CN114191387A

CN114191387A - A kind of preparation method of voriconazole oral liquid

Info

Publication number: CN114191387A
Application number: CN202111606464.3A
Authority: CN
Inventors: 谈邹念; 胡建旭; 王一鸣; 薛鹏; 孙培培; 张金英
Original assignee: Suzhou Haijing Pharmaceutical Technology Co ltd
Current assignee: Suzhou Haijing Pharmaceutical Technology Co ltd
Priority date: 2021-12-26
Filing date: 2021-12-26
Publication date: 2022-03-18

Abstract

本发明涉及一种口服液的制备方法，具体表述为一种含有抗真菌成分的口服给药制剂，它含有：抗真菌剂，包合物环糊精及其衍生物，作为混合液体载体的水性/酸性介质和醇性共溶剂。同时，附有一种或多种药用甜度剂和/或一种或多种药用调味剂能得到适口性较好的口服制剂。本发明还涉及所述制剂及含所述制剂的药物制剂的制备方法。本发明制备的伏立康唑口服溶液，工艺稳定，与参比制剂相比，具有更高的口服生物利用度。The invention relates to a preparation method of an oral liquid, which is specifically expressed as an oral administration preparation containing an antifungal component, which contains: an antifungal agent, an inclusion compound cyclodextrin and derivatives thereof, an aqueous liquid carrier as a mixed liquid carrier /acidic medium and alcoholic co-solvents. Meanwhile, adding one or more medicinal sweeteners and/or one or more medicinal flavoring agents can obtain oral preparations with better palatability. The present invention also relates to the preparation method of the preparation and the pharmaceutical preparation containing the preparation. The voriconazole oral solution prepared by the invention has stable process and higher oral bioavailability compared with the reference preparation.

Description

Preparation method of voriconazole oral liquid

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a novel composition of an antifungal agent with low solubility in an aqueous medium, specifically to voriconazole oral liquid, wherein the inclusion compound of the novel composition is (2R,3S) -2- (2, 4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2, 4-triazol-1-yl) -2-butanol; vortical chemical book conazole/(2R, 3S) -2- (2, 4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl)) -1- (1H-1,2, 4-triazol-1-yl) -2-butanol with the molecular formula C₁₆H₁₄F₃N₅O, molecular weight 349.31, said compound hereinafter being referred to as compound I, compound I having the following structural formula:

background

Voriconazole (Voriconazole) is a novel broad-spectrum triazole antifungal new drug developed by Pfizer company, is a second-generation synthesized fluconazole derivative, is screened in the early 90 s of the 20 th century, and is approved by the FDA in the united states for marketing at 3, 12, 2002. As a novel antifungal drug, compared with fluconazole, the antifungal agent has the characteristics of wider antifungal spectrum and stronger antibacterial effect, not only inhibits the growth of yeast, but also has the important characteristic of killing aspergillus by sun. Has excellent antibacterial activity on Candida albicans with fluconazole resistance, and has higher antibacterial activity on pathogenic microzyme than fluconazole.

Voriconazole (Voriconazole) for use in the treatment of invasive aspergillosis; treatment of severe invasive infections caused by candida albicans resistant to fluconazole (including candida krusei); treating severe infection caused by Actinoplanes and Fusarium. Voriconazole binds to 14-alpha sterol demethylase (CYP51) and inhibits the demethylation of lanosterol, thereby destroying the function of fungal cell membrane and achieving the effect of inhibiting the growth of fungal cells.

Disclosure of Invention

At present, voriconazole is only available in the market in tablets, injections, capsules, dry suspensions and the like in China, and no oral liquid preparation is available in the market temporarily.

The invention relates to an oral solution, comprising: voriconazole as active ingredient, solubilizer or inclusion agent cyclodextrin and its derivatives, aqueous/acidic medium, alcoholic co-solvent or acidic co-solvent. Preferred formulations having improved palatability may be obtained by the addition of one or more pharmaceutically acceptable sweeteners and one or more pharmaceutically acceptable flavoring agents.

