DESC:THE FIELD OF THE INVENTION:-

The present invention relates to manufacture hard Hypromellose (HPMC) capsules and method to manufacture the same.

BACKGROUND OF THE INVENTION:-

Capsule is a popular oral dosage form (both solid and liquid) and being used for several years. Gelatin was most popular for several years due to several properties it possesses useful during manufacturing as well as for its end intended use. Gelatin being from animal origin, have objection from some group of people. The other good alternative found was manufacturing capsules with Hypromellose (HPMC).

Hypromellose has many similarities to gelatin however also has some constraints which unable it to use on same gelatin capsule manufacturing machine.

Several attempts were made to manufacture the capsules. The main constraint was it inability to gel at low temperature. People then supplemented this by adding gelling agents in the composition and manufactures good capsules. Several patents are existing for this way of manufacturing capsules Such as US5264223, US5431917, US5756123 from Shinogi, US6410050 from Su-Heung, EP1057862, EP1057862, WO2007020529.

The challenge in using gelling system is its interference during dissolution mainly due to their sensitivity to cations and pH. Also requirement is to avoid additives as much as possible.

OBJECT OF THE PRESENT INVENTION:-

Object of the present invention is to develop a hard hypromellose capsule and process of manufacturing the same.

It is also the object of invention to provide new composition for manufacturing hard HPMC capsules which will have superior quality, solubility, filling machine performance and also ease of manufacturing.

It is also the object of the present invention to eliminate the drawbacks and / or shortfalls of the prior art.

It is also the object of the present invention is to develop a hard hypromellose capsule using its thermo gelling rheological behavior.

STATEMENT OF INVENTION:

Accordingly, the present invention provides a hard hypromellose capsule comprises hypromellose having methoxygroup between 28 to 30% and hydroxypropyl group between 7,6 to 12%, water, colouring agent between 0.1 to 10%, antimicrobial agent between 0.1 to 3 % , surfactant between 0.1 to 3 % but without any film forming agent and gelling system.
Accordingly, the present invention also provides a process for manufacturing of the hard hypromellose capsule comprising the steps of:

(i) Dispersing Hypromellose in hot water;
(ii) adding required additives such as colouring agents, antimicrobial agents, surfactants etc in step (i);
(iii) allowing the said dispersion step (ii) to cool up to 15 deg C and removing foam / bubbles;
(iv) Pouring the aqueous composition of step (iii) in to dipping dish on capsule making machine;
(v) pre heating the pins to temperature of 80 to 110 deg C just before dipping;
(vi) dipping the said preheated pins of step (v) in dipping solution maintained at temperature between 15 to 25 deg C;
(vii) Withdrawing the pins out of solution with a pre defined velocity-time profile and distributing the wet picked mass around pin;
(viii) subjecting the pins with wet material in oven type tunnel with temperature maintained between 110 and 65 deg C till the water content of wet film reduces up to 50%.
(ix) subjecting the film to hot blowing air having temperature between 30 to 45 deg C till the water content of film reduces up to below 8 %.
(x) removing the dried shell from pin, cutting the dried shell to appropriate size and joining both cap and body parts to form a capsule.

DESCRIPTION OF INVENTION:-

According to the present invention, Hypromellose methoxy and hydroxypropyl content are measured as per various major pharmacopeia methods such as IP, USP, BP etc.

According to the present invention, 2% viscosity is expressed as per various major pharmacopeia methods such as IP, USP, BP etc.

Suitable Hypromellose is available commercially with various chemistry grades and with various viscosity ranges. The different viscosity can be blended to get desired mechanical and rheological properties of the same chemistry.

In a preferred embodiment, the composition is exclusively having Hypromellose as film forming polymer and no other film forming polymer is used and / or blended.

In another preferred embodiment of the present invention, the composition does not have any gelling system.

Manufacturing capsules without any gelling system is described in WO2008050209 and US 2014088202. However, there is a restriction of substitution of methoxy group to be within 27 to 30 % and Hydroxypropyl group to be within 4 to 7.5% . There are challenges in manufacturing hard Hypromellose capsules with Hypromellose having substitution beyond this range.

There are definite advantages with Hypromellose when the Hydroxypropyl substitution goes above 7.5 %. The maximum possible available is up to 12%. High Hydroxypropyl content leads to better clarity and transparency to the solution as well as to the dried capsule. It also improves solubility hence dissolution rate.

