Indian Patents. 223804:A HYDROXYPROPYL METHYL CELLULOSE FILM, METHOD FOR ITS PRODUCTION AND DELIVERY CAPSULE ENCLOSED BY IT

Title of Invention	A HYDROXYPROPYL METHYL CELLULOSE FILM, METHOD FOR ITS PRODUCTION AND DELIVERY CAPSULE ENCLOSED BY IT
Abstract	A hydroxypropyl methyl cellulose film comprises hydroxypropyl methyl cellulose plasticised with aplasticiser comprising an organic acid or a salt of an organic acid, preferably lactic acid, or an alcohol or salt of an alcohol. The film is safe for human consumption and finds use as a wall material of an ingestible delivery capsule, e.g. containing a dose of a pharmaceutical preparation.

Full Text	A HYDROXYPROPYL METHYL CELLULOSE FILM, METHOD FOR ITS PRODUCTION AND DELIVERY CAPSULE ENCLOSE BY IT Field of the invention. This Invention relates to films of modified polymeric materials, more particularly of films of the modified cellulose material hydroxypropyl methyl cellulose (HPMC), and uses of such films. Background of the Invention. Hydroxypropyl methyl cellulose is a synthetic plastics material, which Is a modified form of the naturally occurring polymer, cellulose. Films, (or sheets or membranes) of HPMC are available commercially and have various uses, including proposals for use as wall materials of delivery capsules I.e. capsules designed to retain and protect their contents until an intended site of delivery or conditions of delivery are encountered, at which point the contents of the capsules are released. HPMC is suitable for ingestlon by humans, so delivery capsules with HPMC walls find the potential use as Ingestible capsules, e.g. for the delivery of accurately metered doses of pharmaceutical preparations and dietary supplements, as a possible replacement for gelatin based capsules. See for example, WO 97/35537, WO00/27367 and WO 01/03676, When producing HPMC films, HPMC is usually treated with a plasticlser in order to Impart or improve properties of flexibility to the film. Materials used as plasticisers include polyethylene glycol (PEG), monopropylene glycol, glycerol and also acetins (which are acetates of glycerol). In a typical method of making a cast HPMC film, HPMC, PEC and water are mixed to produce an aqueous solution, followed by optional deaeratlon of the solution if a non-aerated film is required. The film is then fed in a controlled manner to the surface of a continuous belt, producing a cast film of desired thickness which is fed on the belt past heating means for drying the film. The dried film is then removed from the belt and wound onto reels. The present Invention concerns novel plasticiser materials for polymeric films, more particularly HPMC films. Summary of the invention In one aspect of the present invention provides hydroxypropyl methyl cellulose film, comprising hydroxy propyl methyl cellulose plastlcised with a plasticiser comprising an organic acid, or derivative or salt of such an acid. In another aspect of the present invention provides hydroxypropyl methyl cellulose film, comprising hydroxypropyl methyl cellulose plastlcised with an organic alcohol, derivative or salt of such an alcohol. Suitable organic acids are carboxylic acids, such as mono, di, tri, or tetra or other polyvalent carboxylic acids. Carboxylic acids according to the present Invention include the following: C1-C6 saturated or unsaturated, straight or branched chain carboxylic acids, with 1,2,3 or 4 carboxyl groups C1 -C6 hydroxy acids with any combination of 1,2,3,4 hydroxyl/carboxyl groups, including beta hydroxy acids (BHA's) Cyclised acids and cyclised hydroxy acids Specific examples of acids according to the present Invention include the following: unsaturated carboxyiic acids Adipic acid Fumerlc acid Fumaric acid Maleic acid Proprionic acid saturated carboxylie acids Ethanoic acid Propanoic acid Butanoic acid Pentanolc add Hexanoic acid hydroxy adds Alpha hydroxy butyric acid Mandellc acid cyclised acids and cyclised hydroxy acids Garnma butyrolactone Cam ma valerolactone Beta propriolactone In another aspect of the present invention provides hydroxy propyl methyl cellulose film, comprising hydroxy propyl methyl cellulose plasticised with an organic alcohol, derivative or salt of such an alcohol. Alcohols according to the present invention include C1-C8 substituted or unsubstituted, saturated or unsaturated, straight or branched chain aliphatic alcohols. Examples of alcohols according to the present invention incJude the following: Benzyl alcohol Ethanol Propanol Isopropanol Butanol, and structural isomers Pentanol, and structural isomers Hexanol, and