GB2118040A

GB2118040A - Oral anti-diabetic preparation

Info

Publication number: GB2118040A
Application number: GB08204363A
Authority: GB
Inventors: John Anthony Ganley; Stephen Ernest Walker; Celia Margaret Mctaggart
Original assignee: Hoechst UK Ltd
Current assignee: Sanofi Aventis UK Holdings Ltd
Priority date: 1982-02-15
Filing date: 1982-02-15
Publication date: 1983-10-26
Also published as: ZA83986B; KR840003415A; GR78063B; IL67908A0; ES8406879A1; EP0086468A2; FI830483A0; AU1140983A; JPS58152814A; IE830290L; NO830491L; EP0086468A3; PT76236A; DK64183A; ES519771A0; FI830483L; DK64183D0

Abstract

This invention provides a pharmaceutical preparation which comprises a rigid shell, generally a hard gelatin capsule, containing an intrinsically short-acting anti-diabetic sulphonylurea derivative in admixture with a carrier comprising a hot melt having a melting point within the range of from above room temperature to a temperature below that at which thermal damage is caused to the shell, generally from 25 to 90 DEG C. Glibenclamide is particularly preferred as the sulphonylurea derivative.

Description

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GB 2 118 040 A 1

SPECIFICATION

Oral anti-diabetic preparation

The present invention relates to pharmaceutical preparations comprising sulphonylurea derivatives.

5 Hypoglycaemic drugs containing the sulphonylurea grouping have been used for many years to lower blood sugar in maturity-onset diabetes mellitus. A number of compounds have been proposed, and some are widely used, including tolbutamide, chlorpropamide and glibenclamide. Tolbutamide was for meany years the leading product in the oral treatment of diabetes, but it has relatively low potency, and many patients with diabetes cannot be satisfactorily controlled with it. Chlorpropamide is also 10 generally available and widely used. This compound is more potent than tolbutamide, but it has a long plasma half-life of 24 to 72 hours. Although this reduces the number of daily doses necessary, the prolonged duration of effect associated with the long half-life increases the risk of hypoglycaemia, especially at night. Hypoglycaemia can be fatal, particularly in elderly patients, in whom the half-life may be even more prolonged.

15 A number of other sulphonylurea derivatives have a relatively long plasma half-life, but even in those having a relatively short half-life and therefore less risk of excessive hypoglycaemia, the time course of the blood sugar lowering action is still not optimum because there is a lag between the drug administration and the onset of its effect: the time of maximum hypoglycaemia is more than 2 hours after administration in many cases and may even be up to 6 hours.

20 Some attempts have been made to formulate faster-acting sulphonylurea derivatives in a quick-acting form to be taken before each meal, but none of the proposals has resulted in a preparation that has both a rapid onset of action and a short duration of drug effect.

The present invention provides a pharmaceutical preparation which comprises a rigid shell, generally a hard gelatin capsule, containing an intrinsically short-acting oral anti-diabetic sulphonylurea 25 derivative in admixture with a carrier comprising a hot melt having a melting point within the range of from above room temperature to a temperature below that at which thermal damage is caused to the shell, generally having a melting point of from 25 to 90°C.

The term "an intrinsically short-acting oral anti-diabetic sulphonylurea derivative" is used herein to mean a sulphonylurea derivative having blood-sugar lowering effects when administered orally and 30 having a plasma half-life, in conventional tablet form, of 10 hours or less. Examples of such agents are acetohexamide, tolbutamide, glibornuride, gliclazide, glibenclamide, glipizide and gliquidone (ar-form). Of these, glibenclamide is particularly preferred.

The carrier for the sulphonylurea derivative is such that it can be brought into liquid form for dosing into the rigid shell, and that it solidifies sufficiently to lose its liquid properties after it has been 35 dosed into the shell. The active ingredient and the carrier form a solid solution or solid dispersion of microfine crystals.

