspartame tablets is known; therefore, the technical teaching cannot be learned from the patent, as to how to select suitable complex components to improve the stability of fluconazole capsules.
For another example, chinese patent publication No. CN 105520918A discloses a pregabalin capsule, which is composed of pregabalin, a lactose complex, and a pharmaceutically acceptable carrier, where the lactose complex is a lactose-microcrystalline cellulose complex, which can significantly improve the poor stability of the pregabalin capsule, but the technical scheme has the disadvantages that: firstly, the patent adopts a direct mixing process, and because the prescription contains starch with high proportion, the prepared total mixed powder has the risk of fluidity due to poor fluidity of the starch; secondly, because starch has a plurality of varieties with different sources and different types and the property difference among the different varieties is large, the risk of large batch dissolution difference exists; ③ the physicochemical properties of pregabalin are different from fluconazole, so the lactose-microcrystalline cellulose compound can be applied to the development of fluconazole capsules, and the uncertainty exists.
In conclusion, it is a technical problem that those skilled in the art have not solved to select an appropriate composition component and further develop a fluconazole capsule with good fluidity and high stability.
Disclosure of Invention
The invention aims to solve the technical problem of providing a fluconazole pharmaceutical composition and a preparation method thereof.
In order to solve the technical problems, the invention adopts the following technical scheme:
a fluconazole pharmaceutical composition is composed of fluconazole and a 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 particle size distribution D90 of fluconazole is 150-300 μm, D50 is 50-120 μm, and D10 is 10-30 μm.
Preferably, the microcrystalline cellulose complex is one of: silicified microcrystalline cellulose, microcrystalline cellulose-lactose complex, microcrystalline cellulose-carboxymethyl starch sodium complex, microcrystalline cellulose-mannitol complex.
Preferably, the microcrystalline cellulose complex is silicified microcrystalline cellulose or a microcrystalline cellulose-carboxymethyl starch sodium complex.
Preferably, the fluconazole crystal form is one or more of crystal form I, crystal form II, crystal form III or monohydrate crystal form, and preferably, the crystal form II or crystal form III.
Preferably, the composition is filled in gelatin hollow capsules selected from one of the following types: number 2, 3 or 4.
Preferably, the composition consists of fluconazole and silicified microcrystalline cellulose complex in a weight ratio of fluconazole to silicified microcrystalline cellulose complex of 2: 3.
Preferably, the composition consists of fluconazole and microcrystalline cellulose-sodium carboxymethyl starch complex, and the weight ratio of the fluconazole to the microcrystalline cellulose-sodium carboxymethyl starch complex is 2: 3.
A process for preparing a pharmaceutical composition of fluconazole as described above, comprising the steps of:
(1) sieving the fluconazole and microcrystalline cellulose compound with the prescription amount through a screen for later use;
(2) adding the fluconazole and microcrystalline cellulose compound obtained in the step (1) into a mixer, and uniformly mixing;
(3) and (3) filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule.
Preferably, the steps are as follows:
(1) sieving the compound of fluconazole and microcrystalline cellulose with a 40-mesh sieve according to the prescription amount for later use;
(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) and (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:
according to the invention, by selecting a proper microcrystalline cellulose compound, the powder flowability can be increased, the medicine uniformity and dissolution rate can be improved, and the stability of the fluconazole capsule can be obviously improved.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Example 1: prescription and process of fluconazole medicine composition
The prescription is as follows, the dosage (unit: g) of each component in the capsule is calculated by taking the standard of fluconazole as 50 mg/granule and the prescription amount as 1000 granules:
| fluconazole | 50.00g |
| Silicified microcrystalline cellulose | 75.00g |
| No. 3 gelatin hollow capsule | 1000 sets |
Example 1 the formulation had a fluconazole to silicified microcrystalline cellulose content ratio of 2:3, fluconazole in crystal form ii and a fluconazole particle size distribution of D90＝215.28μm，D50＝94.39μm，D1015.14 μm; the bulk density of the silicified microcrystalline cellulose was 0.25g/ml and the tap density was 0.42 g/ml.
