WO2007054599A1 - Oral formulations comprising 3'-azidonucleosides - Google Patents

Abstract

The invention relates to oral formulations comprising 3'-azidonucleosides. The invention comprises formulations, preferably of zidovudine or the pharmaceutically-acceptable derivatives thereof, optionally combined with other active principles, which are intended for oral administration. The inventive formulations can take the form of solids (granulates, tablets, capsules, etc.) and liquids. Said formulations can be used in the treatment of microbial infections in general, as antibacterial agents and preferably as antiviral agents, and are particularly suitable for combating infections caused by retroviruses, such as AIDS.

Description

 ORAL FORMULATIONS THAT INCLUDE 3'-AZIDONUCLEOSIDES

Technical Sector

The present invention is attached to the pharmaceutical sector, specifically to the preparation of oral galenic formulations of active ingredients, in its different presentations (dry granules, capsules, tablets and syrups or liquid formulations in general).

Description:

The present invention relates to pharmaceutical formulations for oral administration containing 3'-azidonucleosides or a pharmaceutically acceptable derivative thereof and their use for the treatment and / or prophylaxis of viral and bacterial infections.

More specifically, the present invention relates to pharmaceutical formulations for ora administration! containing 3'-azido-3'-deoxythymidine (zidovudine) or a pharmaceutically acceptable derivative thereof and its use for the treatment and / or prophylaxis of viral and bacterial infections.

Zidovudine is an important and useful chemotherapeutic agent for the treatment and / or prophylaxis of infections caused by retroviruses and in particular for the treatment and / or prophylaxis of infections caused by the human immunodeficiency virus (HIV), etiological agent of AIDS.

By a pharmaceutically acceptable derivative is meant any salt, ester or sai of said pharmaceutically acceptable ester or any other compound which, after administration, is capable of providing (directly or indirectly) 3'-azidonucleoside. Particularly preferred esters are zidovudine mono-, di- and tri-phosphate esters. Examples of physiologically acceptable salts include salts derived from an appropriate base, such as an alkali metal (for example sodium), or an alkaline earth metal (for example magnesium). The present invention provides a composition comprising 3'-azido-3'-deoxythymidine (zidovudine) useful for the preparation of tablets, capsules and oral solutions or suspensions. Optionally, the formulations of the invention may also comprise other active ingredients, especially those with antiviral and / or antibacterial and / or antimicrobial activity in general, particularly those that potentiate the effects of zidovudine as an antiviral / antimicrobial / antibacterial.

The formulations of the present invention comprise at least 3'-azido-3'-deoxythymidine (zidovudine), useful for fighting infections caused by retroviruses, together with one or more physiologically acceptable vehicles and optionally other therapeutic agents also useful for combating infections caused by retroviruses.

In a further aspect, the present invention also relates to processes for the preparation of zidovudine formulations.

In general, the formulations of the present invention include the step of associating the active ingredient with the necessary excipients.

The synthesis of zidovudine was described for the first time in 1964 by Horwith in the article published in J. Org. Chem. 29 (7), 2076-8. Zidovudine (3'-azido-3'-deoxythymidine), has the following chemical structure.

Zidovudine presents keto-enol tautomería and the use of any of the keto or enol tautomeric forms falls within! scope of the present invention. Detailed description of the invention

The formulations of the present invention, suitable for oral administration, can be presented as discrete units, such as capsules, tablets containing a predetermined amount of active ingredient; either as a powder or granules; or as a solution or a suspension in an aqueous or non-aqueous liquid. All the formulations that are detailed and claimed in the present patent have in common technical characteristics that allow their oral delivery, either in solid form or, especially for those patients who have solid ingestion problems (children, elderly people, patients with diminished consciousness, etc.), in liquid form.

The formulations in the form of granules of the present invention can be prepared by wet granulation of a mixture constituted by at least zidovudine or a derivative thereof as an active ingredient, other different active ingredients may be present, at least one binding agent (for example, povidone, gelatin, hydroxypropylmethylcellulose), at least one inert diluent, at least one disintegrant (e.g., sodium starch giicolate, crosslinked povidone, crosslinked carboxymethylcellulose) and, optionally, other pharmaceutically acceptable agents, preferably a lubricant (more preferably magnesium stearate ).