With rheology terms Hypromellose solution is non Newtonian fluid. Its typical behaviors are Pseudoplastic and Rheopexy. The rheopexy behavior also dominated by the dipping temperatures. At temperatures between 15 to 35 deg C Hypromellose with hydroxypropyl content below 7.5% behaves dominantly rheopectic. However, during same temperature range Hypromellose with hydroxypropyl content between 7.6 to 12% behaves more like Newtonian and does not show rise in viscosity with respect to time. This is critical for manufacturing hard capsules with consistent weight hence dimensions over period of time.
The typical thermogelling behavior of Hypromellose can be measured on any available reputed cone and plate rheometer and using oscillation mode. This measures the storage modulus (G’) and a loss modulus (G’’). Initially loss modulus is high at lower temperatures. As temperature increases storage modulus increases and crosses the loss modulus. This point of intersection is called and gelling point. Typical gelling point of Hypromellose having hydroxypropyl content below 7.5% is between 30 to 40 deg C and with Hypromellose having hydroxypropyl content between 7.6 to 12 % is above 45 deg C. This means that it will require more heat to gel this composition. However, okey for getting uniform dimension capsules with improved solubility.

The another aspect of present invention is to provide process of manufacturing hard Hypromellose capsules for both solid as well as liquid product filling according of dip molding process comprising the steps of-
(i) Dispersing Hypromellose in hot water of temperature above 75 deg C and then cooling it to temperature below 10 deg C to completely solubalise the powder.
(ii) The Hypromellose is of substitution having methoxy content between 28 to 30 % and hydroxypropyl content between 7.6 to 12%. The powder to water ration to be between 15 to 25%. The 2% viscosity range of Hypromellose polymer to be between 4 to 15%
(iii) The aqueous composition above can have processing aids such as surfactant, anti microbial agents, colourants and other processing aids based on requirement between 0.1 to 10%.
(iv) Pins are preheated between 80 to 110 deg C at the time of dipping in to aqueous composition.
(v) The dipping solution temperature is maintained between 15 to 25 deg c.
(vi) The preheated pins are dipped in this aqueous composition and then withdrawn at a pre defined sequence of time and velocity profile.
(vii) The picked up mass is then distributed around pin and set for drying for a pre defined time under temperature initially much above the thermo gelling temperatures.
(viii) The dried shell are then cut to required size and joined on capsule making machine.

The temperatures above in “(iv)” and “(v)” can be varied from mass of the pin being dipped and size of the capsule.

Typically drying step involves many time and temperature profiles. Initially the wet film needs to be subjected only to high temperatures preferably between 55 to 110 deg C in oven like tunnel. Once the wet film moisture lowers from 80 % to 50 %, any other temperature and means of drying can be employed.

Typically there is no new definition is made in capsule its constituents (cap and Body) commonly known dimensions and its volumetric capacities etc.

In a preferred embodiment, the capsule shell contains Hypromellose between 75 to 99%. Preferably between 85 to 95%. More preferably, between 88 to 94% of the shell weight.

In a preferred embodiment, the capsule shell contains water between 2.5 to 9 of the shell weight.

In a preferred embodiment, the capsule shell contains one or more pigments between 0 to 10%, preferably between 0.001 to 6%, more preferably between 0.01% to 5 % of the shell weight.

In a preferred embodiment, the capsule shell contains anti microbial agent between 0 to 10 % preferably between 0.01 to 7% more preferably between 0.01 to 3%.

In a preferred embodiment, the capsule shell contains surfactant between 0 to 10 % preferably between 0.01 to 7% more preferably between 0.01 to 3%.

It is preferred that the hard hypromellose capsules according to the present invention so produced has all identical features such as telescoping, pre locking, locking after filling, venting of air etc.

In another aspect of present invention is, the hard Hypromellose capsules so produced can be used for all kinds of suitable compound filling such as pharmaceuticals, vitamins and nutrients, plant extracts. All can be in solid, liquid or semi solid condition.

In another aspect of present invention is, the hard Hypromellose capsules so produces can be used for applications such as dry powder inhaler.

The present invention will now be described with reference to the examples below:

Example – 1 Preparation of aqueous composition
Aqueous compositions were prepared as follows
Code Hypromellose supplier Chemistry 2% viscosity Methoxy content HP content Powder qty gm Water qty gm
SE Samsung 2910 4.53 28.7 8.3 180 820
SF Samsung 2906 4.56 28.9 6.2 180 820
DE DOW 2910 5.02 29.1 8.8 190 810
DF DOW 2906 4.99 29.5 6.6 190 810

Hypromellose quantity as described above is dispersed in 75 deg C hot water uniformly and as per described quantity. The dispersed slurry is maintained under stirring for 30 mins at same temperature. This is then cooled to 10 deg C till all Hypromellose powder get solubilised. The solution is then observed for clarity and transparency.

