GB2415376A

GB2415376A - Double shell unit dosage form with frangible inner shell

Info

Publication number: GB2415376A
Application number: GB0512453A
Authority: GB
Inventors: Victor M Young
Original assignee: MW Encap Ltd
Current assignee: MW Encap Ltd
Priority date: 2004-06-21
Filing date: 2005-06-20
Publication date: 2005-12-28
Also published as: GB0512453D0; GB0413818D0

Abstract

A dosage unit is comprised of an outer capsule and inner capsule, the inner capsule being located within the body of the outer capsule. The inner capsule contains a first formulation which may be an active ingredient, chemical, mixture of compounds, pharmaceutical, nutraceutical or precursor. A second formulation is contained within the space between shell of the outer and inner capsules. The shell of the inner capsule is at least partially frangible to allow mixing of the first and second formulation.

Description

1 Dosage Unit 3 The present invention relates to the field of dosage 4

units, and in particular dosage units which can be used to administer unstable compounds.

7 Two piece hard shell capsules have been used for 8 medicaments for many years. Typically these are made 9 from gelatin although more recently other materials such as starch or hydroxypropyl methylcellulose (HPMC) have 11 been used and other materials are currently under 12 development.

14 Capsule shells are not stable under all environmental conditions and can also be affected by the formulations, 16 compounds and materials that they are filled with.

17 Gelatin capsules, for example, have a recommended 18 humidity range of 35%RH to 65%RH, within which they are 19 stable. Above this humidity gelatin capsules absorb water and become soft and distorted. Below this range 21 gelatin capsules lose water and become brittle and can 22 crack or shatter. Capsules made from other materials can 1 show similar effects outside the environmental or 2 chemical conditions in which they are known to be stable.

4 The contents (fill formulation) of a capsule can have similar effects on the shell of the capsule due to the 6 transfer or removal of water and/or chemical reactions 7 with the shell. Capsules that become soft and distorted, 8 discoloured, develop holes or splits or become brittle 9 are considered to be defective dosage units, incompatible with their environment or contents and are typically 11 rejected as non viable dosage units.

13 It is well known that in certain circumstances hard shell 14 capsules can become soft or brittle. Until now, the conditions which cause these defects have been identified 16 and modified by capsule producers, specifically to avoid 17 these 'faults'.

19 It is the art and science of a formulation developer to produce formulations that deliver the required dosage of 21 the compound or compounds of choice to the user and are 22 sufficiently stable to maintain this dosage quantity 23 within strict limits over the shelf life of the product.

24 It is, however, not always possible to produce nutriceutical or pharmaceutical compound formulations 26 that are sufficiently stable when delivered as a capsule 27 dosage unit. Formulations which have a potency which 28 changes greatly over the projected shelf life of the 29 product due to degradation or other reasons can not normally be used to produce viable dosage units.

32 In some cases it is not possible to formulate a single 33 mixture containing the desired chemical as the chemical 1 does not display the required stability. Some 2 formulations, compounds and chemicals are so unstable 3 that they would not be able to be stored, for example in 4 shops, or pharmacies. To overcome this problem, in the past it has been known to produce this chemical or 6 compound at or near the time of ingestion, in the desired 7 quantity, by mixing two or more compounds that do show 8 satisfactory stability and interact to produce the 9 desired chemical. This has been achieved, for example, by mixing two materials immediately before consumption.

11 Generally, one or more of these materials is required to 12 be a liquid. The mixing of these materials, or the 13 chemicals in these materials, produces an interaction 14 that produced the desired chemical. However, the time delay between mixing and consumption is typically so 16 short (in comparison to a product shelf life) that the 17 user generally does not ingest the desired chemical in 18 the correct amount.

It would therefore be advantageous to provide a dosage 21 unit, which allow unstable compounds and chemicals to be 22 stored in the normal manner, with an acceptable shelf 23 life.

According to a first aspect of the present invention 26 there is provided a dosage unit comprising: 27 - a first capsule, 28 - a second capsule located within the first capsule, 29 - a first formulation held between the first and second capsule; and 31 - a second formulation held within the second capsule; 1 where the second capsule has a shell which is at least 2 partially frangible to allow mixing of the first and 3 second formulation.

The first and second formulations are typically 6 precursors which upon mixing form the compound being 7 dosed. Typically when the shell of the second capsule is 8 at least partially broken, mixing of the first and second 9 formulations produces a reaction which forms the compound being dosed.

