HK1131890A - Liquid pharmaceutical formulation - Google Patents

Description

Liquid pharmaceutical preparation

The present invention relates to a liquid pharmaceutical formulation of a beta-blocker, which is particularly suitable for oral administration to animals.

Beta-blockers (also known as beta-blockers), such as bisoprolol, carvedilol and atenolol, have long been known in human medicine for the treatment of hypertension, and have recently been known for the treatment of cardiac insufficiency. The use of beta-blockers in veterinary medicine is also being considered.

US 5484776 describes the preparation of "controlled release" formulations of beta-blockers suitable for oral administration. In this process, the beta-blocker is converted (umgemetztt) with a polysaccharide, preferably xanthan gum, in water and usually at elevated temperature.

WO 99/16417 describes sprays and soft gel capsules for buccal administration. The formulations are suitable for a broad spectrum of active ingredients according to the present description.

WO 03/041696 discloses formulations comprising concentrated (S) -bisoprolol and their use for the treatment of cardiovascular diseases.

The requirements placed on pharmaceutical preparations in veterinary medicine are particularly high, especially in the case of oral administration, since they must have sufficient palatability to allow the animal to absorb the entire dose. Beta-blockers are usually administered in chronic conditions, so the treatment lasts for months or years. Furthermore, the animals to be treated (e.g. dogs or cats) vary in weight, and therefore the possibility of variable dosing is also desirable. Thus, there is a need for a β -blocker formulation with high acceptance by animals, good dose variability, and good long-term stability.

The problem is solved by:

aqueous-based liquid pharmaceutical formulations for oral administration comprising a beta-blocker in dissolved form in an amount of up to 1% by weight and having rapid bioavailability.

The active ingredients of beta blockers are well known to those skilled in the art. Examples of beta-blockers are carvedilol, atenolol, acebutolol, propranolol, pindolol, metoprolol, betaxolol, esmolol, nebivolol and bisoprolol.

There are different sub-groups of beta-blockers, such as beta-1-selective, beta-2-selective and non-selective. For example, β -1-selective β -blockers (e.g., atenolol, acebutolol, betaxolol, esmolol, metoprolol, nebivolol, and particularly bisoprolol) are particularly suitable within the scope of the present invention.

Due to their high effectiveness, the beta-blockers are used only in low concentrations, usually up to a concentration of 1% by weight, preferably up to a concentration of 0.5% by weight, in the formulations according to the invention. Accordingly, the typical concentration range of the beta-blockers is from 0.001% to 1% by weight, preferably from 0.005% to 0.5% by weight, particularly preferably from 0.01% to 0.5% by weight.

By "water-based (Auf Wasserbasis)" it is meant that the formulation according to the invention comprises water as the base solvent, i.e. typically at least 40 wt.%, preferably at least 50 wt.%, particularly preferably at least 70 wt.%, and very particularly preferably at least 80 wt.%.

In addition to water, the formulations of the present invention may, if desired, contain other suitable water-miscible solvents.

For use of the pharmaceutical formulations of the present invention, it is generally desirable that the pharmaceutical formulations be somewhat viscous. For this reason, for example, the pharmaceutical preparations according to the invention preferably comprise a water-soluble/miscible thickener, such as glycerol or preferably a water-soluble cellulose derivative (e.g. hydroxypropylcellulose or hydroxypropylmethylcellulose). The concentration of the thickener required in order to prepare a formulation with a suitable viscosity is known in principle. Thus, for example, the gelling agent (e.g., a water-soluble cellulose derivative) is typically present at a concentration of 1% to 10%, preferably 1% to 5%, by weight. Higher concentrations of 1% to 70% by weight, preferably 1% to 60% by weight, are also contemplated if the thickener is a water-miscible solvent (e.g., glycerol).

The solution preferably has a viscosity of 2cP to 20cP, preferably 4cP to 15cP, and particularly preferably 5cP to 10 cP.

To improve palatability, the pharmaceutical preparation according to the invention may comprise a tastant (geschmackstoff) and/or a flavoring agent (Aromastoff). Mention may be made, as examples, of sugars (typical concentration: 2% to 10% by weight, preferably 3% to 8% by weight) and vanilla flavor (typical concentration: 0.05% to 0.3% by weight, preferably 0.1% to 0.2% by weight). Sweeteners such as aspartame, cyclamates, saccharin, acesulfame, sucralose, Thaumatin (Thaumatin), neohesperidin and the like may also be used. However, the recommended concentrations of different sweeteners vary; however, they are generally known to those skilled in the art. Among the sweeteners saccharin, especially the sodium salt thereof is preferred. It is generally used in a concentration of 0.01% to 0.5% by weight, preferably 0.02% to 0.3% by weight.

