MXPA97003839A - Intravenous solutions of lubelu - Google Patents

Abstract

A solution for intravenous administration containing lubelozole or a pharmaceutically acceptable addition salt thereof, an isotonizing agent, water and basic and acidic substances for adjusting the pH of the solution in the range of 2.5 to 3.6, as well as procedures for preparing the same is described.

Description

INTRAVENOUS SOLUTIONS OF LUBELUZOL DESCRIPTIVE MEMORY In US-4, 86, 785 c describe benzoxazole and benzothiozolamine derivatives having an anti-i-anoxy ac activity. In UO-92/14, 731 some of these benzothiazolamma derivatives are described which have useful anti -attack fulminating activity. The present invention includes injectable formulations of (S) -4T (2-benzot? A ol? L) rnet. arn? no-cr- [(3, 4-difluorophenoxy) rnet111-1-p iperid Lnoethanol (generically known as lubeluzol) which has excellent physical stability. The most appropriate route of administration for the treatment of patients suffering from acute fulminant attack is probably the direct treatment of a drug in the veins. A pharmaceutical formulation for intravenous administration has to meet stringent requirements with respect to physical, chemical and biological stability. For example, problems may arise due to the adsorption of the active ingredient to the walls of the intravenous administration equipment. In particular, the substances tend to adsorb to the walls of the infusion bag and to the PVC-tubes in said equipment. WO-92/14, 731 discloses an injectable solution having pH 4 and containing a benzot-aazolylamine derivative, glucose, hydrochloric acid, sodium hydroxide, or droxypropyl- (1-c? Clodext) and water. Lubeluzol shows signifi- cant problems with regard to the absorption of intravenous equipment walls It was found that the adsorption of lubeluzol to the walls of intravenous administration equipment could be significantly reduced by keeping the pH of the formulation below 3.6. , an intravenous solution having superior physical stability was prepared when compared to the formulation of the art.Therefore, the present invention relates to a solution for intravenous administration containing water, lubeluzol or a pharmaceutically acceptable addition salt of the same, an isotonizing agent, and acidic and basic substances to adjust the pH to the solution in the range of 2.5 to 3. fi. The present invention also relates to the use of acidic and basic substances in a solution according to the invention to prevent the adsorption of lubeluzol or a pharmaceutically acceptable addition salt thereof to the walls of the intravenous administration equipment. Lubeluzol is generic for (S) -4- (2-benzo lazoly) rnet ílarni ol-ct-r (3, 4- di luorofenoxi Irne il) -l ?? í pend pend pend pend preparación preparación preparación y y y y y y y described in UO- < 32/14,? 31. The addition salts as mentioned above mean that they comprise the therapeutically active non-toxic addition salt forms that lubeluzol can form, the latter being conveniently obtained by treating the form base with the appropriate acids, such as, for example, inorganic acids such as halogenhydric acids, e.g., hydrochloric or hydrochloric acid, sulfuric, nitric, phosphoric and similar acids, or organic acids such as, for example, acids acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malomatic, succinic, rnaleic, funapco, melic, tartaric, citric, phonic, etansul phonic, benzensulfonic, p-toL-ensulfonic, cyclic, salicylic, p-amy nosalicylic , paronoic and similar. on the contrary, the salt form can be converted into the free base form by treatment with alkaline material. The term "addition salt", as used above, also encompasses the solvates that lubeluzol can form and said solvates are included within the scope of the present invention. Examples of said solvates are, e.g., hydrates, alcoholates and the like. The term "physically stable", as used in Id present, refers to a solution for which less than 10% by weight of active ingredient is absorbed after passing to < raves of an infusion device. Preferably less than 5% by weight of the active ingredient is adsorbed. From now on, the amounts of each of the ingredients in the compositions are expressed as percentages by weight based on the total volume of the formulation, unless otherwise indicated. In a particular aspect of the invention, the concentration of lubeluzol or an addition salt thereof in the present solutions may vary from 0.005% to 5%, preferably from 0.01% to 1%, most preferably 0.02% a 0. 2% and in particular is approximately 0.05%. In addition, solutions in this aspect of the invention conveniently comprise from 1 to 10% of the active agent, in particular glucose is used as the isotonizing agent. The use of glucose as an isotonizing agent has the advantage that very clear solutions are obtained. Preferably, the glucose is used in a concentration of 2 to 10%, most preferably of about 5%. In another particular aspect of the present invention, the concentration of lubeluzol or a pharmaceutically acceptable addition salt thereof in the solutions may be from 0.005% to 5%, preferably from 0.005% to 0.1%, most preferably from 0.01% to 0.05% and in particular it is approximately 0.02%. Rdenas, the solutions in this aspect of the invention conveniently comprise 0.01 to 2% isotonizing agent, in particular sodium chloride is used as an isotonizing agent. The use of sodium chloride as an isotonizing agent is particularly useful for solutions in which the concentration of lubeluzol varies from 0.005% to 0.1%, preferably between 0.005% and 0.05%. Preferably, sodium chloride is used in a concentration of 0.4% to 1.8%, most preferably of about- 0.9%. The solutions of the present invention comprise acidic and basic substances for maintaining the pH of the solutions in the scale of 2.5 to 3.6, preferably in the range of 3.0 to 3.4, most preferably of about 3.2. Preferably, the pH of the solutions is adjusted by appropriate amounts of hydrochloric acid and sodium hydroxide. The pH can also be adjusted by pH regulating systems comprising mixtures of appropriate amounts of an acid such as phosphorus, tartaric or citric acid, and a base, in particular sodium hydroxide. To increase the solubility of lubeluzol or a pharmaceutically acceptable addition salt thereof in the present formulations, a solubilizer can be used. Conveniently, a clodextpna (CD) or a derivative of the same can be used. The appropriate cyclodexture derivatives are a, (3, t-c? Clode? T braces or mixed ethers and ethers thereof where one or more of the hydroxy groups of the anhydroglucose units of the cyclodexternal are replaced by C6-6 alkyl, particularly methyl, ethyl or iso-propyl; Ci-s hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyCi-βalkyl, particularly carboxymethyl or carboxymethyl; 6, particularly acetyl, Ci-β alkyloxycarbom or carboxy C de-6-alkyl-C alquilo--β alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl, C alqu-C ~ alquiloalkyl β-C alquilo alkyl alkyloxycarbonyl, particularly 2-Acetyl-lox, propylene, etc. Especially valuable as complex and / or solubilizer formers are fí ~ CD, 2, 6-d? Met? Lo-ß-CD, 2-hydrox? Et lio-ß-CD, 2-hydro? Et? Lo ~ t-CD, 2-hydrox? Prop? Lo-t-CD and (2-oarhoxirnetoxi) pro ?? lo-ß ~ OD, and in particular 2-h? Dro? Pro ?? lo-P-OD. The term mixed ether d Enotate cyclodextrin derivatives wherein at least 2 hydroxyl groups of the cyclodextrin are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. The average molar substitution (S.fl.) is used as a measure of the average number of moles of alkoxy units per mole of anhydro droglucose. The value je .n. it can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), loop spectrometry (EM) and infrared spectroscopy (TR). Depending on the technique used, slightly different values can be obtained for a given cyclodext derivative. In the hydroxyalkyl derivatives of the cyclodextrin for use in compositions according to the present invention, MS as determined by mass spectrometry is on a scale of 0.125 to 10, in particular 0.3 to 3, or 0.3 to 1.5. .