The carrier may be a hot melt having a melting point within the range of from 25 to 90°C, preferably from 40 to 60°C. One or more substances may be used to produce a carrier having the desired melting point and flow properties; for example, the carrier may be a solid or semi-solid 40 substance itself having the desired hot melt properties, for example, a polyethylene glycol having a molecular weight in the range of from 400 to 20,000, for example, from 1,000 to 6,000 (i.e. PEG 1000 to PEG 6000), or a mixture of two or more such polyethylene glycols. Alternatively, a liquid, solid or semi-solid substance may be used, to which one or more further substance(s) is or are added to give the desired properties. In such a case, the carrier base is generally one or more substances selected from 45 polyethylene glycols each having a molecular weight in the range of from 400 to 20,000, and fixed oils and derivatives thereof, for example, arachis, rape, linseed and palm oils, and fractionated coconut oil (available as Miglyol, Miglyol being a Trade Mark).

Examples of substances capable of modifying the melting point of a carrier base, sometimes called "hardeners" herein, are the following:

50 a) surfactants, for example, ester, for example, polyoxyethylene 40 stearate (Myrj 52),

polyoxyethylene stearate (Myrj 51), sorbitan tristearate (Span 65), and polyoxyethylene (20) sorbitan mono-oleate (Tween 20); and ethers, for example, polyoxyethylene 20 cetyl ether (Bryj 38), ' polyoxyethylene 23 lauryl ether (Bryj 35), and alkyl phenol ethoxylates, for example, Synperonic NP 20 (Myrj, Bryj, Span, Tween and Synperonic being Trade Marks);

55 b) sugars, for example, fructose, sorbitol and mannitol; and c) organic amides, for example, urea.

Any two or more hardeners may be used. Particularly preferred is polyoxyethylene 40 stearate (Myrj 52).

Polyethylene glycols (PEGs) are particularly useful as carriers, for example, the higher molecular 60 weight PEGs e.g., of molecular weight 1000 to 6000 may be used alone or in conjunction with a lower molecular weight PEG e.g., a PEG of molecular weight below 1000, for example PEG 6000 may be used with PEG 400. Polyoxyethylene 40 stearate (Myrj 52) is a preferred hardener for use with a PEG.

In the carrier one or more further substances may be incorporated, for example, selected from basic agents to assist the dissolution of the active ingredient, for example, sodium hydroxide, potassium

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GB 2 118 040 A 2

hydroxide and triethanolamine; stabilising agents, for example, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, E.D.T.A. disodium salt, and citric acid; and agents to adjust the ionic strength, for example, sodium chloride and potassium chloride.

Water may be incorporated to adjust the viscosity and/or hygroscopicity of the carrier.

5 The ratio between the total weight of the carrier and the weight of the active ingredient may be very wide and is, for example, in the range of from 20:1 to 200:1, preferably from 50:1 to 100:1.

The pharmaceutical preparation of the invention is generally produced by warming the carrier base and incorporating, in any order, any hardener(s) used, any other additives, and the active ingredient, and mixing until a homogeneous mix is obtained. The solution is preferably deaerated before it is filled into 10 the rigid shells, generally hard gelatin capsules, on a suitable filling machine. The temperature for mixing and filling is above room temperature and below the temperature at which the rigid shell is damaged, and is generally within the range of from 25 to 90°C, preferably from 40 to 60°C. It will be appreciated that the temperature should be chosen so that the viscosity of the particular mix is suitable for filling.

A suitable filling machine may be prepared by modifying a conventional hard gelatin capsule filling 15 machine by removing the filling head and replacing it by a device capable of dosing a predetermined amount of a liquid, for example, a refillable syringe, a peristaltic pump, a precision shot dispenser or a suitable liquid filling pump. It will be appreciated that it is necessary to provide heating means to ensure that the melt does not solidify or become unduly viscous before or during the dosing into the shell.