To ensure long-term stability, the use of preservatives is recommended. The preservatives are preferably selected in such a way that they exhibit antibacterial and antifungal properties. Examples of preservatives are organic acids (e.g. parabens, sorbic acid, benzoic acid, propionic acid) or salts thereof; alcohols (such as benzyl alcohol, butanol or ethanol) and quaternary ammonium compounds (such as benzalkonium chloride). An example of a particularly suitable preservative is sodium benzoate. Preservatives are generally included in the formulations of the invention in an amount of from 0.01% to 1% by weight, preferably from 0.02% to 0.6% by weight, particularly preferably from 0.02% to 0.4% by weight, relative to the total weight of the formulation.

Furthermore, it may be expedient to adjust the aqueous solution to a defined pH value (generally in the range from 2 to 10, preferably from 3 to 9) by adding suitable buffer substances.

Especially when sodium benzoate is used as preservative, weak acid pH values in the range of 3-7 are preferred, especially 3-5.

In addition, the pharmaceutical preparations according to the invention may contain other customary pharmaceutical auxiliaries and additives. It is also conceivable to add other active ingredients to the formulation than beta-blockers, which improve the effect or broaden the spectrum of activity for other indications.

The drug according to the present invention has rapid bioavailability. They are accordingly characterized by a rapid release kinetics in vitro, i.e. at least 75% of the active ingredient is released within 30 seconds (assay methods see "resolution", "Apparatus 2" in the us pharmacopoeia 29[2006 ").

Rapid bioavailability is achieved in vivo by the maximum plasma concentration (C) of the active ingredient_max) The achievement of (a). It can be reached within 2 hours, preferably within 1.5 hours.

In addition to rapid bioavailability, a high bioavailability is also sought; this means that a high proportion of the active ingredient enters the plasma and reaches the desired point of action, rather than being excreted directly, for example because it is not readily absorbed, nor because metabolism becomes ineffective. The formulations of the present invention also exhibit good bioavailability when administered orally, which is generally comparable to that of intravenous administration.

In order to make it possible to administer a suitable dose, a linear (so-called "dose-linear") and precise correlation between the amount of active ingredient administered and the resulting plasma concentration should also be achieved, in particular in the case of low doses.

Since the formulations of the invention are typically administered regularly (e.g. daily) over an extended period, they should also provide the possibility of repeated, precise dosing over an extended period.

The pharmaceutical preparation according to the present invention can be prepared by mixing the respective ingredients in the desired amounts. This can be achieved, for example, by: providing a portion of the solvent, mixing in other ingredients, adjusting the pH if necessary, and replenishing the desired final volume with other solvents. Temperatures above +40 ℃ are avoided in this preparation, preferably above +30 ℃.

The pharmaceutical formulations according to the invention are generally suitable for administration to humans or animals. They are preferably used in animal breeding and animal breeding for useful animals (Nutztier), breeding animals, zoo animals, laboratory animals and pet animals (Hobbytier).

The pharmaceutical preparation according to the invention is generally used in the treatment of cardiovascular diseases in animals, in particular in the treatment of cardiac insufficiency.

Useful animals and breeding animals include mammals (e.g., cattle, horses, sheep, pigs, goats, camels, buffalo, donkeys, rabbits, fallow deer, reindeer), fur-bearing animals (e.g., mink, chinchilla, racoon) and birds (e.g., chickens, geese, turkeys, ducks, pigeons and avian species raised at home or in zoos).

Laboratory and test animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

The pet animals include rabbits, hamster, guinea pig, mouse, horse, reptile, and the corresponding birds, dogs, and cats.

The formulations according to the invention are preferably applied to pet animals such as horses, cats and dogs. They are particularly suitable for administration to cats, especially dogs.

Examples of preferred useful animals are cattle, sheep, pigs and chickens.

The formulations described herein are preferably intended for oral administration.

Examples

The formulation can be prepared by dissolving all ingredients except the bisoprolol compound in a slightly less than expected final volume of phosphate buffer. The bisoprolol compound is then dissolved in the mixture, the pH adjusted, and the final volume supplemented with phosphate buffer.