structural tsomers The above acids and alcohols are readily available commercially, some or which are approved for pharmaceutical and food use, so some forms of HPMC film in accordance with the present invention is suitable for and approved for food and pharmaceutical use. Some HPMC film In accordance with the present Invention Is suitable for ingestlon by humans. Some HPMC film in accordance with the present Invention can thus be used for ingestlble purposes, e.g. as wall material for ingestible delivery capsules. The currently preferred acid plasticiser according to the present Invention is malelc acid, with fumaric acid and then adipic acid being the next most favoured. In addition, benzyl alcohol has shown favourable characteristics for particular purposes. It Is preferred that the plastidser is in the form of an acid or alcohol rather than a salt of the acid/alcohol, as the non salt form generally has better plasticising properties, (although salts Including partial salts e.g. sodium and potassium salts of the acids/alcohols may be used, and in particular it may be convenient to use buffered casting solutions). The acids, particularly maleic acid and alcohols, particularly benzyl alcohol, are also generally found to have good plasticising properties and to be capable of producing HPMC films with certain benefits and advantages as compared with HPMC films prepared using conventional plastlcisers. These benefits and advantages include the following: a) The film thermoforms very easily at lower temperatures and using less energy. b) The deformed film retains Its shape i.e. the film has no memory. c) The film readily welds to itself and seals at lower temperatures using less heat and pressure. d) The film tastes pleasant and has mouth watering effect. e) The film has a high gloss appearance, Improving the appearance of the finished product f) The plastlciser may comprise one or more materials, including one or more acids/alcohols and/or one or more salts of the acid/alcohol, possibly in combination with one or more other plastlcisers such as those In the prior art e.g. polyethylene glycol, monopropylene glycol, glycerol and acetins. The plastldser Is suitably present in an amount In the range of 2-40% by weight of the total weight of the film, typically about 23% by weight of the total weight of the film. One preferred film thus comprises about 2396 malelc acid and about 77% by weight HPMC. Where a mixture of plastcisers Is used, benefits may nevertheless be seen using an acid or alcohol according to the present Invention, particularly maleic acid, at lower levels, say 5% by weight of the total weight of the film. The film may Include optional colourings, e.g. In the form of known food dyes such as FD and C yellow number 5, optional flavourings, artificial sweeteners, textures etc., in known manner. The film may optionally be foamed, expanded or gasified, with small pockets of gas, e.g. air included In the film structure In known manner. The minimum thickness of single ply unfoamed film, practically, would be 20 microns and the maximum thickness of single pty foamed film, practically, would be 300 microns. The film typically has a thickness in the range 50-200 microns, e.g. in the range 60-130 microns, more preferably 70 - 90 microns, with the film thickness being controllable In known manner. Films of different thickness may be suited to different uses. The film may be made In generally conventional manner, e.g. as described above, as is well known to those skilled in the art. Film in accordance with the Invention finds particular use as wall material for delivery capsules, as discussed above, particularly for ingestible capsules. Other uses include, as biodegradeable packaging, water soluble sachets, carrier material for coating flavours (with flavour Incorporated In the film or In coating on the film) for enrobing tablets etc. In a further aspect, the invention further provides a delivery capsule having an enclosing wall comprising hydroxypropyl methyl cellulose film in accordance with the present invention. Such delivery capsules may be made in generally conventional manner e.g. as disclosed In WO 97/35537, WO 00/27367 and WO 01 /03676. The invention will be further described, by way of illustration, in the following example. Example. A hydroxypropyl methyl cellulose film in accordance with the invention was made, having the following composition by weight Hydroxypropyl methyl cellulose 77% Maleic acid 23% The film was made in generally conventional manner. HPMC, in the form of powder, was mixed with