GB2566983A

GB2566983A - Captopril liquid dosage form and delivery system

Info

Publication number: GB2566983A
Application number: GB1715841.1A
Authority: GB
Inventors: Tickle Stephen; Michael Gould William
Original assignee: Epsilon Pharmaceuticals Ltd
Current assignee: Epsilon Pharmaceuticals Ltd
Priority date: 2017-09-29
Filing date: 2017-09-29
Publication date: 2019-04-03
Also published as: GB201715841D0; WO2019063735A1

Abstract

A container comprising a pharmaceutical dosage form, the dosage form comprising solid and liquid components; the solid component comprising: captopril as active ingredient; and at least one water soluble excipient; the liquid component comprising: water; sodium metabisulphite; at least one sequestrant; and optional further excipients; the container 1 having two separate compartments separated by a breakable barrier, the solid component 10 located in a first compartment 6 and the liquid component (13, Fig. 3) located in a second compartment; the breakable barrier 9 being arranged to be broken by a user to allow the solid component and the liquid component to mix to provide the dosage form for use. The container is engaged with a cap 4 having a tamper-proof seal 5 and a receptacle 6 extending into the container 1. Receptacle 6 has a frangible sealing disc 9 to define a chamber within which the solid component is stored. An upper surface 11 of the cap has a downwardly extending flange 8 which extends to a point 7. When the tamperproof ring and sealing band 12 are removed the cap may be depressed urging projection 7 to rupture the ring and release the solid component into the liquid component.

Description

(57) A container comprising a pharmaceutical dosage form, the dosage form comprising solid and liquid components; the solid component comprising: captopril as active ingredient; and at least one water soluble excipient; the liquid component comprising: water; sodium metabisulphite; at least one sequestrant; and optional further excipients; the container 1 having two separate compartments separated by a breakable barrier, the solid component 10 located in a first compartment 6 and the liquid component (13, Fig. 3) located in a second compartment; the breakable barrier 9 being arranged to be broken by a user to allow the solid component and the liquid component to mix to provide the dosage form for use. The container is engaged with a cap 4 having a tamper-proof seal 5 and a receptacle 6 extending into the container 1. Receptacle 6 has a frangible sealing disc 9 to define a chamber within which the solid component is stored. An upper surface 11 of the cap has a downwardly extending flange 8 which extends to a point 7. When the tamperproof ring and sealing band 12 are removed the cap may be depressed urging projection 7 to rupture the ring and release the solid component into the liquid component.

FIG.

-2/2-

Τ' {*“>

Γ y

CAPTOPRIL LIQUID DOSAGE FORM AND DELIVERY SYS I EM

This invention relates to a dosage form for a liquid pharmaceutical formulation comprising captopril or an enantiomer thereof including salts or other derivatives. Tins 5 invention also relates to a delivery system for dispensing the formulation.

Captopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril contains a primary thiol group which is susceptible to oxidation, for example in the presence of 10 atmospheric oxygen. The major degradation product of pharmaceutical products comprising captopril is captopril disulphide which has a pungent odour.

Liquid captopril formulations suffer from poor stability and. short shelf life. In particular, a liquid dosage containing captopril is currently sold under the trade mark name 15 Noyada TJiis product has a shelflife of one year and once opened should be consumed within 21 davs.

According to the first aspect of the invention there is provided:

a container comprising a pharmaceutical dosage form, tire pharmaceutical dosage 20 form comprising solid and liquid components;

the solid component comprising:

captopril as active ingredient; and at least one water soluble excipient;

the liquid component comprising:

water;

sodium metabisulphi te;

at least one sequestrant; and optional further excipients;

the container having two separate compartments separated by a breakable barrier, the solid component located in a first compartment and the liquid component located in a second compartment;

the breakable hairier being arranged to be broken by a user to allow the solid

T’he solid component preferably comprises a dry powder blend which is may be stable on storage up to two years, for example up to thre<

The captopril ingredient may comprise ingredients may be employed

The present invention permits typical dosages of captopril of 5mg ml or 25mg/5ml to be provided as an oral suspension. Alterative dosages may be provided as required.

