US20080023365A1

US20080023365A1 - Pack

Info

Publication number: US20080023365A1
Application number: US11/649,680
Authority: US
Inventors: Graham Cairns; Neil Hyde; Andrew Knowles; Kerry-Anne Miller
Original assignee: Reckitt Benckiser Healthcare UK Ltd
Current assignee: Alliance Pharmaceuticals Ltd
Priority date: 2006-01-04
Filing date: 2007-01-04
Publication date: 2008-01-31
Also published as: GB2433887A; CN101351194A; AU2006334243B2; EP1968552A1; NZ569218A; CA2636210A1; GB0600075D0; AU2006334243A1; ES2546861T3; EP1968552B1; ZA200805275B; WO2007077421A1

Abstract

A pack contains medicinal tablets containing a phenothiazine derivative, prochlorperazine maleate, as active ingredient. The tablets are protected from damage by water. The pack is suitably a water-occlusive blister pack.

Description

PRIORITY CLAIM

This application claims priority to British Patent Application Serial No. 0600075.6 filed on Jan. 4, 2006, the entire contents of which is hereby incorporated herein by this reference.

TECHNICAL FIELD

This invention relates to a pack of medicinal tablets, in particular, to a pack of medicinal tablets containing a phenothiazine derivative, for example, prochlorperazine maleate, as active ingredient.

BACKGROUND

An existing product containing prochlorperazine maleate is BUCCASTEM (trade mark), a product sold to combat nausea, vomiting, vertigo and migraine.
We have discovered unexpectedly that in a traditional PVC/PVdC blister pack having tablets containing prochlorperazine maleate as the active ingredient, the stored tablets may be affected by moisture. Blister packs themselves are known (see, e.g., U.S. Pat. No. 4,612,755 to Cavanagh and U.S. Pat. No. 5,405,011 to Haber et al., the contents of the entirety of both of which are incorporated herein by this reference).
PVC/PVdC is a laminate of polyvinyl chloride polyvinylidene chloride. It is generally accepted to be a good oxygen and moisture barrier, suitable for the packaging of many medicinal products.
As a consequence of our finding, however, we believe it is desirable to use a better barrier material for tablets of phenothiazine derivatives, for example, of prochlorperazine maleate.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there is provided a pack containing medicinal tablets, wherein the tablets contain a phenothiazine derivative, wherein the tablets in the pack are protected from damage by water.
A phenothiazine derivative is suitably selected from:

- those having a dimethylaminopropyl side chain such as chlorpromazine hydrochloride or methotrimeprazine hydrochloride; or
- those having a piperidine side chain such as pericyazine or piperacetazine, or
- those having a piperazine side chain such as acetophenazine maleate, butaperazine maleate, fluphenazine hydrochloride, perphenazine, prochlorperazine, prochlorperazine edisylate, prochlorperazine maleate, thioethylperazine maleate, thiopropazate hydrochloride, thioproperazine mesylate and trifluoroperazine hydrochloride.