The preparation method comprises the following steps:
(1) respectively sieving the fluconazole and the silicified microcrystalline cellulose with a 40-mesh sieve according to the prescription amount for later use;
(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 15 min;
(3) and (3) filling the total mixed powder obtained in the step (2) into a No. 3 gelatin empty capsule to obtain the capsule.
Example 2: prescription and process of fluconazole medicine composition
The prescription is as follows, the dosage (unit: g) of each component in the capsule is calculated by taking the standard of fluconazole as 50 mg/granule and the prescription amount as 1000 granules:
| fluconazole | 50.00g |
| Microcrystalline cellulose-lactose complex | 200.00g |
| No. 2 gelatin hollow capsule | 1000 sets |
Example 2 the formulation had a fluconazole to microcrystalline cellulose-lactose complex content ratio of 1:4, fluconazole in monohydrate form and a particle size distribution of D90＝169.40μm，D50＝55.91μm，D1012.83 μm; the bulk density of the microcrystalline cellulose-lactose complex was 0.39g/ml and the tap density was 0.57 g/ml.
The preparation method comprises the following steps:
(1) respectively sieving the fluconazole and the microcrystalline cellulose-lactose compound with a 40-mesh sieve according to the prescription amount for later use;
(2) adding the fluconazole and the microcrystalline cellulose-lactose compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 15 min;
(3) and (3) filling the total mixed powder obtained in the step (2) into a No. 2 gelatin empty capsule to obtain the capsule.
Example 3: prescription and process of fluconazole medicine composition
The prescription is as follows, the dosage (unit: g) of each component in the capsule is calculated by taking the standard of fluconazole as 50 mg/granule and the prescription amount as 1000 granules:
| fluconazole | 50.00g |
| Microcrystalline cellulose-mannitol complexes | 25.00g |
| No. 4 gelatin hollow coreCapsule | 1000 sets |
Example 3 the formulation had a fluconazole to microcrystalline cellulose-mannitol complex content ratio of 2:1, fluconazole in form iii, and a particle size distribution of D90＝296.39μm，D50＝118.70μm，D1028.98 μm; the bulk density of the microcrystalline cellulose-lactose complex was 0.30g/ml and the tap density was 0.49 g/ml.
The preparation method comprises the following steps:
(1) sieving the fluconazole and the microcrystalline cellulose-mannitol compound with a 40-mesh sieve according to the prescription amount for later use;
(2) adding the fluconazole and the microcrystalline cellulose-mannitol compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 20 min;
(3) and (3) filling the total mixed powder obtained in the step (2) into a No. 4 gelatin empty capsule to obtain the capsule.
Example 4: prescription and process of fluconazole medicine composition
The prescription is as follows, the dosage (unit: g) of each component in the capsule is calculated by taking the standard of fluconazole as 50 mg/granule and the prescription amount as 1000 granules:
| fluconazole | 50.00g |
| Microcrystalline cellulose-sodium carboxymethyl starch complex | 75.00g |
| No. 3 gelatin hollow capsule | 1000 sets |
Example 4 in the formulation, the content ratio of fluconazole to microcrystalline cellulose-sodium carboxymethyl starch complex is 2:3, fluconazole is in form III, and the particle size distribution of fluconazole is D90＝221.37μm，D50＝99.48μm，D1019.73 μm; the bulk density of the microcrystalline cellulose-lactose complex was 0.28g/ml and the tap density was 0.49 g/ml.
The preparation method comprises the following steps:
(1) sieving the fluconazole and the microcrystalline cellulose-carboxymethyl starch sodium compound with a 40-mesh sieve according to the prescription amount for later use;
(2) adding the fluconazole and the microcrystalline cellulose-carboxymethyl starch sodium compound obtained in the step (1) into a mixer, setting the rotating speed to be 10rpm, and mixing for 20 min;
(3) and (3) filling the total mixed powder obtained in the step (2) into a No. 3 gelatin empty capsule to obtain the capsule.
Example 5: comparative formulations and related test experiments
To illustrate the purpose of the recipe screening of the present invention, this example summarizes the recipes of the comparative formulations based on examples 1-4 (the process is the same as example 1) and the test experiments of the relevant performance of the formulations.