The water soluble excipient of the solid component may be a water soluble sweetener.

cup consisting uf: isomalt, maitodextrin. dextrose, lactose, maltose, maltitol, sucrose, xylite and to surfaces of the container.

Isomalt may confer the further advantage that it is non-animal in origin and has low hygroscopic properties, fsomalt exhibits excellent chemical stability, particularly having no reaction with amino groups and is resistant to degradation by enzymes and acids. It is generally regarded as a non-toxic, noil-allergenic and non-irritant material, being non cariogenie and having a low glycemic response. Isomalt is free from genetically modified organisms and has a pleasant sugar-like natural sweet taste profile.

A preferred grade of isomalt is Galen 1Q720 supplied by Bene Palatinit.

The amount of isoma'-i may be limited by the capacity of the container but a to 80 wt% of the solid component

The solid component may comprise captopril iso-n a It to 97.5 wt%

The liquid component may be stable on storage up to .2 years, alternatively up io 3

The amount of the inorganic antioxidant, sod ium metabisulphite may be 0.05 to 0.40 wt% of the liquid component, preferably 0.20 to 0.30 wt%. The amount of sodium rnels ri sulphite used may be between 50 to 100 times recommended daily intakes.

Sodium metabisulphite has been found to be particularly effective in maintaining the level of captopril disulpl of one to three months.

below 3 wt.% of the liquid dosage form, over a period is selected from the group comprising: ethylenediaminetetraacetic acid, disodium ethylenedia:

ninetetraacetic acid, or mixtures thereof.

The amount of sequestrant may be 0.02 to 0.10 wl% of the liquid component,

The optional further excipients of the liquid component may be selected from the group consisting of: surfactants, antlibaming agents, preservatives, flavourants, sweeteners.

thickeners, butlers and biocides.

The preservative may be selected from the group consisting of: ethanol, sodium benzoate, and mixtures thereof. The amount of preservative may be 0.02 to 0.15 wt% of the component, preferably 0.10 wt%. The amount of sodium benzoate may be 0.02 to 0.08 wt.% of the liquid component, preferably 0.05 wt%

The sweeteners of tbe liquid component may be selected from the group consisting of: sorbitol, sodium saccharin, potassium acesulfame, and mixtures thereof.

Captopril formulations may have an unpleasant taste. Use of sugar containing sweeteners is disadvantageous. The present formulation may be sugar free. A combination of two or more non sugar containing sweeteners may be used to alleviate the taste of captopril. A preferred combination of sweeteners comprises a mixture of sodium saccharine 5 and sorbitol· Use of the two sweeteners in combination intensifies the sweetness and provides satisfactory alleviation of the unpleasant taste of captopril.

in a preferred formulation, the amounts of sodium saccharine and sorbitol of the liquid component are as follows.· sodium saccharine 0.05 to 0.15 wt%, preferably 0.10 wt%;

sorbitol 20 to 40 wt%, preferably 30 wt%.

The organoleptic properties of the dosage form may be further enhanced by addition of a flavouring, for example 0.15 wt% of the liquid component of raspberry flavour.

Advantageous embodiments do not contain a thickener. Use of a thickener may 15 increase retention of air bubbles in the dosage form, leading to a higher .rate of oxidative degradation.

When a thickener is employed hydroxyethylccliufose may be used.

The buffer may be selected to provide a pH of foe mixed formulation in the range

2.0 to 6.5, preferably 3.0 to 5.0. The buffer maybe selected from a group consisting of: citric acid anhydrous, tri-sodium citrate dihydrate, or mixtures thereof. Alternative buffer systems may be used.

tn exemplary embodiments tire surfactant may be a non-ionic or ionic surfactant. Ait amount of 0.01 to 0.4 wt% of the liquid component may bo employed. Polysorbate 80 (polyoxyethylene (2(1) sorbitan monodeate} may be used in an amount of about 0.1 to 0.5 wt% of the liquid component, for example about. 0 1 to about 0.3 wt%. alternatively about 0.2. wt%.