The pharmaceutical preparations of the present invention having a number of advantages over 20 preparations at present on the market, one being the consumer preference for capsules over tablets, and another being the uniformity in the dose of the active ingredient. There are also further, unexpected advantages: the speed of onset and intensity of action of the sulphonylurea derivative, and the short duration of that activity.

Figure 1 of the accompanying drawings shows that plasma glibenclamide levels rise to a peak 45 25 minutes after the administration of a preparation of the invention (preparation of Example 6), and that appreciable levels are present after only 30 minutes. The nadir of plasma glucose concentration in fasting subjects occurs 60 minutes after administration, i.e. the delay between the peak plasma glibenclamide level and the plasma glucose nadir is only 15 minutes. This can be compared with published data on the time course of plasma glucose levels following administration of glibenclamide by 30 an intravenous bolus injection (see the accompanying Table): in this latter case, the peak glibenclamide plasma levels occur at the time of injection, but the nadir in plasma glucose levels is not seen until about 40 minutes thereafter (range: 30 to 90 minutes).

The second unexpected feature is the very short plasma half-life of the sulphonylurea derivative when present in a preparation of the present invention. This is illustrated in Figures 2 and 3 of the 35 accompanying drawings.

Figure 2 shows the plasma glibenclamide levels (mean of six subjects) observed with the preparation of Example 6 and with a conventional glibenclamide tablet. It can be seen that the plasma glibenclamide levels obtained with a preparation of the invention have reached a maximum (approximately twice that of the conventional tablet), and have already dropped to half of the maximum 40 value before the plasma glibenclamide levels with the conventional preparation have reached their peak.

Figure 3 of the accompanying drawings shows the plasma glucose levels of 8 subjects treated with a conventional glibenclamide tablet and with the preparation of Example 6. As shown in Figure 3, the subjects were given breakfast 30 minutes after the administration of an active or placebo preparation, and lunch 3 hours thereafter. From Figure 3, it can be seen that the preparation of the 45 present invention starts reducing the blood sugar level 30 minutes after administration i.e. when breakfast is taken, and completely eliminates the post-breakfast glucose peak, whereas with the conventional preparation, the blood sugar levels are still rising at this time, and only start to fall more than an hour after administration. The effect of the glibenclamide in the conventional preparation is still apparent at lunch time, serving to reduce the blood sugar level after lunch, whereas the blood sugar 50 level observed after lunch in the case of the glibenclamide preparation of the present invention is, by this time, the same as with the placebo. The effect of the glibenclamide in the conventional preparation lasted for 8 hours, but only for 3.5 hours in the preparation of the present invention.

The preparations of the present invention therefore provide a blood sugar lowering effect that is both rapid in its onset and short lived. They are therefore particularly suitable for administration before 55 each main meal, providing a "quasi-physiological" insulin release to cover meal-associated glucose peaks, but with a short duration of action which avoids inappropriate prolonged glucose lowering with its associated troublesome pre-prandial hypoglycaemia.

The preparations of the invention preferably comprise a unit dose of the sulphonylurea derivative suitable for lowering a meal-time blood glucose increase, for example, a suitable unit dose in the case of 60 glibenclamide is preferably 0.5 to 6 mg. A unit dose is to be taken before each main meal, for example, up to 30 minutes before a meal, and normally three doses will be taken per day. It will be appreciated that using the preparations of the invention the treatment of diabetes mellitus can be much more flexible, for example, the timing of meals can be varied without the danger of hypoglycaemia.

The following Examples illustrate the invention.

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GB 2 118 040 A 3

EXAMPLE 1

Ingredient mg per capsule

Glibenclamide PEG 400 Myrj 52

1N NaOH solution

2.00 147.60 138.40 10.44

Procedure

The PEG was warmed at 60°C until molten, then the glibenclamide was added and mixed thoroughly, followed by the sodium hydroxide solution and molten Myrj 52. The mixture was mixed at 10 60°C until homogeneous. The mixture was then deaerated before it was filled at 60°C into size 1 hard gelatin capsules on a Zanasi L 264 hard gelatin capsule filling machine that had been modified by the replacement of the filling head by a precision shot dispenser or HIBAR liquid filling pump.