Comparative formulation 1: the formulation components 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 complex | 12.50g |
| No. 4 gelatin hollow capsule | 1000 sets |
Comparative formulation 2: the dosage (unit: g) of each component in the capsule is as follows according to the specification of fluconazole of 50 mg/capsule and the prescription amount of 1000 capsules:
| fluconazole | 50.00g |
| Lactose | 50.00g |
| Corn starch | 16.70g |
| Silicon dioxide | 0.12g |
| Magnesium stearate | 1.18g |
| No. 3 gelatin hollow capsule | 1000 sets |
Comparative formulation 3: the prescription composition was 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 |
| No. 2 gelatin hollow capsule | 1000 sets |
Comparative formulation 4: the prescription composition was the same as in example 1 except that the content ratio of fluconazole to the compound was changed to 5: 2.
| Fluconazole | 50.00g |
| Microcrystalline cellulose-silicified microcrystalline cellulose composite | 20.00g |
| No. 4 gelatin hollow capsule | 1000 sets |
Reference formulation: fluconazole capsules prepared by feverfew (trade name:
specification: 50 mg).
First, powder particle fluidity test
In the invention, evaluation indexes of powder fluidity test are angle of repose and compression index.
Determination of compressibility index: a certain amount of powder is filled into a measuring cylinder under the condition of no vibration, and the apparent volume V is measured1Tapping to a tap volume V with no change in final volume2. The compression index is calculated as follows: compression index ═ V1－V2)/V1×100％。 USP<1174>The judgment criteria of the medium mobility and the compression index are as follows:
| fluidity of the resin | Compression index (%) |
| Is excellent in | ≤10 |
| Good taste | 11～15 |
| In general | 16～20 |
| Can pass through | 21～25 |
| Difference (D) | 26～31 |
| Is very poor | 32～37 |
| Very poor | ＞38 |
Measurement of angle of repose: referring to USP <1174> powder flowability measurements, the funnel was fixed to a horizontal coordinate paper at a suitable height using the fixed funnel method, such that the lower mouth of the funnel was at a distance H from the coordinate paper, and the powder was carefully poured into the funnel until the tip of the cone formed below the funnel contacted the outlet of the funnel, the radius r of the cone being measurable from the coordinate paper.
The angle of repose α is calculated as follows: alpha-tan-1(H/r)
The criteria for fluidity versus angle of repose in USP <1174> are as follows:
| fluidity of the resin | Angle of repose (°) |
| Is very good | 25～30 |
| Is very good | 31～35 |
| Without the need for auxiliary substances | 36～40 |
| Acceptable-auxiliary substances need to be added | 41～45 |
| Difference (D) | 46～55 |
| Very poor | 55～65 |
| Is very poor | >66 |
Second, in vitro dissolution test
In the invention, the in vitro dissolution rate is measured by the following method: according to a dissolution and release determination method (0931 first method of the general rules of the Chinese pharmacopoeia 2015), taking 500ml of 0.1mol/L hydrochloric acid solution (9 ml of hydrochloric acid is measured and diluted to 1000ml by adding water), pH4.5 acetate buffer solution (18 g of sodium acetate, 9.8ml of glacial acetic acid and water are added to dilute to 1000ml) as a dissolution medium, and sampling respectively at 5min, 10min, 15min, 30min and 45min according to the method operation, taking a proper amount of solution, filtering, and taking a subsequent filtrate as a test solution; and precisely weighing a proper amount of fluconazole reference substance, adding a dissolving medium to dissolve, and quantitatively diluting to prepare a solution containing about 0.1mg of fluconazole in each 1ml of solution as the reference substance solution. And (4) measuring according to a method under the content measurement item, and calculating the dissolution rate of each granule.
Stability investigation test
The influencing factors are as follows: taking the samples of the examples and the comparative examples of the invention, placing the samples under the conditions of high temperature (60 +/-2 ℃), high humidity (90% +/-5% RH) and illumination (4500Lx +/-500 Lx) for 10 days, sampling on the 10 th day, detecting the dissolution rate, and comparing the dissolution rate with the dissolution rate of the sample on the 0 th day.
Accelerating sample retention: taking the samples of the examples and the comparative examples of the invention, packaging the samples by aluminum plastic, and coating a composite film bag (the reference preparation adopts a commercially available package), placing the samples for 6 months under the conditions of 40 ℃ and 75% RH, sampling after the placement, detecting the dissolution rate, and comparing the dissolution rate with the dissolution rate of the sample of 0 day.