The sufficient amount of the cyclodextrin derivative in the present invention means a cyclodextrin derivative which is substituted in the structure. The cyclodextrin molecular structure comprises 6, 7 and 8 glucose unit molecules, wherein each glucose unit molecule is combined into a ring by a 1, 4-glucoside bond and is alpha cyclodextrin, beta cyclodextrin and gamma cyclodextrin respectively. Cyclodextrin has a slightly tapered hollow cylindrical three-dimensional ring structure, and has an outer upper end (larger opening end) C in its hollow structure₂And C₃Is composed of secondary hydroxyl groups, the lower end (the smaller open end) is composed of C₆The primary hydroxyl group is hydrophilic, and a hydrophobic region is formed in the cavity due to the shielding effect of a C-H bond. The catalyst has no reducing end or non-reducing end and no reducibility; is stable in alkaline medium, but can be cracked by strong acid; can be hydrolyzed only by alpha-amylase but not by beta-amylase, and has stronger tolerance to acid and common amylase than amylose; in aqueous solution and alcohol aqueous solution, the crystal can be well crystallized; the material has no fixed melting point, starts to decompose when heated to about 200 ℃, and has better thermal stability; no hygroscopicity, but easy formation of various stable hydrates; various organic compounds can be embedded into the hydrophobic cavity of the complex to form an inclusion compound and change the physicochemical property of the inclusion compound; many functional groups can be crosslinked on the cyclodextrin molecule or the cyclodextrin can be crosslinked on the polymer to carry out chemical modification or carry out polymerization by taking the cyclodextrin as a monomer. According to the invention, 5% to 50% (W/V) hydroxypropyl betacyclodextrin or sulfobutyl betacyclodextrin is preferred, with 40% (W/V) being most preferred.

In the invention, in order to improve the dissolution speed of the insoluble antifungal agent in the production process, an alcoholic cosolvent or an acidic solvent is added into the preparation to achieve the purpose of solubilization, and ethanol, propylene glycol, glycerol, hydrochloric acid solution and the like can be selected, wherein propylene glycol is preferred. In the absence of alcoholic co-solvents, voriconazole dissolves very slowly in aqueous acidic cyclodextrin media. The alcoholic cosolvent is added in the range of 1% (V/V) to 20% (V/V), preferably 10% (V/V).

The liquid carrier is mixed with an acidic medium, such as a strong pharmaceutically acceptable acid, e.g., hydrochloric acid. The bioavailability of acidic antifungal agents is contrary to the palatability of oral formulations, with the optimum effect being at pH 1.0-4.0.

Since the mixed liquid is an acidic solution and contains an alcoholic cosolvent, it contains sour taste due to low pH and bitter taste due to the alcoholic cosolvent and the active ingredient, and therefore, it is necessary to add a medicinal sweetener and a flavoring agent.

The medicinal sweetening agent preferably comprises at least one intense sweetening agent, such as saccharin sodium, saccharin or saccharin calcium; the common sweetener is selected from sorbitol, mannitol, fructose, sucrose, etc. The sweetness enhancer is saccharin sodium as an example, and the concentration range is 0.04-0.2% (W/V), and preferably 0.08%. The common sweetener can be used effectively in large amount, and the dosage is about 10-35% (W/V), preferably 20% (W/V).

The medicinal flavoring agent is preferably fruit flavoring agent, such as common essence of orange, strawberry, pineapple, banana, etc. The voriconazole has no special pungent smell after being dissolved, and the special smell of the mixed liquid is mainly from an alcoholic cosolvent. The dosage of each flavoring agent is 0.05 percent to 1 percent (W/V).

In summary, according to the present invention, a preferred formulation comprises the following ingredients in weight/volume or volume/volume percentages, based on the total volume of the formulation as denominator):

a) 1-2% (W/V) voriconazole;

b) 40% (W/V) hydroxypropyl betacyclodextrin or sulfobutyl betacyclodextrin;

c) 10% (V/V) propylene glycol or ethanolic acid solution;

d) adjusting the pH of the composition to 1.0-4.0;

e) 20% (V/V) sorbitol solution (70%);

f) 0.04-0.2% (W/V) of saccharin sodium;

g) (ii) no more than 1% (W/V) of one or more flavoring agents;

h) and (3) water.

The preparation process of the preparation comprises the following steps:

a) dissolving the active ingredient in an alcoholic cosolvent or an acidic solvent;

b) dissolving cyclodextrin derivative in water, and adding the solution obtained in the step (a) to a homogeneous phase under stirring;

c) adding a sweetening agent and a flavoring agent, and adjusting the pH value to 1.0-4.0;

d) the formulation was diluted to the desired volume with water.

Drawings

FIG. 1 shows the in vivo release curves of voriconazole (n ═ 6) in oral liquid (Homemade formulation) and commercially available voriconazole tablets (trade name: Vpend) for Beagle dogs

Detailed Description

Example 1:

composition (I)	Dosage of
		Voriconazole	10g
Propylene glycol	100mL
		Hydroxypropyl betacyclodextrin	400g
Non-crystalline sorbitol solution	190mL
		Saccharin sodium salt	0.6g
10% hydrochloric acid solution	Proper amount of
		10% sodium hydroxide solution	Proper amount of
Purified water	To 1000mL

The method comprises the following steps:

1. 100mL of propylene glycol was added to about 20mL of dilute hydrochloric acid, mixed, and 10g of voriconazole was added and dissolved with stirring.