A preferred phenothiazine derivative in the pack of the present invention is prochlorperazine maleate.
Preferably, each tablet contains at least 1 mg of the phenothiazine derivative, more preferably at least 2 mg, and most preferably at least 3 mg.
Preferably, each tablet comprises up to 20 mg of the phenothiazine derivative, more preferably up to 15 mg, and most preferably up to 10 mg. In especially preferred embodiments, each tablet contains up to 8 mg of the phenothiazine derivative, especially up to 6 mg.
More preferably, the tablets contain 3 mg to 6 mg of the phenothiazine derivative, most preferably 3 mg or, especially, 6 mg.
Preferably, the tablets comprise at least one monosaccharide or disaccharide or a mixture thereof.
Preferably, the tablets comprise a mixture of xanthan gum and locust bean gum, preferably in a weight ratio of 3:1 to 1:1.
Preferably, the weight total of the mono- and/or disaccharides relative to the combined weight of the xanthan and locust bean gums (when all of these components are present) is in the ratio of 20:1 to 5:1, more preferably 16:1 to 7.5:1.
When a monosaccharide is present, it is preferably selected from glucose, galactose, fructose, mannose, mannitol and sorbitol.
When a disaccharide is present, it is preferably selected from maltose, lactose and sucrose.
The pack may be a bottle or pot. The bottle or pot may have a water-occlusive wall material and a cap sealingly secured thereto, at least when sold, and preferably also when re-closed, in use. However in a preferred embodiment, the pack is a blister pack.
In a preferred embodiment, a pack of this invention is a flexible flat pack of a water-occlusive material. For example, when, as is preferred, it is a blister pack, it may have a water-occlusive wall or barrier member and a water-occlusive closure, lid or other type of seal. By “water-occlusive material,” we mean a material that preferably has a higher degree of water occlusivity under test conditions, 40° C. and 75% Relative Humidity (RH), than a traditional PVC/PVdC material.
In a PVC/PVdC material, the PVC is believed to be the “weak link.” If a water-occlusive material as used in the present invention is to be a plastics material, it could be formed of Aclar barrier film, currently believed to provide the best moisture barrier available in a clear film, or of PVdC alone, should that become available. Other suitable materials include polyethylene and polypropylene. These may be laminated with PVdC and/or Aclar. PVC could be included as a layer but preferred materials do not include PVC.
Preferably, a blister pack of the invention comprises or is formed of a metallic material, for example, aluminum or an aluminum alloy. Most preferably, the base part, containing the pockets for tablets, may be of a cold-formable foil, comprising a metallic layer, over which a breachable-by-tablet metallic foil is laid, to close the pack. Especially preferred is a foil comprising a layer of a metallic material, for example, aluminum or aluminum alloy, laminated to a layer of aliphatic polyamide and/or a layer of PVC. Especially preferred is a foil having a layer of aliphatic polyamide 10 to 40 μm thick, then a metallic layer 30 to 60 μm thick, then a layer of PVC 40 to 80 μm thick, the latter being the product contact surface.
Preferably, a blister pack of the invention contains at least six tablets, more preferably at least eight tablets.
Preferably, a blister pack of the invention contains up to 14 tablets, especially up to 12 tablets.
Preferably, the pack of the invention has a use-by date at least six months after its date of packing; more preferably at least nine months. The use-by date may be recorded on the pack itself or on secondary packaging therefor.
In accordance with another aspect of the invention, there is provided a method of providing and/or administering tablets of a phenothiazine derivative in or from a pack of the first aspect.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be further described, by way of example, with reference to the following illustrative examples.

Medicament tablets were made, containing the following ingredients.



Component	Quantity/tablet (mg)	Function

Prochlorperazine	6.00	Active ingredient
maleate
Compressible sugar	46.32	Filler/bulking agent
Povidone K30	3.00	Binder
Locust bean gum	1.50	Gelling agent
Xanthan gum	1.50	Gelling agent
Talc, sterilized	1.00	Glidant (compression aid)
Magnesium stearate	0.50	Lubricant (compression aid)
B-carotene 1% CWS	0.18	Coloring agent
TOTAL	60.00

The tablets were prepared as follows.
The solid ingredients, excluding magnesium stearate and talc, were granulated in a mixed alkanol/water solvent system. To this end, the active ingredient was suspended in alkanol, and the colorant was dissolved in water. These two components were mixed together to form a uniform alkanol/water suspension that was added to the dry powder mixture during the granulation process. The granules were dried in a tray dryer at moderate elevated temperature for approximately two hours, were sieved, and were then blended with the magnesium stearate and talc, using a tumble blender. The resulting pre-tabletting mix was then compressed on a rotary tablet press to produce round, bi-convex tablets, 5.6 mm in diameter, of tablet weight 60 mg.
The resulting tablets were packed into two types of blister pack: one in accordance with the present invention, which had a cold form aluminum foil tray, heat sealed by an aluminum-breachable foil lid; the other a “250/60” PVC/PVdC tray (250 μm thickness PVC, 60 μm thickness PVdC), with an aluminum-breachable foil lid. The blister packs contained ten tablets. Packing was carried out in dry air. Each tablet pocket was individually sealed by the breachable aluminum foil lid. Tablets were packed into the blister trays and sealed immediately after their manufacture.
The cold-form aluminum foil tray was a laminate of 25 μm thickness aliphatic polyamide, 46 μm thickness aluminum and 60 μm thickness PVC (the material in contact with the tablets).
The aluminum-breachable foil lid was a 50 g/m²lidding foil of 12 μm PET/25 μm aluminum/6-8 g/m²PVC/PVA lacquer (product contact surface).