maleic acid and water to produce an aqueous solution with stirring. The composition of the HPMC casting solution was (%w:w) HPMC 10, water 87 maleic acid 3. The solution was deaerated by application of a vacuum.The solution was then fed into a feed hopper, including an elongate exit slot located a small distance above the upper surface of a moving conveyor belt to an end thereof, with the slot extending perpendicularly with respect to the direction of movement of the belt away from the feed hopper, forming a film. The film was passed on the belt through a heating zone In which hot air heated the film, driving off water and so drying the film. The resulting dried cast film was removed from the belt and wound onto reels. The water content of the dried film was about 4% by weight, In the form of bound (non-free) water. The thickness of the dried film was about 120 microns. The film has certain benefits and advantages as compared with films prepared using conventional plasticlsers. These include the following: a) The film thermoforms very easily at lower temperatures and using less energy. b) The deformed film retains its shape i.e. the film has no memory. c) The film readily welds' to itself and seals at lower temperatures using less heat and pressure. d) The film tastes pleasant and has mouth watering effect. e) The film has a high gloss appearance, improving the appearance of the finished product The resulting film Is suitable for human consumption, and one use is as a wall material for ingestible delivery capsules e.g. containing a dose of a pharmaceutical preparation or a dietary supplement. Such capsules may be made using known techniques, e.g. as described In WO 97/35537, WO 00/27367 and WO 01 /03676. We Claim: 1. A hydroxypropyl methyl cellulose film, comprising hydroxypropyl methyl cellulose plasticised with a plasticiser comprising one or more of adipic acid; fumeric acid; fumaric acid; maleic acid; ethanoic acid; propanoic acid; alpha hydroxyl butyric acid; mandelic acid; gamma butyrolactone; gamma valerolactone; beta propriolactone; benzyl alcohol; ethanol; propanol; isopropanol; butanol; structural isomers of butanol; pentanol; structural isomers of pentanol; hexanol; structural isomers of hexanol; and/or a salt of any of the preceding acids or alcohols, wherein the plasticiser is present in the amount in the range of 2 to 40% by weight of the total weight of the film. 2. A hydroxypropyl methyl cellulose film, comprising hydroxypropyl methyl cellulose plasticised with a plasticiser comprising one or more of benzyl alcohol; ethanol; propanol; isopropanol; butanol; structural isomers of butanol; pentanol; structural isomers of pentanol; hexanol; structural isomers of hexanol; and/or a salt of any of the preceding alcohols. 3. A film as claimed in claim 2, wherein the plasticiser comprises one or more of maleic acid, fumaric acid, adipic acid, fumeric acid, propionic acid, ethanoic acid, propanoic acid, alpha hydroxyl butyric acid, mandelic acid, gamma butyrolactone, gamma valerolactone, and beta propriolactone. 4. A film as claimed in claim 1, wherein the plasticiser comprises one or more of maleic acid, fumaric acid, and adipic acid. 5. A film as claimed in claim 4, wherein the plasticiser comprises maleic acid. 6. A film as claimed in claim s 1 to 5 wherein the plasticiser comprises benzyl alcohol 7. A film as claimed in claim 1 wherein the plasticiser is present in the amount of 23% by weight of the total weight of the film. 8. A film as claimed in claim s 5 or 6, comprising about 23% by weight of the plasticiser and 77% by weight of HPMC. 9. A film as claimed in any one of the preceding claims, wherein the film is foamed, expanded, or gasified. 10. A film as claimed in any one of the preceding claims, wherein the film has a thickness of between 50 to 200 microns. 11. A delivery capsule having an enclosing wall comprising a film in accordance with any one of the preceding claims. 12. A method of producing an HPMC film suitable for forming into a capsule, comprising treating the HPMC film with acids and/or alcohols mentioned in any preceding claim, before and/or during when the film is manipulated to form a capsule. A hydroxypropyl methyl cellulose film comprises hydroxypropyl methyl cellulose plasticised with aplasticiser comprising an organic acid or a salt of an organic acid, preferably lactic acid, or an alcohol or salt of an alcohol. The film is safe for human consumption and finds use as a wall material of an ingestible delivery capsule, e.g. containing a dose of a pharmaceutical preparation.