2. In another container, 400g of hydroxypropyl betacyclodextrin was dissolved in 400mL of purified water, and the active ingredient solution was slowly added with stirring.

3. To the mixture, 190mL of sorbitol solution was added and stirred until homogeneous.

4. 0.6g of saccharin sodium was added to the mixture and stirred until homogeneous.

5. Adding sweetener and flavoring agent, and stirring.

6. Adjusting the pH of the mixture to 1.6-2.0 with sodium hydroxide solution. The resulting solution was diluted to 1L, and the mixed solution was filtered through a 0.22 μm filter.

7. Packaging the mixed solution into appropriate container, filling inert gas such as nitrogen, and storing at below 25 deg.C.

Example 2:

composition (I)	Dosage of
		Voriconazole	20g
Propylene glycol	150mL
		Hydroxypropyl radicalBeta-cyclodextrin	420g
Non-crystalline sorbitol solution	210mL
		Saccharin sodium salt	0.8g
10% hydrochloric acid solution	Proper amount of
		10% sodium hydroxide solution	Proper amount of
Purified water	To 1000mL

The method comprises the following steps:

1. weighing 150mL of propylene glycol, adding about 30mL of dilute hydrochloric acid, uniformly mixing, adding 20g of voriconazole, and stirring for dissolving.

2. In another container, 420g of hydroxypropyl betacyclodextrin was dissolved in 420mL of purified water in a 50 ℃ water bath, and the active ingredient solution was slowly added with stirring.

3. 210mL of sorbitol solution was added to the mixture and stirred until homogeneous.

4. 0.8g of saccharin sodium was added to the mixture and stirred until homogeneous.

5. Adding sweetener and flavoring agent, and stirring.

6. The pH of the mixture was adjusted to 2.0. + -. 0.1 with sodium hydroxide solution. The resulting solution was diluted to 1L, and the mixed solution was filtered through a 0.22 μm filter.

Example 3:

composition (I)	Dosage of
		Voriconazole	15g
Propylene glycol	120mL
		Hydroxypropyl betacyclodextrin	410g
Non-crystalline sorbitol solution	200mL
		Saccharin sodium salt	0.6g
10% hydrochloric acid solution	Proper amount of
		10% sodium hydroxide solution	Proper amount of
Purified water	To 1000mL

The method comprises the following steps:

1. 120mL of propylene glycol is weighed, about 24mL of diluted hydrochloric acid is added, the mixture is uniformly mixed, 15g of voriconazole is added, and the mixture is stirred and dissolved.

2. In another container, 410g of hydroxypropyl betacyclodextrin was dissolved in 410mL of purified water in a 40 ℃ water bath, and the active ingredient solution was slowly added with stirring.

3. 200mL of sorbitol solution was added to the mixture and stirred until homogeneous.

5. Adding sweetener and flavoring agent, and stirring.

Example 4:

composition (I)	Dosage of
		Voriconazole	12g
Propylene glycol	100mL
		Hydroxypropyl betacyclodextrin	400g
Non-crystalline sorbitol solution	190mL
		Saccharin sodium salt	0.6g
10% hydrochloric acid solution	Proper amount of
		10% sodium hydroxide solution	Proper amount of
Purified water	To 1000mL

The method comprises the following steps:

1. 100mL of propylene glycol was added to about 20mL of dilute hydrochloric acid, mixed, and 12g of voriconazole was added and dissolved with stirring.

2. Taking another container, taking 400g of hydroxypropyl betacyclodextrin, dissolving in 400mL of purified water in a water bath at 60 ℃, and slowly adding the active ingredient solution under stirring.

5. Adding sweetener and flavoring agent, and stirring.

Example 5:

the voriconazole oral solution prepared in example 1 was left at high temperature (60 ℃) for 30 days with the changes shown in table 1:

table 1: voriconazole oral liquid high-temperature sample detection result

Item	Day	0	5 days	10 days	30 days
						Content (%)	100.1	99.9	100.2	100.1
Related substance (%)	0.11	0.16	0.21	0.24
					pH value	1.81	1.86	1.88	1.87
Traits	Yellow transparent liquid	Yellow transparent liquid	Yellow transparent liquid	Yellow transparent liquid