A biocide may be employed. Domi phen bromide (N,N-tlimuthyi-N-(2· phenoxyethyl; oodecan-1-ammonium bromide;· may be used as a biocide for example in an amount of about 0.1 wt% of tin.· liquid component. Alternative biocides may be used.

The liquid component may further comprise at least one organic antioxidant.

The organic antioxidant may be selected from the group consisting of: butylatcd hydroxyanisole, alpha cyelodextrin, ascorbic acid, or mixtures thereof Preferably ascorbic acid is used.

The amount of organic antioxidant may be 0.055 to 0.095 wt% of the liquid component, preferably 0.065 to 0.085 wt%, even more preferably 0.075 wt%.

In a preferred formulation, the amounts of sodium metabisulphite and ascorbic acid of the liquid component may be as foliows:sodium metabisulphite 0.20 to 0.30 wt%. preferably 0.25 wt%:

ascorbic acid 0.065 to 0,085 wt%, preferably 0.075 wt%.

The combination, of the above amounts of sodium metabisulphite and ascorbic acid has been found to be particularly effective in maintaining the level of captopril disulphide at a level below 3 wt% of the liquid dosage form over a period of one to three months, or longer.

The liquid component may further comprise a suspending agent, A hydrocolloid may be used, for example a gum such as xanthan gum. An amount of about 0.01 to about 0,75 wi% of the liquid component may be employed.

The captopril may be provided in the form of granules or other solid particles which may be mixed with the water soluble excipient so -bat the excipient is allowed to adhere to the active ingredient granules or other particles when blended, Tlris serves to provide a temporary coating upon the particles reducing any likelihood of decomposition in the presence o.i atmospheric moisture. When the blend is released into the aqueous component the isomalt quickly absorbs water and dissolves allowing the captopril particles to be released and dispersed into the liquid phase. The dosage tonn is therefore stable on storage but provides an oral suspension before use.

The second compartment may be located in a receptacle of a cap or other closure, the closure being adapted to releasably dose the container.

The breakable barrier may be located between tire receptacle and second compartment. The receptacle may include a means for mpturing the breakable harrier Io the container.

breakable barrier may be arranged to allow lor mixing of the solid and Ik d eorrroonenis

The receptacle may include a breakable barrier between side and lower wails of the compartment which is firmly held inside and below the container of the bottle. The patient would be required to apply reasonable force to the cap to rupture the edge of the compartment, releasing the blend into the diluent. An exemplary container cap is manufactured by Roviphann.

The breakable barrier may be broken by twisting or pushing down on the closure so that a piercing member contained within the closure is driven towards and through the breakable barrier, thereby rupturing the breakable barrier and allowing the solid and liquid components to mix to provide the dosage form.

The container usually comprises a bottle. The bottle or other container may provide a light barrier, for example the container may be composed of amber coloured polyethylene terephthalate (PET) material. Ari amber or otherwise coloured glass bottle may be used. The container therefore serves to protect the reconstituted dosage form from degradation by light.

^ro necessary to disperse the captopril arid dissolve the soluble excipient in the liquid phase

4em in accordance with this invention confers several advantages. Individual doses or small batches of doses of captopril may be provided and stored before use without degradation of the active ingredient. The separate liquid and solid comnonents may have a shelf life of 3 years. When required for use the delivery system may

Λ v Z Λ Z J ·.· be activated, for example by removal of a security tab followed by release of the solid phase period of up to 3 months, or longer. The period may be selected to allow a course of treatment to be completed using a single dosage form.