Preferably, the ES varies from around 0.3 to approximately 0.8, in particular from about 0.35 to about 0.5 and most particularly about 0.4. The EM values determined by NMR or TR preferably range from 0.1 to 1, in particular from 0..55 to 0.75. The degree of average substitution (G.S.) refers to the average number of substituted hydroxyl per unit of anhydroglucose. The value of G.S. it can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (EM) and infrared spectroscopy (TR). Depending on the technique used, slightly different values can be obtained for a given c-clodextnna derivative. In the cyclodextrin derivatives to be used in the compositions according to the present invention, the G.S. As determined by MS, it is on the scale of 0.25 to 3, in particular of 0. a or 0.2 to 1.5. Preferably, the G.S. it varies from about 0.2 to about 0.P, in particular from about 0.35 to about 0.5 and very particularly about 0.4. The values of G.S. determined by NMR or IR preferably vary from 0.3 to 1, in particular from 0.55 to 0.75. The hydroxyalkyl derivatives of the mostpartial hydroxyl groups for use in the compositions according to the present invention are partially substituted cyclodextrin derivatives wherein the average degree of alkylation in hydroxyl groups of different positions of the anhydroglucose units it is around 0% to 20% for the 3 position, 2% to 70% for the 2 position and from around 5% to 90% for the 6 position. Preferably, in the amount of (3 or t-ciciodext quarrel Non-substituted is less than 5% of the content of total lodexture and in particular is less than 1.5% Another derivative of cyclodexture that is particularly interesting is the randomly ethylated ß-cyclodextrin. for use in the present invention are those ethers (partially substituted cyclodextria or teres successes having hydroxypropyl, hydroxyethyl substituents and in particular 2-hydroxypropylene and / or 2- (1-hr) oxypropyl.) The most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl-β-cyclodextrin which has an E.M. on the scale from 0.35 to 0.50 and containing less than 1.5% of unsubstituted β-cyclodextri. The values of E.M. determined by NMR or IR, it will be from 0.55 to 0.75. To minimize the risk of adverse reactions, an intravenous formulation preferably contains as few ingredients as possible. Therefore, a formulation without a solubilizer (e.g., a cyclodextrin) is preferred. It was found that, for formulations without a solubilizer, the solubility of lubelozol in the present formulations ranges from about 9.2 rng / rnl (pH 2.5) to about 2 rng / l (pH 3.6). The pH 3.2 formulations without a solubilizer comprise at most about 3 μg / ml of dissolved lubelozol. In addition, the present solutions preferably do not contain a preservative. To ensure biological stability, the solutions are conveniently manufactured in unit dose containers, e.g., unit dose sacks or bottles, ampoules and the like. It may also be advantageous to manufacture the solutions of the present invention in pre-filled syringes, in particular filled syringes adapted for use with devices and melters. The solutions herein are conveniently used in the treatment of patients suffering from acute fulminating attack. In general, it is contemplated that an effective daily amount would be 0.1 to 100 mg, preferably 50 mg of active ingredient. It is evident that said daily effective amount can be reduced or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present invention. The daily effective quantity scales mentioned above are therefore reference quantities only and are not intended to limit the scope or use <the invention to no degree. The solutions herein may conveniently be coadministered with a physiological salt solution in accordance with fusion procedures known in the art. One aspect of the invention particularly relates to solutions comprising: (a) 0.005 a)% lublozole or an acceptable pharmaceutically acceptable addition salt thereof; (b) 1 to L0% isotonizing agent; (c) acidic and / or basic substances to adjust e? pH in the range of 2.5 to 3.6; and (d) water at a sufficient amount for 100%. Preferably, this aspect of the invention relates to solutions comprising: (a) 0.01 to 1% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 2 to 10% glucose; (c) hydrochloric acid and sodium hydroxide to adjust the pH in the range of 3.0 to 3.4; and (d) water in a sufficient amount by 100%. Another aspect of the present invention particularly relates to solutions comprising: (a) 0.005 to 5% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 0.1 to 2% isotonic agent; (c) acidic and / or basic substances to adjust the pH in the range of 2.5 to 3.6; and id) water to a sufficient amount for 100%. Preferably, this aspect of the invention relates to solutions comprising: (a) 0.005 to 0.1% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 0.4 to 1.8% sodium chloride; (c) hydrochloric acid and sodium hydroxide to adjust the pH on the scale from 3.0 to 3.4; and (d) water to an amount sufficient for 10%. Optionally, the above formulations further comprise a cyclodextine or a derivative thereof. Most preferably, the invention in all its aspects refers to solutions containing approximately: (a) 0.05% lubeiozole or a pharmaceutically acceptable addition salt thereof; (b) 5% glucose; (c) hydrochloric acid and sodium hydroxide to adjust the pH to about 3.2; and (d) water at a sufficient amount for 100%; and solutions containing approximately: (a) 0.02% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 0.9% sodium chloride; (c) hydrochloric acid and sodium hydroxide to adjust the pH to approximately 3.2; and (d) water at a sufficient amount for 100%. In addition, the present invention relates to the preparation of the solutions described. The preparation involves the intimate mixing of the active ingredient with water, the isotonizing agent and the acid and base substances. In particular, the preparation involves the following steps: (a) the active ingredient, the isotonizing agent and the acid are mixed with an appropriate amount of water; (b) the base is added in an amount sufficient to reach the desired pH; and (c) added water to the desired final volume. Optionally, the solution is sterilized using known techniques. The above process can be conducted under an inert atmosphere, e.g., nitrogen or argon without oxygen. It is advantageous to use a zoned form of lubelozole or a pharmaceutically acceptable addition salt thereof, in particular material having an average particle size of less than 100 microns, preferably less than 75 microns and in particular having an average particle size not greater than 15 years. The controlled forms can be prepared by known milling techniques, e.g., by grinding in appropriate mills and sieving through appropriate sieves. Since the product is to be administered acutely to patients suffering from fulminating attack, ie in the ambulance, emergency room or intensive care unit, an infusion package for acute fulminant attack treatment comprising the product together with a disposable independent drive unit is considered to be the most useful product presentation according to the present invention. As independent drive units for driving the syringes, in particular prefilled syringes, some gas operated and operated ba or vacuum operated driving units may be named, the latter being preferred for their more reliable flow control. The following examples are intended to illustrate the scope of the present invention in all its aspects.