Full Text

A HYDROXYPROPYL METHYL CELLULOSE FILM, METHOD FOR ITS PRODUCTION AND
DELIVERY CAPSULE ENCLOSE BY IT
Field of the invention.
This Invention relates to films of modified polymeric materials, more
particularly of films of the modified cellulose material hydroxypropyl
methyl cellulose (HPMC), and uses of such films.
Background of the Invention.
Hydroxypropyl methyl cellulose is a synthetic plastics material, which Is a
modified form of the naturally occurring polymer, cellulose. Films, (or
sheets or membranes) of HPMC are available commercially and have
various uses, including proposals for use as wall materials of delivery
capsules I.e. capsules designed to retain and protect their contents until
an intended site of delivery or conditions of delivery are encountered, at
which point the contents of the capsules are released. HPMC is suitable
for ingestlon by humans, so delivery capsules with HPMC walls find the
potential use as Ingestible capsules, e.g. for the delivery of accurately
metered doses of pharmaceutical preparations and dietary supplements,
as a possible replacement for gelatin based capsules. See for example,
WO 97/35537, WO00/27367 and WO 01/03676,
When producing HPMC films, HPMC is usually treated with a plasticlser in
order to Impart or improve properties of flexibility to the film. Materials
used as plasticisers include polyethylene glycol (PEG), monopropylene
glycol, glycerol and also acetins (which are acetates of glycerol).
In a typical method of making a cast HPMC film, HPMC, PEC and water are
mixed to produce an aqueous solution, followed by optional deaeratlon
of the solution if a non-aerated film is required. The film is then fed in a
controlled manner to the surface of a continuous belt, producing a cast
film of desired thickness which is fed on the belt past heating means for
drying the film. The dried film is then removed from the belt and wound
onto reels.
The present Invention concerns novel plasticiser materials for polymeric
films, more particularly HPMC films.
Summary of the invention
In one aspect of the present invention provides hydroxypropyl methyl
cellulose film, comprising hydroxy propyl methyl cellulose plastlcised
with a plasticiser comprising an organic acid, or derivative or salt of
such an acid.
In another aspect of the present invention provides hydroxypropyl methyl
cellulose film, comprising hydroxypropyl methyl cellulose plastlcised with
an organic alcohol, derivative or salt of such an alcohol.
Suitable organic acids are carboxylic acids, such as mono, di, tri, or tetra
or other polyvalent carboxylic acids.
Carboxylic acids according to the present Invention include the following:
C1-C6 saturated or unsaturated, straight or branched chain carboxylic
acids, with 1,2,3 or 4 carboxyl groups
C1 -C6 hydroxy acids with any combination of 1,2,3,4 hydroxyl/carboxyl
groups, including beta hydroxy acids (BHA's)
Cyclised acids and cyclised hydroxy acids
Specific examples of acids according to the present Invention include the
following:
unsaturated carboxyiic acids
Adipic acid
Fumerlc acid
Fumaric acid
Maleic acid
Proprionic acid
saturated carboxylie acids
Ethanoic acid
Propanoic acid
Butanoic acid
Pentanolc add
Hexanoic acid
hydroxy adds
Alpha hydroxy butyric acid
Mandellc acid
cyclised acids and cyclised hydroxy acids
Garnma butyrolactone
Cam ma valerolactone
Beta propriolactone
In another aspect of the present invention provides hydroxy propyl
methyl cellulose film, comprising hydroxy propyl methyl cellulose
plasticised with an organic alcohol, derivative or salt of such an alcohol.
Alcohols according to the present invention include C1-C8 substituted or
unsubstituted, saturated or unsaturated, straight or branched chain
aliphatic alcohols.
Examples of alcohols according to the present invention incJude the
following:
Benzyl alcohol
Ethanol
Propanol
Isopropanol
Butanol, and structural isomers
Pentanol, and structural isomers
Hexanol, and structural tsomers
The above acids and alcohols are readily available commercially, some or
which are approved for pharmaceutical and food use, so some forms of
HPMC film in accordance with the present invention is suitable for and
approved for food and pharmaceutical use. Some HPMC film In
accordance with the present Invention Is suitable for ingestlon by
humans. Some HPMC film in accordance with the present Invention can
thus be used for ingestlble purposes, e.g. as wall material for ingestible
delivery capsules.
The currently preferred acid plasticiser according to the present Invention
is malelc acid, with fumaric acid and then adipic acid being the next most