And (3) long-term sample retention: taking the samples of the examples and the comparative examples of the invention, packaging the samples by aluminum plastic, and coating a composite film bag (the reference preparation adopts a commercially available package), placing the samples for 12 months (or 24 months) at 25 ℃ and 60% RH, sampling after placing, detecting the dissolution rate, and comparing the dissolution rate with the dissolution rate of the samples for 0 day.
Example 6: investigation of influence of prescription on powder flowability of preparation
This example is intended to evaluate the 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 described in 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 |
In combination with the compression index and the determination criteria for the angle of repose, it can be seen from table 1 that:
1) the compression index of the examples 1 to 4 is between 16% and 20%, the angle of repose is between 31 ° and 40 °, which indicates that the powder flowability is good, and the content ratio of the fluconazole to the compound is in the range of (1:4) to (2: 1); in particular, in example 4, the powder flowability was the best, and the content ratio of fluconazole to compound was 2: 3.
2) The compression index of the comparative preparations 1 and 2 and the reference preparation is between 26% and 31%, and the angle of repose is between 46 degrees and 55 degrees, which indicates that the powder flowability is poor.
3) The compression index of the comparative preparations 3 and 4 is between 21% and 25%, which is in the standard range of "pass", but the angle of repose is between 46 ° and 55 °, which is in the standard range of "good" or "acceptable", indicating that the powder flowability is better than that of the comparative preparations 1 and 2, and the content ratio of the fluconazole to the compound is <1:4 or >2: 1.
Example 7: investigation of influence of prescription on in vitro dissolution rate of preparation
This example aims to evaluate dissolution rates and within-batch differences of the formulations by testing the in vitro dissolution rates of examples 1-4, comparative formulations 1-4, and reference formulations.
In the method for testing in vitro dissolution rate described in this example, see example 5, firstly, the in vitro cumulative dissolution rate of examples 1 to 4, comparative preparations 1 to 4 and reference preparation is tested in the presence of 0.1mol/L hydrochloric acid solution as dissolution medium, and the cumulative dissolution rate of all experimental groups is found to be greater than 85% at 15 min. Next, the results of the in vitro cumulative elution amounts of examples 1 to 4, comparative preparations 1 to 4, and reference preparations were measured in the presence of acetate buffer solution having an elution medium of pH4.5, and are shown in Table 2.
TABLE 2 test results of cumulative elution amount of sample at 0 day of standing
Note: "/" indicates standing at room temperature without special treatment.
According to the regulation of the general guidelines for dissolution test of oral solid preparations of the general State food and drug administration in 2015, 2 months and 5 days: when the cumulative dissolution amount is less than or equal to 85 percent at 15min, the relative standard deviation of the dissolution amount at the first sampling time point is more than 20 percent, and the relative standard deviation of the dissolution amount at the other sampling time points is more than 10 percent, the dissolution difference in batches is considered to be large.
From table 2, it can be seen that:
1) the dissolution rate of the samples 1-4 in 15min is more than 85%, the dissolution rate RSD value of 5min is less than 10%, the dissolution rate RSD value of 10-45 min is less than 3%, the rapid dissolution is realized, and the dissolution difference in batches is small.
2) The cumulative dissolution amount of the comparative preparations 1-4 in 15min is respectively 70.5%, 57.6%, 84.1% and 79.4%, and is less than 85%; and the RSD values of dissolution rates in 5min are all more than 20%, and the RSD values of dissolution rates in 10min are all more than 10%, so that the dissolution difference in batches is large.
3) The accumulative dissolution amount of the reference preparation in 15min is 62.9 percent, the dissolution rate RSD value in 5min is 38.0 percent, and the dissolution rate RSD values in 10-15 min are 24.8 percent and 17.0 percent respectively, so that the dissolution difference in batches is large.
4) As can be seen, examples 1 to 4 have higher dissolution rates and small intra-batch variations from comparative preparations 1 to 4 and the reference preparation.
Example 8: investigation of influence of prescription on stability of preparation
This example is intended to evaluate the stability of the formulations by testing the cumulative elution amounts of examples 1 to 4, comparative formulations 1 to 4, and reference formulations under different standing conditions.