Example 6:

the voriconazole oral solution prepared in example 2 was left at high temperature (60 ℃) for 30 days with the changes shown in table 2:

table 2: voriconazole oral liquid high-temperature sample detection result

Item	Day	0	5 days	10 days	30 days
						Content (%)	100.3	99.8	100.1	100.2
Related substance (%)	0.13	0.19	0.22	0.21
					pH value	1.78	1.86	1.84	1.88
Traits	Yellow transparent liquid	Yellow transparent liquid	Yellow transparent liquid	Yellow transparent liquid

Example 7:

the voriconazole oral solution prepared in example 3 was left for 30 days under light conditions, and the changes are shown in table 3:

table 3: voriconazole oral liquid illumination sample detection result

Item	Day	0	5 days	10 days	30 days
						Content (%)	99.9	100.1	99.8	100.2
Related substance (%)	0.12	0.17	0.23	0.22
					pH value	1.82	1.84	1.86	1.85
Traits	Yellow transparent liquid	Yellow transparent liquid	Yellow transparent liquid	Yellow transparent liquid

Example 8:

this experiment compared the relative bioavailability of voriconazole oral liquid (Homemade formulation) and commercial voriconazole tablets (trade name: Vfend) in Beagle dogs. Beagle dogs, male, 6, body weights 6 + -1 kg, were randomly divided into two groups of 3 dogs each. The experiment adopts a two-cycle cross administration mode, and the administration dose is 5 mg/kg. Fasting was overnight before dosing, 100g of feed was given on the day of dosing, gavage was given 30 minutes after the start of feeding and 100ml of purified water was given. Plasma samples were immediately withdrawn at 0.5, 1,2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours and collected in heparin tubes. Plasma was processed and analyzed by HPLC-MS with a drug elution period of 2 weeks and the sequence of administration and pharmacokinetic parameters are shown in tables 4 and 5.

Table 4: beagle dog dosing sequence chart

Table 5: voriconazole oral liquid and Vpend pharmacokinetic parameters in Beagle dogs (n ═ 6)

The pharmacokinetic experiment result shows that the relative bioavailability of the voriconazole oral liquid is 117.8%, and compared with a reference preparation, the voriconazole oral liquid has better oral bioavailability.

Claims

1. a preparation suitable for oral administration, be specifically expressed as a kind of oral administration preparation containing antifungal agent, described preparation contains: antifungal agent, inclusion complex cyclodextrin or derivative thereof, as mixed liquid Aqueous/acidic medium and alcoholic co-solvent for the carrier.

2. The formulation of claim 1, further comprising one or more sweetening agents, one or more flavoring agents.

3. The formulation of claim 1 or 2, wherein the antifungal agent is voriconazole and the cyclodextrin is hydroxypropyl beta cyclodextrin or sulfobutyl beta cyclodextrin.

4. The formulation of claim 1 or 2, wherein the alcoholic co-solvent is glycerol, propylene glycol or ethanol.

5. The preparation according to claim 1 or 2, which has a pH of 1.0 to 4.0.

6. The formulation according to claim 1 or 2, wherein the pharmaceutically acceptable sweetener comprises at least one intense sweetener and/or optionally one ordinary sweetener.

7. The preparation according to claim 6, wherein the strong sweetener is selected from the group consisting of alitame, glycerol, cyclamate, sucralose, acesulfame potassium, stevioside, aspartame, thomastin, glycyrrhizin, One or more mixtures of aspartame, potassium dioxythiazine, sodium cyclamate, saccharin, sodium saccharin or calcium saccharin, and common sweeteners are selected from sorbitol, mannose One or more mixtures of sugar alcohols, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

8. According to the described preparation of claim 1 or 2, in terms of weight/volume or volume/volume percentage (taking the total volume of the preparation as the denominator), the preparation contains at least one of the following:

a) 1%～2%(W/V) voriconazole;

b) 5%～50% (W/V) hydroxypropyl beta cyclodextrin or sulfobutyl beta cyclodextrin;

c) 1%～20% (V/V) propylene glycol or ethanolic acid solution;

d) adjusting the pH of the composition to be between 1.0 and 3.0;

e) 10%～35% (V/V) sorbitol solution (70%);

f) 0.04%～0.2% (W/V) sodium saccharin;

g) not more than 1% (W/V) of one or more flavouring agents;

h) water.

9. according to the preparation method of the described preparation of claim 1 or 2, it is characterized in that described method is as follows:

a) put the active ingredient solution in an alcoholic co-solvent or an acidic solvent;

b) Dissolving the cyclodextrin derivative in water, and adding the solution of step (a) to a homogeneous phase with stirring;

c) Add sweetener and flavoring agent, adjust pH to 1.0～4.0;

d) Dilute the formulation with water to the desired volume.