In This specification ainou-tts or other quantities are by weight unless indicated otherwise. Amounts are selected from any percentages or ranges quoted, to total to 100%

The invention is further described by means of example but not in any limitative sense with reference to the accompanying drawings of which:

Figure ] illustrates the components of a delivery system before use;

Figure 2 is a cross sectional view of an upper part of the delivery* system; and

Figures 3 to 5 illustrate successive stages in use of die delivery system.

Example 1 - Ingredients used

Formulation / - Liquid componeni

Ingredients	Concentration wt%
Sodium metabisulphite	iji
Sorbitol syrup 70%	30.0
Ethanol 96%	10.0
Sodium saccharin	0..10
Citric acid anhydrous	0.05
Tri-sodium citrate dihydrate	0.216
Disodium EDTA	0.05
.Ascorbic acid	0.075
Raspberry flavour	0.15
Purified water	To 100

Formulation 2 Liquid component

Ingredients	Concentration wt%
Sodium metabisulphite	0.25
Sorbitol syrup 70%	30.0
Sodi imi be; iz.oat e	0.05
Sodium saccharin	0.10
Citric acid anhydrous	0.05
Tri-sodium citrate dihydmte	0.216
Disodiurn EDTA	0.05

Ascorbic acid	0.075
Raspberry flavour	0.15
Purified water	To 100

Formulation 1 - Solid component

Ingredients j Concentration for 2g of powdei blend


wt%	Mg/5 ml as solution
Captopril I (Ph Eur monograph 1079) \|	25	25
Isomalt (galen)Q^fM721) i	75	75

Forrnulation 2 -- Solid component

Ingredients	Concentration for 2g of powder blend
wt%	Mg/5 in) as solution
Captopri I (Ph Eur monograph 1079)	5	5
Isomalt (galenlQ™ 721)	95	95

The following manufacturing steps were used to make the above solid and liquid components.

Formulation I - Liquid component

1. To a vessel equipped with a variable speed stirrer was added approximately litres of purified water.

2. The vessel was then sparged with nitrogen at a flow rate of 2 - 4 litres per minute.

3. Add sorbitol syrup (70%) to the vessel and stir until homogeneous.

4. Add in turn to the vessel, stirring to dissolve each one, tri-sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, disodium EDTA, ascorbic acid and sodium metabisulphite.

5. Add ethanol (96%) to the vessel and stir until homogeneous.

0.0% and cap.

6.

7.

8.

10.

Dilute to volume with purified water and stir until homogeneous.

Continue to sparge with nitrogen d uring the addition of purified water.

Pransfer the solution in 100ml volumes into 200ml amber PET glass bottles

Formulation 2 Liauid comoonent .1

-ί

Hires of punf minute.

2.

3.

4.

dihydrate, citri sodium metab·

0.0%

7.

9.

10.

led water.

The vessel was then sparged with nitrogen at a flow rate of 2 - 4 litres per .Add sorbitol syrup (70%) to the vessel and stir until homogeneous acid anhydrous, sodium saccharin, disodium EDTA. ascorbic acid and sulnhite.

o the vessel and stir until homogeneous.

Add raspberry flavouring and stir until homogeneous.

Measure the dissolved oxygen content of the solution, which should be

Dilute to volume with purified water and stir until homogeneous.

Continue to sparge with nitrogen during the addition, of purified water.

Transfer 150ml of the solution into 200ml amber PET glass bottles and cap.

Formulation 1 and 2 - Solid component

1.

To a vessel, equipped with a 850-micron sieve, was sieved captopril (Ph Eur monograph 1079) and isomalt (galenlQ were present.

^ilM 721) so that no lumps or agglomerates

The tablet core ingredients were then mixed using a Turbula mixer for a time period sufficient to produce a homogenous ble id.

Transfer 2 g of the blend into the lower lid compartment, attach the upper cap compartment to the lower cap compartment to form the complete cap, then securely fit the cap onto the 200ml amber PET glass bottles containing the 150ml of liquid solution.