The liquid used for wet granulation can be aqueous, alcoholic or hydroalcoholic and is removed by drying the granulated wet mass.

The pharmaceutical formulations according to the present invention may optionally contain other therapeutic agents and other active ingredients such as antimicrobial or antiviral or antibacterial agents.

These formulations in the form of granules can be compressed to obtain tablets or used to fill capsules or to prepare solutions or suspensions. Zidovudine used as matter! For the formulations of the present invention, it can have a particle size between 200 μm and 0.2 μm. These particle sizes can be achieved by crystallization techniques or by particle size reduction techniques such as e! ground or micronization.

Typically, solid oral formulations of the present invention have a solution of! 85% at fifteen minutes. The amount of dissolved zidovudine is determined by an appropriate anaitic technique, for example by ultraviolet (UV) analysis or by high performance liquid chromatography (HPLC).

The present invention proposes a granule formulation containing:

a therapeutically effective amount of zidovudine

from 2 to 6% by weight, relative to the active ingredient, of a hydrophilic binding agent

from 16 to 80% by weight, based on the weight of the active ingredient, of a diluting agent

from 1 to 9% by weight, based on the weight of the active ingredient, of a disintegrating agent.

Preferred binders are starch in a proportion of at least 5.6% by weight with respect to! active ingredient and polyvinylpyrrolidone, in a proportion of approximately 2.3% by weight with respect to! active ingredient.

The starch can be rice, wheat or corn. The preferred starch is corn starch and can be a partially pregelatinized starch, such as 1500 starch (Coorcon). In addition to its function as a binder, part of the starch, especially in zidovudine 100 mg capsules, can perform diluent functions,

Any suitable polyvinylpyrrolidone capable of acting as a binder can be used. Polyvinylpyrrolidone can be a linear polymer of 1-vinyl-2-pyrrolidone which has an average molecular weight of about 40,000, such as Povidone K30 (ISP Pharmaceutical).

The preferred diluting agent is microcrystalline cellulose or mixtures thereof with starch.

The preferred disintegrating agent is sodium starch glycolate.

The granule formulations of the present invention are obtained from a process comprising wet granular:

Zidovudine, the diluting agent, and optionally the disintegrating agent, in the presence of a hydrophilic binding agent, and optionally mixing with the same or other disintegrating agent and / or also with other pharmaceutically acceptable auxiliary agents.

Pharmaceutically acceptable auxiliary agents, preferred in the present invention are, among others:

- Lubricants, such as sodium benzoate, used in a range of 0.25-5% with respect to the weight of active substance.

Pigments, such as titanium dioxide, preferably used in tablets, to provide them with white color and in an approximate concentration of 0.61% with respect to the weight of active substance.

The liquid oral formulations contain, in addition to the active ingredient, zidovudine or its derivatives, alone or with other active ingredients, at least one liquid vehicle for dissolving or suspending the active ingredient, wetting agents, sweetening agents, flavoring substances, preservatives and acidifying agents to neutralize the bitter taste of zidovudine.

It is convenient that the liquid oral formulations to be used probably contain a soluble preservative agent repeatedly. The Concentration of the preservatives can vary from 0.05% to 1% w / v, particularly from 0.1% to 0.5% w / v and in a very particular way is about 0.2% w / v. The most preferred preservative is sodium benzoate.

The bitter aroma of zidovudine can be optionally masked by one or more intense sweetening agents such as saccharin, sodium, potassium or caustic saccharin or sodium cyclamate. The concentration of the sweetening agent may vary from 0.05% to 0.5% w / v and in particular it is approximately 0.2% w / v. Optionally, the palatabidity of the present solutions can be further optimized by the addition of one or more flavoring substances. Suitable flavoring substances are fruit aromas. Strawberry aroma has been found to produce very satisfactory masked aroma results. The total concentration of the flavoring substances may vary from 0.01% to 0.2% w / v, preferably from 0.02% to 0.1% w / v and in particular is approximately 0.025% w / v.

AND! Preferred acidifying agent is citric acid.