The tablets were then stored under constant conditions of 40° C. temperature, 75% Relative Humidity (RH). Samples were studied after six, twelve, twenty-six and thirty-nine weeks under these conditions, for visual appearance, water content and perchlorperazine maleate (PCP) content. The results are presented below:



			Water	Water	PCP	PCP
	Visual	Visual	content (%	content	content	content
	appearance	appearance	w/w)	(% w/w)	(mg)	(mg)
Time	PVC/PVdC	Alu/Alu	PVC/PVdC	Alu/Alu	PVC/PVdC	Alu/Alu

Initial	Pale yellow	Pale Yellow	1.46	1.04	5.98	5.99
6 weeks	As initial	As initial	2.04	1.07	5.93	5.90
12 weeks	Slightly	As initial	1.55	0.97	5.93	5.95
	darker
26 weeks	Darker than	Very	2.17	1.11	6.15	5.93
	initial,	slightly
	mottled,	paler than
	damp-looking	initial
39 weeks	Darker than	Very	3.26	1.12	5.87	5.90
	initial,	slightly
	mottled,	paler than
	damp-looking	initial

Although the initial water content of the two sets of tablets was different, they were from the same batch. Evidently, the initial pick-up of water by the two sets of tablets differed. While that in itself is of interest, of particular interest was the fact that the rate at which the two sets picked up water over an extended period differed. In relation to this aspect, the results showed a progressively increasing difference in their water content over time. Water-absorption was clearly shown in the tablets of the PVC/PVdC pack, but not in the tablets of the Alu/Alu pack.
Neither set of tablets showed any evidence of chemical decomposition of the active ingredient after any of these time periods. However, in the case of the PVC/PVdC pack, some darkening and mottling of the tablets was observed, starting at 12 weeks. With the tablets packed into the aluminum blister pack, only a very slight color change, a slight lightening, was observed, starting at 26 weeks.
The foregoing embodiments and descriptions merely provide examples of various embodiments. Therefore, the embodiments disclosed do not limit the scope of the invention or its equivalents, which are governed only by the claims.

Claims

1. A pack containing medicinal tablets, wherein the medicinal tablets contain a phenothiazine derivative, and wherein the medicinal tablets in the pack are protected from damage by water.

2. The pack of claim 1, wherein the medicinal tablets each contain from about 3 mg to about 10 mg of a prochlorperazine derivative.

3. The pack of claim 1, wherein the medicinal tablets comprise a monosaccharide or a disaccharide or a mixture thereof.

4. The pack of claim 3, wherein the medicinal tablets comprise sucrose.

5. The pack of claim 2, wherein the medicinal tablets comprise a monosaccharide or a disaccharide or a mixture thereof.

6. The pack of claim 5, wherein the medicinal tablets comprise sucrose.

7. The pack of claim 1, wherein the medicinal tablets comprise a mixture of xanthan gum and locust bean gum.

8. The pack of claim 2, wherein the medicinal tablets comprise a mixture of xanthan gum and locust bean gum.

9. The pack of claim 3, wherein the medicinal tablets comprise a mixture of xanthan gum and locust bean gum.

10. The pack of claim 4, wherein the medicinal tablets comprise a mixture of xanthan gum and locust bean gum.

11. The pack of claim 5, wherein the medicinal tablets comprise a mixture of xanthan gum and locust bean gum.

12. The pack of claim 6, wherein the medicinal tablets comprise a mixture of xanthan gum and locust bean gum.

13. The pack of claim 2, wherein each medicinal tablet thereof contains from about 3 mg to about 6 mg of prochlorperazine maleate.

14. The pack of any preceding claim, wherein the pack has a use-by date at least six months after packing the medicinal tablets into the pack.

15. The pack of any preceding claim, wherein the pack is made of water-occlusive material.

16. The pack of any preceding claim, wherein the pack is a blister pack.

17. The pack of claim 16, wherein the blister pack comprises a metallic layer.

18. A method of providing and/or administering tablets in or from the pack of any preceding claim.

19. A blister pack of the type for containing medicinal tablets, wherein the blister pack comprises a metallic layer and is made of a water-occlusive material for protecting the medicinal tablets from damage by water, said blister pack further characterized in that the medicinal tablets contained therein comprise: (a) from about 3 mg to about 10 mg of a prochlorperazine derivative, (b) a monosaccharide, disaccharide or mixture thereof, and (c) a mixture of xanthan gum and locust bean gum.

20. The blister pack of claim 19, wherein the blister pack has a use-by date of at least six months after packing the medicinal tablets into the blister pack.