Formulations 1 and 2 of the solid component may be used with either formulation I or 2 of the liquid component.

Example 2 - Antimicrobial activity of the formulation

Laboratory scale batches of were prepared and analysed. The efficacy of antimicrobial preservation for each formulation at all levels satisfied the requirements of European Pharmaceopoeia.

Example 3 --- Determination of disulphide concentration over time

T he following solution was prepared.

Ingredients	Concentration wt %
Captopril	0.50
Sorbitol syrup 70%	30.0
Ethanol 96%	10.0
Sodium saccharin	0.10
Citric acid anhydrous	0.05
Tri-sodium citrate dihydrate	0.216
Disodium EDTA	0.05
Ascorbic acid	0.075
R aspberry flavo ur	0.15
Purified water	To 100

I. The solution was split into three parts and sodium metabisulphite was added to the solutions at concentrations of 0.05, 0,10 and 0.25 wt%.

2. The pH of each solution were then determined. as detailed below:

Control (oo sodium metabisulphite): 3.89

With 0.05 wt% sodium metabisulphite: 3.88

With 0,10 wl% sodium metabisulphite: 3.87

With 0.25 wi?o sodium metabisulphite: 3.95

3. The solutions were filled into 75 ml amber glass bottles, capped ami placed on storage in equal numbers at 4°C and 25''C.

4. The control solution and solutions containing sodium metabisulphite were then assayed for captopril and impurities. The results of the assays are shown in Die following table.

Storage Time (Days)	Sodium Metabisulphite Concentration (wt%)	Storage Temperature (°C)	Captopril Content (mg/ml)	Disulphide Content (% Relative to captopril)	Total impurities (% Relative to captopri i)
()	All	n/a	4.98	0.27	1.26

24	0.05	4	5.12	0.17	1.49
		25	4.77	0.94	5.96
	0.10	4	5.11	0.19	2.20
		25	4.91	0.64	1.94
	0.25	4	4.97	0.31	2.51
		25	5.02	0.37	2.39

42	0.05	4	5.00	0.18	0.72
		25	4.83	2.18	3.39
	0.10	4	4.97	0.20	0.49
		25	4.85	1.43	2.56
	0.25	4	4.94	0.23	0.35
		25	4.89	0.75	:...........154......

75	0.05	4	4.94	0.53	•A·.
		25	4.60	5.17 0.40	.-
	0.10	I
		25	4.79	2.72
	0.25	4:	4.95	0.31
		25	4.79	1.23	!...................................

The data displayed in the above table shows that a sodium metabisulphite concentration of 0,10 wt% and 0.25 wt% confer high stability on the dosage forms by restricting formation of captopril disulphide over a period of 75 days at 25°C storage. Especially beneficial results were obtained through use 0.2:5 wt% of sodium metabisulphite, lire product was free from the malodour and objectionable taste that accompany degraded captopril solutions. Beneficial results were seen with all concentrations of sodium 5 metabisulphite over 75 days at 4°C storage.

Example 4 - In-use stability tests

Two in-use stability tests were run. one for 20 days and one for 6 weeks. The results of both studies showed the captopril content of the samples to remain within specification with acceptable impurity levels throughout. The samples passed the preservative efficacy test 10 at the end of the test period.

Example 5 ·--- Unsuccessful early stage formulation work

Table 1

The following solution was prepared.

Raw materials	Concentration wt.%
Captopril	0.50
Sorbitol syrup 70%	30.0
Ethanol 96%	10.0
Hydroxyethylcellulo.se	0.40
Polassi un AcesuI fa· ne	0.02
Sodium saccharine	0.08
Citric acid anhydrous	0.07
Trisodium citrate	0.186
Di sodium EDTA	0.05
Ascorbic acid	0.06
Raspberry flavouring (Firrnenich 501091 A)	0.15
Purified water	To 100

Stability testing was performed on the formulation of Talik- 1 at 25¹<7(·'Ο%Κ.Η and

40°C/75%RH and showed stability in line with the literature data. i.e. about one month at

25^,:’C. Further attempts to increase the stability of' the captopril by the addition of alpha :3 cyclodextrin together with a reduction in the water content of the formulation were made but without success. Glycerol was tried as a replacement solvent for water and vitamin E was also incorporated as antioxidant but solubility problems were encountered tor some of the excipients and this line of investigation was abandoned.