A liquid oral composition according to the present invention comprises:

0.5% to 1.5% w / v zidovudine

0.1% to 0.5% w / v preservatives

0.01% to 0.2% w / v flavorings

0.05% to 0.5% w / v sweeteners

0.15% to 0.5% w / v of acidulants 5% to 15% w / v of humectants

30% to 80% w / v hydrogenated glucose syrup and purified water, in sufficient quantity up to 100%, as liquid vehicles

The most preferred liquid oral composition according to the present invention comprises:

1% w / v (0.01 g / mi) of zidovudine, as active ingredient 0.2% w / v (0.002 g / mi) of sodium benzoate, as a preservative 0.025% w / v (0.00025 g / mi ) strawberry flavor, as 0.2% w / v (0.002 g / mi) sodium saccharin flavoring, as a sweetener 0.35% w / v (0.0035 g / mi) of citric acid, as acidulant

10% w / v (0.1 g / m!) Of glycerol, as a humectant and

64% (0.64 g / mi) of hydrogenated glucose syrup and purified water, in sufficient quantity up to 100% (1 mi), as liquid vehicles

The liquid formulations of the present invention are obtained from a process comprising:

Dissolve the glycerol and strawberry aroma in a part of the water, and then add the active ingredient, hydrogenated glucose syrup, citric acid, sodium benzoate ₇ and sodium saccharin, stir for a while and make up to! determined volume

The following examples are set forth in order to provide the skilled person with a sufficiently clear and complete explanation of the present invention, but should not be considered as limitations on the essential aspects of the object thereof, as they have been set forth. in the previous sections of this description

Example 1: Tablet formulations

The zidovudine, the microcrystalline cellulose and the sodium starch giicolate are mixed, and passed together through a 0.8 mm mesh screen. A solution of poüvinylpyrrolidone in water or in a mixture of water and ethanol is added and added. Knead for a certain time The wet mass is passed through a granulator and the granulate obtained is dried at a suitable temperature for the necessary time. AND! Dry granulated is calibrated through a sieve and mixed intimately with e! titanium dioxide and magnesium stearate. Free flowing granule powder is obtained.

The granulate is compressed in a compression machine. The tablets obtained can be optionally coated.

Example 2: Capsule formulations

The zidovudine, microcrystalline cellulose and corn starch are mixed, ethanol is added and kneaded for a certain time. The wet mass is passed through a granulator and the granulate obtained is dried for the necessary time. The dried granulate is calibrated through a sieve and mixed intimately with the sodium starch gcolato and magnesium stearate. Free flowing granule powder is obtained.

The granulate is used to fill the capsules.

In an alternative process, zidovudine and microcrystalline cellulose are mixed, a starch paste is prepared, added over the previous mixture and kneaded for a certain time. The wet dough is posing as a granulator ye! obtained granulate is dried for the necessary time. The dried granulate is calibrated through a sieve and mixed intimately with the sodium starch glycolate and magnesium stearate. Free flowing granule powder is obtained. The granulate is used to fill the capsules. Example 3: Liquid Formulations

A mixture of glycerol, strawberry aroma and part of the water is stirred. Subsequently, the active ingredient, the hydrogenated glucose syrup, citric acid, sodium benzoate and sodium saccharin, is added, stirred for a certain time, made up to a certain volume and dosed in bottles.