In stability investigation, the selection of the placing conditions is as follows: high temperature, high humidity, light, acceleration (6 months), long term (12 months), the selective dissolution media are: 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 of stability test of the samples of example 1
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 3, the cumulative elution amount at 15min of the sample of example 1 was more than 85% under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long-term (12 months), and there was no significant difference from the room-temperature conditions.
TABLE 4 test results of stability test of example 2 samples
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 4, the cumulative elution amount of the sample of example 2 at 15min was more than 85% under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long-term (12 months), and there was no significant difference from the room-temperature conditions.
TABLE 5 test results of example 3 stability test of samples
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 5, the cumulative elution amount of the sample of example 3 at 15min was more than 85% under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long-term (12 months), and there was no significant difference from the room-temperature conditions.
TABLE 6 test results of stability test of the samples of example 4
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 6, the cumulative elution amount at 15min of the sample of example 4 was more than 85% under the special conditions of high temperature, high humidity, light irradiation, acceleration (6 months) and long-term (12 months), and there was no significant difference from the room-temperature conditions.
TABLE 7 test results for stability test of comparative formulation 1 sample
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 7, the cumulative elution amount of the sample of comparative formulation 1 at 15min was greater than 85% under the special standing conditions of high temperature, high humidity, light irradiation and long term (12 months), and there was no significant difference from the room temperature standing conditions; however, under accelerated (6 months) special standing conditions, the sample of comparative formulation 1 exhibited a 72.5% cumulative dissolution at 15min, which was about 17% lower than the 15min cumulative dissolution at room temperature. In addition, the dissolution rate RSD values of 10min are all larger than 10%, which indicates that the dissolution difference in batches is large.
TABLE 8 test results for stability test of comparative formulation 2 sample
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 8, the cumulative elution amount of the sample of comparative formulation 2 at 15min was greater than 85% under the special standing conditions of high temperature, high humidity, light irradiation and long term (12 months), and there was no significant difference from the room temperature standing conditions; however, under accelerated (6 months) special standing conditions, the sample of comparative formulation 2 exhibited 65.6% cumulative dissolution at 15min, which was about 20% lower than that observed under room temperature standing conditions at 15 min. In addition, the dissolution rate RSD values of 10min are all larger than 10%, which indicates that the dissolution difference in batches is large.
TABLE 9 test results for stability test of comparative formulation 3 samples
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 9, the cumulative elution amount of the comparative formulation 3 sample at 15min was greater than 85% under the special standing conditions of high temperature, high humidity, light irradiation and long term (12 months), and there was no significant difference from the room temperature standing conditions; however, under accelerated (6 months) special standing conditions, the sample of comparative formulation 3 exhibited a cumulative elution amount of 84.5% at 15min, which was reduced by about 5% compared to the 15min standing condition at room temperature. In addition, the dissolution rate RSD values of 10min are all larger than 10%, which indicates that the dissolution difference in batches is large.
TABLE 10 test results for stability test of comparative formulation 4 sample
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 10, the cumulative elution amount of the sample of comparative formulation 4 at 15min was greater than 85% under the special standing conditions of high temperature, high humidity, light irradiation, and long term (12 months), and there was no significant difference from the room temperature standing conditions; however, under accelerated (6 months) special standing conditions, the sample of comparative formulation 4 exhibited a 73.5% cumulative dissolution at 15min, which was about 16% lower than the 15min cumulative dissolution at room temperature. In addition, the dissolution rate RSD values of 10min are all larger than 10%, which indicates that the dissolution difference in batches is large.
TABLE 11 test results for stability test of reference formulation samples
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 11, under the special standing conditions of high temperature, high humidity, light irradiation and long term (12 months), the cumulative dissolution amount of the reference formulation sample at 15min was all greater than 85%, and there was no significant difference compared with the standing condition at room temperature; however, under accelerated (6 months) special standing conditions, the reference formulation sample exhibited a 72.3% cumulative dissolution at 15min, which was about 27% lower than the 15min cumulative dissolution at room temperature. In addition, the dissolution rate RSD values of 10min are all larger than 10%, which indicates that the dissolution difference in batches is large.