It was decided to retain the early stage active liquid formulation but remove the viscosity modi Iler tHydroxyethyl cellulose)., use one sweetener only and increase the antioxidant to die maximum recommended level. Ascorbic acid was again chosen as the antioxidant as it cun be used at a considerably higher level than the BHA and is more suitable 10 for use in an aqueous system. The pH of this solution was 3.79. 'The first task was to produce a fully formulated liquid with a shelflife at room temperature of at least one month.

Table 2

The following solution was prepared.

Raw materials	Concentration wt%
Captopril	0.50
Sorbitol syrup 70%	30,0
Ethanol 96%	10.0
Sodium saccharine	0.10
Citric acid anhydrous	0.08
Trisodium citrate dihydrate	0.216
Disodium EDTA	0.05
Ascorbic acid	0.075
Raspberry flavouring (Firmenich 501091A)	0.15
Purified water	To 100

As the above solution contain dissolved oxygen which could oxidise the captopril, it was decided to remove die oxygen to reduce the degradation of the captopril. Accordingly, a placebo solution of the formulation of Table 2 but without captopril was prepared and split into three equal aliquots

Aliquot A: TJiis was the control. to which was added 0.5 wt% of captopril. The Solution, was then filled <70 ml volumes) into 4x 0 ml amber glass bottles and capped with plastic screw caps. Two bottles were kept at 4°C and two at 25°C.

Aliquot B: This was sparged with oxygen-free nitrogen via a sintered metal diffuser for ten minutes, then 0.5 wt.% of captopril was added and dissolved whilst a nitrogen blanket was maintained over the solution, The captopril solution was then dispensed in 70 ml volumes into 4 bottles as for aliquot A, the bottle headspaces nitrogen tilled and the bottles capped. The bottles were stored as for aliquot A.

Aliquot C: The placebo solution was sonicated for ten minutes in a sonic bath to deaerate it. This technique is routinely used to deaerate HPLC solvents. 0.5 wt% captopril was then added and the solution dispensed into 70 ml bottles with nitrogen gassed headspace etc. and storage as for aliquot B.

Initial control samples for all three aliquots were then analysed for captopril and related substances contents and again after storage for suitable periods.

Aliquot C: The placebo solution was sonicated tor ten minutes in a sonic bath to 20 deaerate it. This technique is routinely used to deaerate HPLC solvents. 0.5 wt% captopril was then added and the solution dispensed into 70 ml bottles with nitrogen gassed headspace etc, and storage as for aliquot B.

Initial control samples for ail three aliquots were then analysed for captopril and 25 related substances contents and again after storage for suitable periods.

The results are shown below in Table 3.

fable 3

Aliquot	Initial Sample	20 Days Storage	43 Days \|
	25°C	4°C	: 25°C
A (Control)
Captopril (mghnl)	5.08	5.05	4.95	4.87	4.95
Disulphide (% Rel)	0.43	0.4«	2.25	0.71	4.70

Total RS (% Rel)	1.355	2.125	3.70	3.49	7.18
B (Nitrogen Sparged)
Captopril (mg/ml)	5.12	5.17	5.09	5.19	4.98
Disulphide (% Rel)	0.41	0.435	0.94	0.50	3.01
Ί otal RS (% Rel)	1.36	2.14	2.165	:3.28	16.69
C (Sonicated)
Captopril t mg/ml)	4.96	5.06	4.95	5.14	::4.96
Disulphide (% ReB	0.28	0.415	1.225	j 0.46	2.03
Total RS (% Ref)	1.515	2.12	^; 2.82	2.48	5.69

In all cases, even the untreated control solution, the captopril level remained at more than 95% of its initial concentration and at 4^CC. the disulphide level remained below 1% relative to the captopril concentration. At 25°C, the disulphide levels increased significantly 5 above the 1% limit deemed to be acceptable. The results showed that removal of the dissolved oxygen improved the API stability.

it was decided to re-examine the use of ACD using a wider range of captopril to cyclodextrin ratios. The formulation was further simplified to minimise possible side 10 interactions by omitting the sorbitol and the flavouring.