favoured. In addition, benzyl alcohol has shown favourable characteristics
for particular purposes.
It Is preferred that the plastidser is in the form of an acid or alcohol
rather than a salt of the acid/alcohol, as the non salt form generally has
better plasticising properties, (although salts Including partial salts e.g.
sodium and potassium salts of the acids/alcohols may be used, and in
particular it may be convenient to use buffered casting solutions).
The acids, particularly maleic acid and alcohols, particularly benzyl
alcohol, are also generally found to have good plasticising properties and
to be capable of producing HPMC films with certain benefits and
advantages as compared with HPMC films prepared using conventional
plastlcisers. These benefits and advantages include the following:
a) The film thermoforms very easily at lower temperatures and using
less energy.
b) The deformed film retains Its shape i.e. the film has no memory.
c) The film readily welds to itself and seals at lower temperatures
using less heat and pressure.
d) The film tastes pleasant and has mouth watering effect.
e) The film has a high gloss appearance, Improving the appearance of
the finished product
f) The plastlciser may comprise one or more materials, including one
or more acids/alcohols and/or one or more salts of the
acid/alcohol, possibly in combination with one or more other
plastlcisers such as those In the prior art e.g. polyethylene glycol,
monopropylene glycol, glycerol and acetins.
The plastldser Is suitably present in an amount In the range of 2-40% by
weight of the total weight of the film, typically about 23% by weight of the
total weight of the film. One preferred film thus comprises about 2396
malelc acid and about 77% by weight HPMC. Where a mixture of
plastcisers Is used, benefits may nevertheless be seen using an acid or
alcohol according to the present Invention, particularly maleic acid, at
lower levels, say 5% by weight of the total weight of the film.
The film may Include optional colourings, e.g. In the form of known food
dyes such as FD and C yellow number 5, optional flavourings, artificial
sweeteners, textures etc., in known manner.
The film may optionally be foamed, expanded or gasified, with small
pockets of gas, e.g. air included In the film structure In known manner.
The minimum thickness of single ply unfoamed film, practically, would be
20 microns and the maximum thickness of single pty foamed film,
practically, would be 300 microns.
The film typically has a thickness in the range 50-200 microns, e.g. in
the range 60-130 microns, more preferably 70 - 90 microns, with the
film thickness being controllable In known manner. Films of different
thickness may be suited to different uses.
The film may be made In generally conventional manner, e.g. as
described above, as is well known to those skilled in the art.
Film in accordance with the Invention finds particular use as wall material
for delivery capsules, as discussed above, particularly for ingestible
capsules. Other uses include, as biodegradeable packaging, water soluble
sachets, carrier material for coating flavours (with flavour Incorporated In
the film or In coating on the film) for enrobing tablets etc.
In a further aspect, the invention further provides a delivery capsule
having an enclosing wall comprising hydroxypropyl methyl cellulose film
in accordance with the present invention.
Such delivery capsules may be made in generally conventional manner
e.g. as disclosed In WO 97/35537, WO 00/27367 and WO 01 /03676.
The invention will be further described, by way of illustration, in the
following example.
Example.
A hydroxypropyl methyl cellulose film in accordance with the invention
was made, having the following composition by weight
Hydroxypropyl methyl cellulose 77%
Maleic acid 23%
The film was made in generally conventional manner. HPMC, in the form
of powder, was mixed with maleic acid and water to produce an aqueous
solution with stirring.
The composition of the HPMC casting solution was (%w:w) HPMC 10,
water 87 maleic acid 3. The solution was deaerated by application of a
vacuum.The solution was then fed into a feed hopper, including an
elongate exit slot located a small distance above the upper surface of a
moving conveyor belt to an end thereof, with the slot extending
perpendicularly with respect to the direction of movement of the belt
away from the feed hopper, forming a film. The film was passed on the
belt through a heating zone In which hot air heated the film, driving off
water and so drying the film. The resulting dried cast film was removed
from the belt and wound onto reels. The water content of the dried film