EXAMPLE 1 Fl Ingredient Lublozole Amount 0.5 mg Anhydrous Glucose 50 rng Concentrated Hydrochloric Acid 0.332 mg Sodium Hydrochloride c.b.p. pH - 3.2 Water for injections c.b.p. 1 rnl Preparation: (a) 0.5 ng of lubelozol, 50 g of anhydrous glucose and 0.332 microliters of hydrochloric acid were concentrated with 0.8 ml of water; (b) sodium hydroxide was added until pH-3.2 t 0. 1; (c) water was added n 1 i. In a similar way they were prepared: F2 Ingredient Amount Lubelozol 1 rng Anhydrous glucose 50 rng Concentrated hydrochloric acid 0.489 mg Hydroxy or sodium c.b.p. pH - 3.2 Water for injections c.b.p. 1 rnl F3 Ingredient Amount Lubelozol 0.5 rng Anhydrous glucose 50 rng Concentrated hydrochloric acid 0.332 rng Sodium hydroxide c.b.p. pH - 3.1 Water for injections c.b.p. 1 rnl F4 Ingredient Can idad Lubelozol 0.2 mg Anhydrous glucose 9 g Concentrated hydrochloric acid 0.192 mg H i di? X LtJo do so io c.b.p. pH - 1.2 Water for injections c.b.p. 1 rnl F5 Ingredient Canoe Lubelozol 0.25 mg Anhydrous glucose 50 ng Concentrated hydrochloric acid 0.25 rng Sodium hydroxide c.b. pH = 3.2 Water for injections c.b.p. 1 mi EXAMPLE 2 PHYSICAL STABILITY The above solutions were pumped through an infusion device at a rate of 10 ml / hour for 48 hours. The fractions were collected at different time intervals and the lubelozol concentration was determined. The percentage adsorbed (by weight) of lubelozol was less than 4% at any time during the experiment. Therefore, the solutions described meet the requirements of a physically stable formulation as indicated above.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. A solution for intravenous administration containing water, lubelozole or a pharmaceutically acceptable addition salt thereof, an isot or lifting agent, and acidic and basic substances for adjusting the pH of the solution in the range of 2.5 to 3.6.