Solutions were prepared containing ACD at ACD:captopril ratios of 1:1, 1.5:1., 2:1, 2.5:1, 3:1 and 4:1 molar which translated (for ().5%w/v captopril) to 2.237, 3.356. 4.474, 5.593, 6.711 and 8.948 wt% ACD respectively.

The formulations prepared for testing are shown in Table 4 below. Preliminary work had established that at an ACD:captopril ratio of 1.5:1, the ACD did not interfere with the HPLC determination of the captopril, and that the addition of the ACD did not change the solution pH to any significant extent. The pHs ot'the below tost solutions were in the range 20 3.90-3.95.

Table 4

The following solution was prepared.

Ingredients	Concentration wt%
Captopril	0.50
Sodium saccharine	0.10
Citric acid anhydrous	0.05
Trisodium citrate dibydrate	0.216
Disodium EDTA	0.05
.Ascorbic acid	0.075
Ethanol (96%)	ΐδ.δδ
ΛI ph a cyclod ex tri n	4.474 to 8.948
Purified water	To 100

ml voltanes of the prepared test solutions were placed in 75ml amber glass bottles, stoppered and placed on storage at 4°C and 25°C. Samples of the solutions were also assayed for captopril and Impurities immediately f or comparison.

The test solutions were examined visually after 3 hours on storage when it was found that crystallisation had resulted in all of the 3:1 and 4:1 ACDicaptopril solutions.

These samples were withdrawn from test. The natures of the precipitates were not determined but were almost certainly.

ACD or ACD/captopnl complex since the other components could not have 15 accounted for the amounts seen,

Assays were carried out on the remaining samples at 18 days with the exception of the 2:1 ACDicaptopril solution at 4°C since this contained precipitated solid also.

The analytical results are shown in Table 5.

Table 5:

Test. Solution	Initial Sample	18 Days Storage
4°C	25°C
1:1 ACD: Captopril
Captopril (mg/rnl)	5.1	5.19	5.14
Disulphide (% Rel)	0.33	0.62	2.58
Total RS (%Rel)	A	0.75	2.96
1.5:1
ACD:Captopril	5.05	5.28	5.24
Captopril (mg/ml)	0.35	0.84	2.08
Disulphide (% Rel)		1.11	2.43
Total RS (%Rel)
2:1 ACD:Captoprii
Captopri 1 (mg/rnl)	5.15	*<	5.24
Disulphide t% Rel)	0.357	*	1.97
Total RS (%Rcl)		:A	2.51

The results showed no improvement over the control solution from Table 4, This approach was curtailed.

Figures I and 2 show a delivery system for a dosage form in accordance with this invention. A container (1) having screw {bread (2) and cylindrical opening (3) may be engaged with a cap (4) having a tamper-proof seal (5) and a receptacle (6) extending downwardly into the container (1) through the neck (3), Tire receptacle (6) is generally cylindrical and has a frangible sealing disc (9) to define a container within which the solid 10 component (IO) may be stored. Upper surface (11) of the cap (4) has a downwardly extending flange (8) having a lower portion (7) extending to a point close io the frangible disc (9). When the tamper-proof'ring (5) and sealing band (12) are removed the rim of the cap (4) may be depressed urging the projection (7) into contact with the frangible ring (9). This causes the ring (9) to rupture releasing the solid component (10) from the receptacle (6).