12 Preferably the shell of the outer capsule is flexible.

14 Preferably mixing of the first and second formulations is achieved by exerting force on the shell of the first 16 capsule which causes it to deform towards the shell of 17 the second capsule which then at least partially breaks.

19 In a first embodiment the shell of the second capsule is made to be breakable by virtue of dehydration. Typically 21 the shell of the second capsule is dehydrated prior to 22 insertion of the second capsule into the first capsule.

24 In a second embodiment the shell of the second capsule is made to be breakable by virtue of a chemical interaction.

26 The chemical interaction may take place prior to 27 insertion of the second capsule into the first capsule.

29 Preferably the chemical interaction takes place after insertion of the second capsule into the first capsule.

1 Typically either of the first or second formulations are 2 capable of acting on the shell of the second capsule to 3 render it at least partially breakable.

Preferably the action of the first or second formulations 6 in rendering the shell of the second capsule at least 7 partially breakable does not take effect until after the 8 second capsule has been inserted into the first capsule.

Preferably the first or second formulation embrittles the 11 shell of the second capsule over a period of several 12 days.

14 The first or second formulation may include a chemical such an aldehyde or ketone which embrittles the shell of 16 the second capsule.

18 The first or second formulation may include a dehydrating 19 agent such as a low molecular weight polyethylene glycol (PEG) which embrittles the shell of the second capsule.

22 The first or second formulation may inherently be capable 23 of acting on the shell of the second capsule to render it 24 at least partially breakable.

26 Alternatively the first or second formulation may contain 27 an additive which is capable of acting on the shell of 28 the second capsule to render it at least partially 29 breakable.

31 In a yet further alternative the first or second 32 formulation may be provided in a carrier substance which 1 is capable of acting on the shell of the second capsule 2 to render it at least partially breakable.

4 The first and second capsules may be manufactured from any suitable material such as polyethylene glycol (PEG), 6 gelatin, hydroxypropyl methylcellulose (HPMC) or 7 combinations thereof.

9 Preferably the second capsule is manufactured from gelatin.

12 Preferably the first capsule is made from hydroxypropyl 13 methylcellulose (HPMC).

According to a second aspect of the present invention 16 there is provided a method of administering an unstable 17 compound using the dosage unit of the first aspect of the 18 present invention, the method comprising the steps of: 19 - encapsulating a first stable precursor of the compound within the second capsule; 21 - encapsulating a second stable precursor of the compound 22 between the first and second capsule, such that it is 23 not in direct contact with the first stable precursor; 24 - when required, breaking the shell of the second capsule, by exerting pressure on the shell of the first 26 capsule in order to mix the first and second stable 27 precursors to form the unstable compound.

29 According to a third aspect of the present invention, there is provided a method of administering a first 31 compound together with a second compound using the dosage 32 unit comprising the steps of: 1 encapsulating the first compound within the second 2 capsule; 3 encapsulating the second compound between the first 4 and second capsule, such that it is not in direct contact with the first compound; 6 - when required, breaking shell of the second capsule, 7 by exerting pressure on the shell of the first 8 capsule in order to mix the first and second 9 compound.

11 An example of the present invention will now be described 12 with reference to Figure 1 which is an illustration of 13 the dosage unit of the present invention.

The Applicant has discovered that by introducing 16 conditions that will induce capsule shell embrittlement, 17 a new dosage unit can be provided which allows unstable 18 compounds or chemicals to be stored or held for a period 19 of time, and normal shelf life, prior to consumption.

21 Referring to Figure 1 the dosage unit of the present 22 invention is generally depicted at 1 and is comprised of 23 outer capsule 2 and inner capsule 3, the inner capsule 3 24 being located within the body of the outer capsule 2. In Figure 1, both the outer capsule 2 and inner capsule 3 26 can be viewed, however in use, the inner capsule 3 will 27 generally not be seen as it is wholly contained within 28 outer capsule 2.

The inner capsule 3 contains a first formulation 6 which 31 may be an active principal, a chemical, chemical mixture, 32 compound, mixture of compounds, pharmaceutical or 33 nutriceutical. The inner capsule 3 is encapsulated 1 within larger outer capsule 2 and a second formulation 7 2 may be contained in the space 5 between the shells of the 3 outer 2 and inner 3 capsules. In this manner the first 4 and second formulations 6,7 are kept separate and out of contact. Once inside the outer capsule 2 the brittle 6 inner capsule 3 is protected from damage by the outer 7 capsule 2 and the second formulation 7 present between 8 the shell walls.