Claims

Claims 1. A solid pharmaceutical formulation for oral administration comprising a therapeutically effective amount of 3'-azido-3'-deoxyttmidine (zidovudine) or a pharmaceutically acceptable derivative thereof, together with: at least one hydrophilic binding agent, at least one diluting agent _τ and at least one disintegrating agent, 2. A pharmaceutical formulation for oral administration according to claim 1 characterized in that it is in solid form. 3.- A pharmaceutical formulation for administration now! according to claim 2 characterized in that it is in the form of granules. A - A pharmaceutical formulation for oral administration according to claim 2 characterized in that it is in the form of a tablet. 5. A pharmaceutical formulation for oral administration according to claim 2 characterized in that it is in capsule form. 6. A pharmaceutical formulation for oral administration according to any of claims 1 to 5 characterized in that the hydrophilic binding agent is present between 2 and 55% by weight with respect to the weight of the active ingredient, the diluting agent is present in 16 and 80% by weight with respect to the weight of the active ingredient, and the disintegrating agent is present between 1% and 9% by weight with respect to the weight of the active ingredient. 7. A pharmaceutical formulation for oral administration, according to any of claims 1 to 6, characterized in that The hydrophilic binding agent is starch or polyvinipyrrolidone, The diluting agent is microcrystalline cellulose or mixtures thereof with starch, and the disintegrating agent is sodium starch glycolate. 8. A pharmaceutical formulation for oral administration, according to claim 7, comprising from 52 to 72% by weight of zidovudine, from 4 to 29% by weight of starch, from 13 to 18% by weight of microcrystalline cellulose, from 4 to 6% by weight of sodium glycolate of starch. 9. A pharmaceutical formulation for oral administration, according to claim 7, comprising from 52 to 85% by weight of zidovudine, from 1 to 2% by weight of polyvinylpirroiidone, from 10 to 46% by weight of microcrystalline cellulose, from 1 to 6% by weight of sodium glycolate of starch. 10. A solid pharmaceutical formulation for oral administration according to claims 7 or 8 characterized in that e! Hydrophilic binding agent is starch and is present in at least 5% by weight with respect to the weight of the active ingredient, the diluting agent is microcrystalline cellulose and is present between 20 to 30% by weight with respect to the weight of the active ingredient and The disintegrating agent is sodium starch glycolate and is present in approximately 8% by weight based on the weight of the active ingredient. 1 1. A solid pharmaceutical formulation for oral administration according to claims 7 or 9 characterized in that the hydrophilic binding agent is polyvinylpropylidone and is present between 2 and 3% by weight with respect to the weight of the active ingredient, the agent The diluent is microcrystalline cellulose and is present between 12 and 25% by weight with respect to the weight of the active ingredient and the disintegrating agent is sodium starch glycolate and is present between 1 and 3% by weight with respect to the weight of the active ingredient. . 12. A pharmaceutical formulation for oral administration according to claim 4, characterized in that it additionally contains in its composition titanium dioxide. 13. A pharmaceutical formulation for oral administration according to any of the preceding claims, characterized in that it has in its composition, additionally, a lubricating compound, preferably magnesium stearate 14.- A pharmaceutical formulation for oraí administration according to any of the preceding claims, characterized in that it has a solution of zidovudine of 85% at 15 minutes. 15.- A pharmaceutical formulation for administration now! according to claim 1 characterized in that it is in liquid form. 16. A pharmaceutical formulation for oral administration, according to claim 15, comprising a therapeutically effective amount of 3'-azido-3'-deoxythymidine (zidovudine) or a pharmaceutically acceptable derivative thereof, characterized in that it also contains: at least one preservative, at least one flavoring agent, at least one sweetener, at least one acidulant, at least one humectant and at least one liquid vehicle 17.- A pharmaceutical formulation for oral administration according to claim 16 containing: 0.5% to 1.5% w / v zidovudine 0.1% to 0.5% w / v preservatives 0.01% to 0.2% w / v of flavorings 0.05% to 0.5% w / v of sweeteners 0.15% to 0.5% w / v of acidulants 5% to 15% w / v of moisturizers 30% to 80% w / v hydrogenated glucose syrup purified water, sufficient amount up to 100% 18, - A pharmaceutical formulation for oral administration according to claims 16 or 17, characterized in that the flavoring agent is strawberry flavor. 19. A formulation for oral administration according to any of claims 16 to 18, in which sodium benzoate is preferably used as a preservative. 20. A formulation for oral administration according to claim 16 to 19 in which citric acid is used as an acidulant. 21.- A formulation for administration now! according to any of claims 16 to 20 containing 1% (0.01 g / mi) of zidovudine, 0.2% (0.002 g / mi) of sodium benzoate, 0.025% (0.00025 g / mi) of strawberry aroma, 0.35% (0.0035 g / mi) of citric acid, 64% (0.64 g / mi) of hydrogenated glucose syrup, purified water, in sufficient quantity up to 1 ml, and optionally one or more sweetening or wetting agents 22.- A formulation for oral administration according to claim 21 containing as a sweetener 0.2% (0.002 g / mi) of sodium saccharin and as a humectant 10% (0.1 g / m!) Of glycerol! 23.- A formulation for oral administration according to any of the preceding claims, characterized in that the zidovudine used as the active principle has a particle size between 0.2 μm and 200 μm.