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EXAMPLE 2

Ingredients mg per capsule

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Glibenclamide PEG 400 Bryj 38

1N NaOH solution

2.00 24.80 23.20 .10.44

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Procedure

20 As described in Example 1, using Bryj 38 (polyoxyethylene 20 cetyl ether) instead of Myrj 52.

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EXAMPLE 3

Ingredients mg per capsule

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Glibenclamide 1.00

PEG 400 39.90

Fructose 34.60

1N NaOH solution 5.22

Procedure

As described in Example 1, using fructose instead of Myrj 52.

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EXAMPLE 4

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Ingredients mg per ospsule

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Glibenclamide PEG 6000 1N NaOH solution

2.50 37.00 13.05

Procedure

35 The PEG was warmed at 60°C until molten. The glibenclamide was added and mixed thoroughly, 35 followed by the sodium hydroxide solution. The filling was carried out as described in Example 1.

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GB 2 118 040 A 4

EXAMPLE 5

Ingredients mg per capsule

Glibenclamide PEG 400 Urea Water

0.50 10.5 25.0 4.0

Procedure

As described in Example 1, using urea instead of Myrj 52, and adding the water to the PEG 400.

EXAMPLE 6

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Ingredients mg per capsule

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Glibenclamide PEG 400 Myrj 52 Distilled water 1N NaOH solution Propyl gallate EDTA, disodium salt

2.500 184.500 173.000 23.333 13.044 0.370 0.017

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Procedure

As described in Example 1, adding the distilled water, the propyl gallate and the EDTA salt to the 20 PEG 400.

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EXAMPLE 7

Ingredients mg per capsule

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Glibenclamide Propylene glycol PEG 6000 Triethanolamine

1.0 20.0 54.0 5.0

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Procedure

As described in Example 1, adding the propylene glycol to the PEG 6000.

EXAMPLE 8

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Ingredients mg per capsule

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Glibenclamide PEG 400

Synperonic NP 20 1N NaOH solution

2.00 147.60 138,40 10.44

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GB 2 118 040 A 5

Procedure

As described in Example 1, using Synperonic NP 20 (an alkyl phenol ethoxylate) instead of Myrj 52, and triethanolamine instead of sodium hydroxide.

EXAMPLE 9

5 Ingredients mg per capsule

Glibenclamide 2.00

PEG 4000 100.02

PEG 400 12.61

EDTA disodium salt 0.01

10 Potassium hydroxide 0.56

Distilled water 4.80

Procedure

As described in Example 1, adding the EDTA and potassium hydroxide to the PEG melt.

Claims

15 1. A pharmaceutical preparation which comprises a rigid shell containing an intrinsically short-acting oral anti-diabetic sulphonylurea derivative (as hereinbefore defined), in admixture with a carrier comprising a hot melt having a melting point within the range of from above room temperature to a temperature below that at which thermal damage is caused to the shell.

2. A pharmaceutical preparation as claimed in claim 1, wherein the sulphonylurea derivative is

20 glibenclamide.

3. A pharmaceutical preparation as claimed in claim 1, wherein the sulphonylurea derivative is acetohexamide, tolbutamide, glibornuride, gliclazide, glipizide or gliquidone tar-form).'

4. A pharmaceutical preparation as claimed in claim 1, wherein the rigid shell is a hard gelatin capsule.

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5. A pharmaceutical preparation as claimed in any one of claims 1 to 4, wherein the melting point of the carrier is within the range of from 25 to 90°C.