2. A solution according to claim 1, further characterized in that the isotonizing agent is glucose.

3. A solution according to claim 1, comprising acidic and basic substances to adjust the pH of the solution in the range of 3.0 to 3.4.

4. A solution according to claim 1, comprising: (a) 0.005 to 5% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 1 to 10% isotonizing agent; (c) acidic and / or basic substances to adjust the pH in the range of 2.5 to 3.6; and (d) water at a sufficient amount for 100%.

5. A solution according to claim 4, comprising: (a) 0.01 to 1% lubelozole or a pharmaceutically acceptable addition salt of the ism; (b) 2 to 10% glucose; (c) hydrochloric acid and sodium hydroxide to adjust the pH on the scale of 3.0 to 3.4; and (d) water in an amount sufficient for 100%.

6. A solution according to claim 5, comprising: (a) 0.05% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 5% glucose; (c) hydrochloric acid and sodium hydroxide to adjust the pH to about 3.2; and (d) water at a sufficient amount for 100%;

7. A solution according to claim 1, further characterized in that the isotonizing agent is sodium chloride.

8. A solution according to claim 1, comprising: (a) 0.005 to 5% lubeiozole or a pharmaceutically acceptable addition salt thereof; (b) 0.1 to 2% isotonic agent; (c) acidic and / or basic substances to adjust the pH in the range of 2.5 to 3.6; and (d) water at a sufficient amount for 100%.

9. A solution according to claim 8, comprising: (a) 0.005 to 0.1% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 0.4 to 1.8% sodium chloride; (c) hydrochloric acid and sodium hydroxide pair to adjust the pH on the scale of 3.0 to 3.4; and (d) water at a sufficient amount for 100%.

10. A solution according to claim 9, which contains approximately: (a) 0.02% lubelozole or a pharmaceutically acceptable addition salt thereof; (b) 0.9% sodium chloride; (c) hydrochloric acid and sodium hydr-oxide to adjust the pH to about 3.2; and (d) water at a sufficient amount for 100%.

11. A method for preparing a solution according to any of claims 1 to 10, further characterized in that an appropriate amount of lubelozol Or a pharmaceutically acceptable addition salt thereof is intimately mixed with appropriate amounts of water, isotonizing agent and acidic and basic substances.

12. A prefilled syringe comprising a solution according to any of the claims 1 to 10.

13. A pre-filled syringe according to claim 12, adapted for use with infusor devices.

14. An infusion package for the acute fulminating attack treatment comprising a solution according to any of claims 1 to 10, and an independent, disposable driving unit.

15. An infusion package in accordance with the r-ei vindication 14, further characterized in that the dependent driving unit is operated with gas or is operated under vacuum.

16. An infusion package according to claim 14, characterized in that the solution is manufactured in a pre-filled syringe according to claim 12 or 13.

17. The use of acidic and basic substances in a solution according to any of claims 1 to 10 to prevent the adsorption of lubelozol or a pharmaceutically acceptable addition salt thereof to the walls of the intravenous administration equipment.