Example 1

0.008% by weight bisoprolol hemifumarate,

0.20% by weight of sodium benzoate,

0.20% by weight of sodium propionate,

0.15% by weight of a vanilla flavour,

5.00% by weight of a sugar,

4.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 2

0.05% by weight of bisoprolol hemifumarate,

0.2% by weight of sodium benzoate,

0.20% by weight of a vanilla flavour,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 3

0.40% by weight of bisoprolol hemifumarate,

0.20% by weight of sodium benzoate,

0.15% by weight of a vanilla flavour,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 4

0.02% by weight of bisoprolol hemifumarate,

0.20% by weight of sodium benzoate,

0.20% by weight of sodium propionate,

0.15% by weight of a vanilla flavour,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 5

0.005% by weight of bisoprolol hemifumarate,

0.20% by weight of sodium benzoate,

0.20% by weight of sodium propionate,

0.15% by weight of a vanilla flavour,

5.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 6

0.02% by weight of bisoprolol hemifumarate,

0.14% by weight of methyl 4-hydroxybenzoate (methylparaben),

0.02% by weight of propyl 4-hydroxybenzoate (propyl p-hydroxybenzoate),

0.02% by weight of butylhydroxyanisole,

(ii) 50% by weight of glycerol,

0.25% by weight of vanilla flavor

Adding phosphate buffer solution with pH of 6.5 to 100 wt%

Example 7

0.02% by weight of bisoprolol hemifumarate,

0.30% by weight of sodium benzoate,

0.15% by weight of a vanilla flavour,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 8

0.02% by weight of metoprolol tartrate,

0.30% by weight of sodium benzoate,

0.15% by weight of a vanilla flavour,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 9

0.02% by weight of bisoprolol hemifumarate,

0.20% by weight of sodium benzoate,

0.20% by weight of sodium propionate,

0.15% by weight of a vanilla flavour,

5.00% by weight of a sugar,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 10

0.005% by weight of bisoprolol hemifumarate,

0.05% by weight of sodium benzoate,

0.15% by weight of a vanilla flavour,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 11

0.01% by weight of bisoprolol hemifumarate,

0.075% by weight of sodium benzoate,

0.15% by weight of saccharin sodium salt,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 12

0.08% by weight of bisoprolol hemifumarate,

0.075% by weight of sodium benzoate,

0.15% by weight of saccharin sodium salt,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 13

0.33% by weight of bisoprolol hemifumarate,

0.075% by weight of sodium benzoate,

0.15% by weight of saccharin sodium salt,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Example 14

0.05% by weight of bisoprolol hemifumarate,

0.3% by weight of sodium benzoate,

0.15% by weight of a vanilla flavour,

0.05% by weight of saccharin sodium salt,

2.00 wt% HPM cellulose 5cP

Adding phosphate buffer solution of pH4.0 to 100 wt%

Biological examples

A. Pharmacokinetic Studies

The study was conducted with a total of 18 adult dogs (6 per group). The test substances were administered orally to dogs once at a dose of 0.01mg/kg body weight, 0.05mg/kg body weight and 0.1mg/kg body weight, respectively. Blood samples of approximately 4ml were taken at the following time points after administration of the active ingredient: 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration of the active ingredient.

The results for the formulation of example 6 are illustrated in figure 1. Mean serum concentrations of bisoprolol (. mu.g/L) are plotted against time (hours). The three curves show the change in serum concentration at different doses, dose group 1: 0.01mg/kg bisoprolol; group 2: 0.05mg/kg bisoprolol; group 3: 0.1mg/kg bisoprolol.

B. Comparison of bioavailability for oral and intravenous administration

In another study with 24 dogs, bisoprolol hemifumarate was administered orally to 12 dogs and intravenously to 12 dogs at 0.2mg/kg body weight (formulation according to example 14). Bisoprolol concentrations in plasma were determined at various times after dosing. The results are shown in FIG. 2, where the mean serum concentration (. mu.g/L) is plotted against time (hours) in FIG. 2. Oral administration was found to give unusually high bioavailability, which is almost as high as direct intravenous administration.

Claims (10)

1. Aqueous-based liquid pharmaceutical formulations for oral administration comprising a beta-blocker in dissolved form in an amount of up to 1% by weight, which formulations have a rapid bioavailability.

2. The pharmaceutical formulation according to claim 1, comprising up to 0.5% by weight of a beta-blocker.

3. Pharmaceutical formulation according to one of the preceding claims, comprising bisoprolol as a water-soluble beta-blocker.

4. Pharmaceutical formulation according to one of the preceding claims, additionally comprising a water-soluble thickener.

5. Pharmaceutical formulation according to one of the preceding claims, additionally comprising one or more tastants and/or flavourings.

6. The pharmaceutical formulation according to one of claims 4 or 5, comprising a gelling agent as thickener.

7. The pharmaceutical formulation according to claim 6, comprising from 1% to 10% by weight of a gelling agent.

8. The pharmaceutical formulation according to one of claims 6 or 7, comprising a water-soluble cellulose derivative as a gelling agent.

9. The pharmaceutical formulation according to claim 8, comprising hydroxypropylcellulose as a gelling agent. 10. The pharmaceutical formulation according to claim 8, comprising hydroxypropylmethylcellulose as a gelling agent.

11. Use of a pharmaceutical formulation according to any one of the preceding claims for the manufacture of a medicament for the treatment of cardiovascular disease in an animal.