In summary, the stability of the fluconazole pharmaceutical composition provided by the invention (examples 1-4) is superior to that of the comparative preparations 1-4 and the reference preparation.
Example 9: investigation of influence of prescription on long-term stability of preparation
On the basis of example 8, the long-term (24-month) stability examination was performed on examples 1 to 4 of the present invention to screen out the optimum prescription.
When the stability is investigated, a dissolution medium is selected to be 0.1mol/L hydrochloric acid; the test methods are shown in example 5 of the present invention, and the test results are shown in Table 12.
TABLE 12 test results of stability test of samples of examples 1 to 4 of the present invention
Note: "/" indicates standing at room temperature without special treatment.
As can be seen from table 12, it is,
1) after long-term (24 months) standing, the cumulative dissolution amounts of example 1 and example 4 at 15min are 94.9%, 96.8%, and both are greater than 85%, and have no significant difference compared with the room-temperature standing condition; and the dissolution rate RSD values at 5min are all less than 10%, the dissolution rate RSD values at 10-45 min are all less than 3%, and the dissolution difference in batches is small.
2) After long-term (24 months) placement, although the RSD values of the dissolution rates in 5min are both less than 20% in the examples 2 and 3, the RSD values of the dissolution rates in 10-45 min are both less than 10%, and the dissolution difference in batches is small; however, the cumulative elution amounts at 15min were 83.5% and 84.2%, respectively, and were less than 85%, which were not similar to the elution amounts at room temperature.
In summary, the microcrystalline cellulose complex in the optimum formula of the fluconazole composition provided by the invention can be silicified microcrystalline cellulose and microcrystalline cellulose-sodium carboxymethyl starch complex.
Claims (10)
1. A fluconazole pharmaceutical composition is characterized by consisting of fluconazole and a microcrystalline cellulose compound in a weight ratio of: fluconazole-microcrystalline cellulose complex (1:4) - (2: 1).
2. The fluconazole pharmaceutical composition of claim 1, wherein said fluconazole particle size distribution D90150 to 300 μm, D50Is 50 to 120 mu m, D10Is 10-30 μm.
3. The fluconazole pharmaceutical composition of claim 1, wherein said microcrystalline cellulose complex is one of: silicified microcrystalline cellulose, microcrystalline cellulose-lactose complex, microcrystalline cellulose-carboxymethyl starch sodium complex, microcrystalline cellulose-mannitol complex.
4. The fluconazole pharmaceutical composition of claim 3, wherein said microcrystalline cellulose complex is silicified microcrystalline cellulose or microcrystalline cellulose-sodium carboxymethyl starch complex.
5. The fluconazole pharmaceutical composition according to claim 1, wherein the fluconazole crystalline form is one or more of crystalline form I, crystalline form II, crystalline form III or crystalline form monohydrate, preferably crystalline form II or crystalline form III.
6. The fluconazole pharmaceutical composition of claim 1, wherein the composition is filled into a gelatin hollow capsule selected from one of the following types: number 2, 3 or 4.
7. The fluconazole pharmaceutical composition according to any one of claims 1 to 6, wherein said composition consists of fluconazole and silicified microcrystalline cellulose complex in a weight ratio of 2: 3.
8. The fluconazole pharmaceutical composition according to any one of claims 1 to 6, wherein the composition consists of fluconazole and microcrystalline cellulose-sodium carboxymethyl starch complex, and the weight ratio of the fluconazole to the microcrystalline cellulose-sodium carboxymethyl starch complex is 2: 3.
9. A process for preparing a pharmaceutical composition of fluconazole of claim 1, which comprises the following steps:
(1) sieving the fluconazole and microcrystalline cellulose compound with the prescription amount through a screen for later use;
(2) adding the fluconazole and microcrystalline cellulose compound obtained in the step (1) into a mixer, and uniformly mixing;
(3) and (3) filling the total mixed powder obtained in the step (2) into a gelatin hollow capsule.
10. The preparation method of the fluconazole pharmaceutical composition of claim 9, which is characterized by comprising the following steps:
(1) sieving the compound of fluconazole and microcrystalline cellulose with a 40-mesh sieve according to the prescription amount for later use;
(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) and (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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