6. A pharmaceutical preparation as claimed in claim 5, wherein the melting point is within the range of from 40 to 60°C.

7. A pharmaceutical preparation as claimed in any one of claims 1 to 6, wherein the carrier is a

30 polyethylene glycol having a molecular weight in the range of from 400 to 20,000 or a mixture of two or more such polyethylene glycols.

8. A pharmaceutical preparation as claimed in any one of claims 1 to 6, wherein the carrier comprises a liquid, solid or semi-solid carrier base substance with which one or more further substance(s) is or are incorporated to bring the melting point within the defined range.

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9. A pharmaceutical preparation as claimed in claim 8, wherein the carrier base is one or more substances selected from polyethyleneglycols having a molecular weight in the range of from 400 to 20,000, and fixed oils and derivatives thereof.

10. A pharmaceutical preparation as claimed in claim 9, wherein a fixed oil or derivative thereof is arachis, rape, linseed or palm oil, or a fractionated coconut oil.

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11. A pharmaceutical preparation as claimed in any one of claims 8 to 10, wherein the further substance(s) is or are selected from surfactants, sugars or organic acids.

12. A pharmaceutical preparation as claimed in claim 11, wherein a surfactant is polyoxyethylene 40 stearate, polyoxyethylene stearate, sorbitan tristearate, polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene 20 cetyl ether, polyoxyethylene 23 lauryl ether or an alkyl phenol ethoxylate.

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13. A pharmaceutical preparation as claimed in claim 11, wherein a sugar id fructose, sorbitol or mannitol.

14. A pharmaceutical, preparation as claimed in claim 8, wherein the carrier comprises one or more polyethylene glycols as defined in claim 9, and polyoxyethylene 40 stearate.

15. A pharmaceutical preparation as claimed in claim 8, wherein an organic amide is urea.

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16. A pharmaceutical preparation as claimed in any one of claims 1 to 15, which also comprises one or more further substances selected from basic substances, stabilising agents, agents to adjust the ionic strength, and water.

17. A pharmaceutical preparation as claimed in any one of claims 1 to 16, wherein the ratio by weight total carrier: active ingredient is from 20:1 to 200:1.

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18. A pharmaceutical preparation as claimed in claim 17, wherein the ratio is from 50:1 to 100:1.

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GB 2 118 040 A 6

19. A pharmaceutical preparation as claimed in any one of claims 1 to 18, which comprises a unit dose of the sulphonylurea derivative suitable for lowering a meal-time blood glucose increase.

20. A pharmaceutical preparation as claimed in claim 19, which comprises from 0.5 to 6 mg of glibenclamide per unit dose.

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21. A pharmaceutical preparation as claimed in claim 1, substantially as described in any one of 5 the Examples herein.

22. A method of producing a pharmaceutical preparation as claimed in any one of claims 1 to 21,

which comprises warming the carrier or carrier base and incorporating, in any order, any hardener(s)

used, any other additive(s), and the active ingredient, mixing until a homogeneous mixture is obtained,

10 and filling the mixture into a rigid shell. 10

23. A method as claimed in claim 22, wherein the mixture is filled using a hard gelatin capsule filling machine modified by the replacement of the filling head with a device capable of dosing a predetermined amount of a liquid.

24. A method as claimed in claim 23, wherein the dosing device is a refillable syringe, a peristaltic

15 pump, a precision shot dispenser, or a liquid filling pump. 15

25. A method as claimed in claim 22, carried out substantially as described in any one of the Examples herein.

26. A pharmaceutical preparation as claimed in claim 1, whenever produced by a method as claimed in any one of claims 22 to 25.

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27. A pharmaceutical preparation as claimed in any one of claims 1 to 21 and claim 26, for use in 20 the treatment of diabetes mellitus.

28. A pharmaceutical preparation as claimed in claim 27, to be taken before each main meal.

29. A pharmaceutical preparation as claimed in claim 28, to be taken substantially 30 minutes before each main meal.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983; Published by the Patent Office 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.