was about 4% by weight, In the form of bound (non-free) water. The
thickness of the dried film was about 120 microns.
The film has certain benefits and advantages as compared with films
prepared using conventional plasticlsers. These include the following:
a) The film thermoforms very easily at lower temperatures and using
less energy.
b) The deformed film retains its shape i.e. the film has no memory.
c) The film readily welds' to itself and seals at lower temperatures
using less heat and pressure.
d) The film tastes pleasant and has mouth watering effect.
e) The film has a high gloss appearance, improving the appearance of
the finished product
The resulting film Is suitable for human consumption, and one use is as a
wall material for ingestible delivery capsules e.g. containing a dose of a
pharmaceutical preparation or a dietary supplement. Such capsules may
be made using known techniques, e.g. as described In WO 97/35537, WO
00/27367 and WO 01 /03676.
We Claim:
1. A hydroxypropyl methyl cellulose film, comprising hydroxypropyl methyl cellulose
plasticised with a plasticiser comprising one or more of adipic acid; fumeric acid; fumaric
acid; maleic acid; ethanoic acid; propanoic acid; alpha hydroxyl butyric acid; mandelic acid;
gamma butyrolactone; gamma valerolactone; beta propriolactone; benzyl alcohol; ethanol;
propanol; isopropanol; butanol; structural isomers of butanol; pentanol; structural isomers of
pentanol; hexanol; structural isomers of hexanol; and/or a salt of any of the preceding acids
or alcohols, wherein the plasticiser is present in the amount in the range of 2 to 40% by
weight of the total weight of the film.
2. A hydroxypropyl methyl cellulose film, comprising hydroxypropyl methyl cellulose
plasticised with a plasticiser comprising one or more of benzyl alcohol; ethanol; propanol;
isopropanol; butanol; structural isomers of butanol; pentanol; structural isomers of pentanol;
hexanol; structural isomers of hexanol; and/or a salt of any of the preceding alcohols.
3. A film as claimed in claim 2, wherein the plasticiser comprises one or more of
maleic acid, fumaric acid, adipic acid, fumeric acid, propionic acid, ethanoic acid, propanoic
acid, alpha hydroxyl butyric acid, mandelic acid, gamma butyrolactone, gamma
valerolactone, and beta propriolactone.
4. A film as claimed in claim 1, wherein the plasticiser comprises one or more of maleic
acid, fumaric acid, and adipic acid.
5. A film as claimed in claim 4, wherein the plasticiser comprises maleic acid.
6. A film as claimed in claim s 1 to 5 wherein the plasticiser comprises benzyl alcohol
7. A film as claimed in claim 1 wherein the plasticiser is present in the amount of 23%
by weight of the total weight of the film.
8. A film as claimed in claim s 5 or 6, comprising about 23% by weight of the plasticiser
and 77% by weight of HPMC.
9. A film as claimed in any one of the preceding claims, wherein the film is foamed,
expanded, or gasified.
10. A film as claimed in any one of the preceding claims, wherein the film has a thickness
of between 50 to 200 microns.
11. A delivery capsule having an enclosing wall comprising a film in accordance with any
one of the preceding claims.
12. A method of producing an HPMC film suitable for forming into a capsule, comprising
treating the HPMC film with acids and/or alcohols mentioned in any preceding claim, before
and/or during when the film is manipulated to form a capsule.
A hydroxypropyl methyl cellulose film comprises hydroxypropyl methyl cellulose plasticised with aplasticiser comprising
an organic acid or a salt of an organic acid, preferably lactic acid, or an alcohol or salt of an alcohol. The film is safe for
human consumption and finds use as a wall material of an ingestible delivery capsule, e.g. containing a dose of a pharmaceutical
preparation.

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Patent Number

223804

Indian Patent Application Number

01815/KOLNP/2004

PG Journal Number

39/2008

Publication Date

26-Sep-2008

Grant Date

23-Sep-2008

Date of Filing

30-Nov-2004

Name of Patentee

BIOPROGRESS TECHNOLOGY INTERNATIONAL INC.

Applicant Address

9055 HUNTCLIFF TRACE, ATLANTA, CA 30350

Inventors:

#	Inventor's Name	Inventor's Address
1	AYERS VICTORIA JANE	72 WEST END, MARCH, CAMBRIDGESHIRE PE15 8QD
2	TECKOE JASON	23 WEST END, ELY, CAMBRIDGESHIRE CB6 3AY
3	NOWAK EDWARD ZBYGNIEW	4 DAVEY CLOSE, IMPINGTON, CAMBRIDGE CB4 9YJ

PCT International Classification Number

C08L 1/28

PCT International Application Number

PCT/GB03/01996

PCT International Filing date

2003-05-12

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0210859.5	2002-05-13	U.K.