The shell 8 of the outer capsule 2 is flexible and can be 11 made of any suitable material, such as gelatin, 12 polyethylene glycol (PEG), hydroxypropyl methylcellulose 13 or a combination thereof. The shell 9 of the inner 14 capsule 3 will also be manufactured from a material such of those described above, but differs from the shell of 16 the outer capsule 2 as it is at least partially brittle, 17 frangible or breakable.

19 When the shell 9 of the inner capsule 3 is broken the first and second formulations 6,7 are allowed to mix.

21 Thus, the dosage unit 1 can be used to hold stable 22 precursors of an unstable chemical, compound, 23 pharmaceutical, nutriceutical etc prior to consumption or 24 dosing. When the unstable chemical, compound, pharmaceutical, nutraceutical is to be administered or 26 taken the shell 9 of the inner capsule 3 is broken to mix 27 the first and second formulations 6,7 which will undergo 28 a reaction and form the unstable chemical, compound, 29 pharmaceutical, nutraceutical. The user then ingests the mixed formulation as a single dosage unit. The mixing of 31 the formulations 6,7 is achieved by pressing on the shell 32 8 of the flexible outer capsule 2. When sufficient 33 pressure is applied to the shell 8 of the outer capsule 2 1 it will deform towards the inner capsule 3 which in turn 2 will break and the first formulation 6 will be released.

4 Embrittlement of a capsule, has previously been considered an undesirable defect. However in the present 6 invention this is used to advantage to produce a novel 7 dosage device permitting the mixing of different 8 compounds in a clean and accurate manner shortly before 9 ingestion to produce a chemical or chemicals, at the desired therapeutic level, that has not been present up 11 until this point.

13 Embrittlement of the shell 9 of the inner capsule 3 can 14 be achieved in a number of different ways. Embrittlement may take place prior to sealing the inner capsule 3 16 within the body of the outer capsule 2. However in the 17 preferred embodiment Embrittlement of the shell 9 of the 18 inner capsule 3 will take place after the inner capsule 3 19 is sealed in the outer capsule 2 to allow the inner capsule 3 to withstand the action of placing it within 21 the outer capsule 2 during manufacture. Manufacture of 22 the entire dosage unit can therefore be completed before 23 the inner capsule 3 becomes brittle.

Embrittlement may be carried out by dehydration of the 26 shell, for example by using a dehydrating agent such as 27 low molecule weight polyethylene glycol or other chemical 28 which induces Embrittlement such as aldehydes and 29 ketones. It should be appreciated that any other means that produces an embrittled capsule could also be used in 31 this Application.

1 Either of the first or second formulations 6,7 may 2 contain a chemical or agent which enduces embrittlement 3 of the shell of the second capsule. Generally the inner 4 capsule 3 will be filled with a formulation 6 which either has the inherent property to cause embrittlement 6 of the shell of the capsule that it fills, or will 7 contain a chemical which has this property, or 8 alternatively will be provided in a carrier with this 9 property. Embrittlement may be achieved by exposure to chemicals such as aldehydes or ketones or by exposure to 11 formulations containing dehydrating materials such as the 12 liquid low molecular weight polyethylene glycols (PEGs).

13 The means of embrittlement is not limited to those of the 14 above examples, supplied by way of illustration.

16 Typically the embrittled inner capsule 3 is made from 17 gelatin. Both or either of the inner and outer capsules 18 2,3 making up the dosage unit may optionally be sealed by 19 banding. The outer capsule 2 is typically made from HPMC.

22 The dosage unit of the present invention has the inherent 23 advantage that it permits the delivery of two or more 24 separate ingredients (such as stable precursors of an unstable compound) in a single dosage unit that, where 26 normally, the unstable compound can only be delivered as 27 two separate mixtures or provided separately and mixed 28 shortly before ingestion. The dosage unit also allows 29 two compounds which could not normally be taken together, perhaps because when mixed they react over time to form 31 an unstable, or non-active, or in other way undesirable 32 product, to be administered together.

1 Further modifications and improvements may be 2 incorporated without departing from the scope of the 3 invention herein intended.

Claims

1 CLAIMS 3 1. A dosage unit comprising: - a first capsule, 6 - a second

capsule located within the first capsule, 7 - a first formulation held between the first and 8 second capsule; and 9 - a second formulation held within the second capsule; 12 where the second capsule has a shell which is at 13 least partially frangible to allow mixing of the 14 first and second formulation.