Figure 3 shows the assembled delivery system before use wherein the liquid component (13) is disposed within the bottle (1).

In Figure 4 the tamper proof ring (5) and sealing band (12) have been removed and the cap may then be depressed as shown in Figure 5, releasing the solid phase (10) into the liquid component (13). The mixture of the solid component and liquid component are then shaken together before the cap is removed and the dosage form administered orally.

Various modifications will be apparent to those embodiment foe container is a bottle composed of amber (PET), The bottle has a total volume capacity of 200 ml. Typically 150 mi of the liquid component is added to the bottle to allow for 50 ml of headspace volume to allow for skilled in the art. In an alternative colon red poly eth yl ene terepi i thala te fix j' um vigorous agitation following addition of the solid component

Claims

1.

A container comprising a pharmaceutical dosage form, the pharmaceutical dosage ·ΠΠ^: form comprising solid and liquid components;

the solid component, comprising captopril as active ingredient; and the liquid component comprising:

IQ sodium metabisulphite;

at least one sequestrant; and optional further excipients;

the container having two separate compartments separated by a breakable barrier, the solid component located in a first, compartment and the liquid component located in a second compartment:

the breakable barrier being arranged to be broken by a user to allow the solid component and the liquid component to mix to provide the dosage form for use.

A container comprising a pharmaceutical dosage form wherein the amount of sodium metabisulphite is 0.05 to 0.40 wt.% <>

Oi preferably 0.20% to 0.30% w/v.

•n <

A container comprising a pharmaceutical dosage fonn as claimed in claim 1 or 2, the liquid component further comprising an organic antioxidant, wherem the organic antioxidant is selected from the group consisting of: butylatcd hydroxyuni sole, alpha cyclodextrii ascorbic acid, and mixtures thereof

A container comprising a pharmaceutical dosage form wherein the organic antioxidant is ascorbic acid.

5.

A container comprising a pharmaceutical dosage form as

6,

A container comprising a pharmaceutical dosage form as claimed in claim 3.

the as wherein the amount of organic antioxidant is 0.065 to 0.085 wt% of the o' liquid component claimed in c liquid component.

A container comprising a pharmaceutical dosage form as claimed in any preceding claim.

wherein the sequcst ethy cn ed i am i n e tetr a a cet i c aci d

8.

A container· comprising a pharmaceutical dosage fonn as claimed in any preceding claim, wherein the amount of seq resirant is 0.02 io 0.10 wt% of the liquid component.

9.

wherein the amount of sequestrant. is 0,03 to 0.06 wt% of the liquid component

Αι

10.

A container comprising a pharmaceutical dosage form as claimed in any preceding claim, the liquid component further comprising a preservative, wherein the preservative is selected from the group comprising: ethanol, sodium benzoate, and mixtures thereof

IL

A container comprising a pharmaceutical dosage form as claimed in claim 10, wt% of'the liquid component.

A container comprising a pharmaceutica dosage form as claimed in any preceding claim, wherein the water soluble excipient of the solid component is a sweetener.

A container comprising a pharmaceutical dosage form as claimed in claim 12.

Z-i wherein the water soluble excipient is selected from the group comprising: ison alt maltodextrin, dextrose, lactose, maltose, mahitol, sucrose, xy itol and mixtures thereof.

A container comprising a pharmaceutical dosage form claimed in ciaun

13, wherein the water soluble excipient is isomalt.

15.

A container comprising a pharmaceutical dosage form as el aimed in claim

14, wherein the solid component comprises:

2.5 to 30 wt%: and isomalt

70 to 97,5 wt%.

16.

•ecepiacle of a closure, tire closure being adapted to rcleasablv close the container.

FT release the solid coraponer

18. A coniainer comprising, a pharmaceutical dosage form as claimed in any preceding claim, wherein the breakable barrier is a frangible barrier.

Intellectual Property Office

Application No: GB1715841.1 Examiner: Mr Chris Archer