16 2. A dosage unit as claimed in Claim 1, where the first 17 and second formulations are precursors which upon 18 mixing form an active compound.

3. A dosage unit as claimed in the preceding Claims, 21 where the shell of the outer capsule is flexible.

23 4. A dosage unit as claimed in Claim 3, where the shell 24 of the first capsule is adapted to deform towards the shell of the second capsule upon exertion of 26 force on said shell of the first capsule, which 27 causes the shell of the second capsule to at least 28 partially break.

5. A dosage unit as claimed in the preceding Claims, 31 where the shell of the second capsule is embrittled 32 by dehydration.

1 6. A dosage unit as claimed in Claims 1 to 4, where 2 the shell of the second capsule is embrittled by 3 chemical interaction.

7. A dosage unit as claimed in the preceding Claims, 6 where one or both of the first and second 7 formulation is adapted to act on the shell of the 8 second capsule to render it at least partially 9 frangible.

11 8. A dosage unit as claimed in Claim 7, where one or 12 both of the first and second formulation may include 13 an aldehyde.

9. A dosage unit as claimed in Claims 7 to 8, where one 16 or both of the first and second formulation includes 17 a dehydrating agent, such a low molecular weight 18 polyethylene glycol (PEG).

10. A dosage unit as claimed in the preceding Claims, 21 where one or both of the first and second 22 formulation contains an additive which acts on the 23 shell of the second capsule to render it at least 24 partially breakable.

26 11. A dosage unit as claimed in Claims 7 to 9, where one 27 or both of the first and second formulation is 28 provided in a carrier substance capable of acting on 29 the shell of the second capsule to render it at least partially frangible.

1 12. A dosage unit as claimed in the preceding Claims, 2 where one or both of the first and second capsule is 3 manufactured from polyethylene glycol (PEG).

13. A dosage unit as claimed in Claims 1 to 12, where 6 one or both of the first and second capsule is 7 manufactured from gelatin.

9 14. A dosage unit as claimed in Claims 1 to 12, where one or both of the first and second capsule is 11 manufactured from hydroxypropyl methylcellulose 12 (HPMC).

14 15. A method of administering an unstable compound using the dosage unit of Claims 1 to 14, comprising the 16 steps of: 18 - encapsulating a first stable precursor of the 19 compound within the second capsule; encapsulating a second stable precursor of the 21 compound between the first and second capsule, 22 such that it is not in direct contact with the 23 first stable precursor; 24 - when required, breaking the shell of the second capsule, by exerting pressure on the shell of the 26 first capsule in order to mix the first and second 27 stable precursors to form the unstable compound.

29 16. A method of administering a first compound, together with a second compound using the dosage unit of 31 Claims 1 to 14, comprising the steps of: 1 - encapsulating the first compound within the 2 second capsule; 3 encapsulating the second compound between the 4 first and second capsule, such that it is not in direct contact with the first compound; 6 - when required, breaking the shell of the second 7 capsule, by exerting pressure on the shell of 8 the first capsule in order to mix the first and 9 second compound.

11 17. A method as claimed in Claims 15 to 16, comprising 12 the additional step of dehydrating the shell of the 13 second capsule prior to insertion into the first 14 capsule in order to render it frangible.

16 18. A method a claimed in Claims 15 to 16, comprising 17 the additional step of subjecting the shell of the 18 second capsule to chemical modification, in order to 19 render it frangible.

21 19. A method as claimed in Claim 18, where the step of 22 subjecting the second capsule to chemical 23 modification occurs after insertion into the first 24 capsule, in order to render it frangible.

26 20. A method as claimed in Claim 19, where the step of 27 subjecting the second capsule to chemical 28 modification occurs prior to insertion into the 29 first capsule, in order to render it frangible.

31 21. A method as claimed in Claim 15, where one or both 32 of the first and second stable precursors act on the 1 shell of the second capsule to render it at least 2 partially frangible.

4 22. A method as claimed in Claim 15, where one or both of the first and second compounds act on the shell 6 of the second capsule to render it at least 7 partially frangible.

9 23. A method as claimed in Claims 21 to 22, where the action of rendering the shell of the second capsule 11 at least partially frangible does not take effect 12 until after the second capsule has been inserted 13 into the first capsule.

24. A method as claimed in Claim 23, rendering the shell 16 of the second capsule at least partially frangible, 17 takes place over a period of several days.