Result –
SE and DE solutions were very clear and transparent. SF and DF solutions were cloudy and turbid.

Example – 2 Film clarity and Transparency
Films were casted on ACPL inhouse film coating machine with aqueous composition made as per example 1. 100 micron film was made and dried. Film of 25 x 25 mm is cut and compared visually for clarity and transparency.

Result –
Films of SE and DE were very clear. Films of SF and DF were clear but not transparent.

Example – 3 Study of gel point and maximum viscosity
Small sample of aqueous composition made as per example 1 is tested on Anton Paar rheometer MCR51. The solution is subjected for oscillation mode on 20% strain and angular frequency of 10 rad / sec. Storage modulus and loss modulus were measured and Gel point is estimated by gradually heating solution from 20 to 85 deg C.

Also the viscosity and temperature relationship is measured by subjecting the solution in rotation mode and by heating the solution from 20 to 85 deg C and keeping shear rate at 0.5 sec-1. Onset of gelation and peak viscosity is measured.

Result –
Code Gelation temperature by Oscillation method Onset of gelation temp by Rotation method Peak viscosity by rotation method.
In deg C In deg C In cps
SE 57 58 65000
SF 52 47 115000
DE 58 54 70000
DF 53 46 113000

The gelation point for SE and DE are high as compared to SF and DF. Indicates that the heat required will be high to form shells of SE and DE.

Example – 4 Study of rheopexy behavior
Solutions were prepared as per example 1 of SE and SF only. The solutions were maintained at 20 deg C and 30 deg C and under constant stirring at 200 RPM with Marine propeller and in 1 ltr glass flask kept in constant temperature water bath. Viscosity was measured every 4 hrs on Brookefield viscometer ( LVDV II+ pro) with spindle no S-31 and 100 rpm. The study is done for 24 hrs.

Result –
Time in hrs Solution maintained at 20 deg C Solution maintained at 30 deg C
SE viscosity – cps SF viscosity - cps SE viscosity - cps SF viscosity – cps
0 1900 2200 1900 2180
4 1900 2250 1900 2400
8 1910 2300 1915 3500
12 1920 2350 1915 3800
16 1910 2450 1920 4100
20 1920 2600 1918 4400
24 1915 2675 1930 4700

As can be seen that the viscosity substantially increases for SF solution and very significant at 30 degC. This lead to inconsistent pick up weight hence dimensional non uniformity. The SE solution does not demonstrate rheopectic behavior.

Example – 5 Capsule manufacturing
100 ltr solution was prepared as per SE composition described in example 1 ratios. The capsules were attempted to manufacture as per table below. Capsules were dipped in ACPl’s mini dipping machine and then dried in oven specially made to accommodate the full pin bar.
Code Dipping solution temp in deg C Pin temp in deg C Drying oven temp in deg C Drying time
5-1 15 110 70 60
5-2 20 80 85 45
5-3 22 86 80 40
5-4 22 90 80 40
5-5 22 92 80 40
5-6 27 98 50 50
5-7 32 110 45 50
5-8 35 105 50 70

Results –
Code Capsule formation Drying Defects
5-1 OK but low dome OK Some wrinkles
5-2 Good Good Slight over dried
5-3 Good Good Good capsules
5-4 Good Good Good capsules
5-5 Good Good Good but high weight
5-6 Good Wet capsules Required extra drying + defects
5-7 High weight Wet capsules Required extra drying + defects
5-8 High weight Wet capsules Required extra drying + defects

As can be seen that by properly selecting solution temperature, pin temperature , drying temperature and time, Good capsules can be manufactured with Hypromellose of methoxy content between 28-30% and hydroxypropyl content between 7.6 to 12%.

Example – 6 Disolution test at 0.1 N HCL buffer and 6.8 Mixed phosphate buffer.
Capsules were produced with gelling agent for comparison as follows
950 gm of Hypromellose ( E chemistry) is dispersed in 4050 gm of hot water. 4.3 gm of potassium chloride is added in it. 8.0 gm of K-carrageenan is also added in the solution. The solution is cooled up to 35 deg C. The solution is stirred till complete solution is formed. The solution is then heated to 45 deg C and capsules were produced on ACPL’s mini dipping machine.

Capsules produced as per 5-4 above were also taken for in Vitro dissolution testing. Dissolution test is done at 0.1 N HCL buffer and 6.8 pH mixed phosphate buffer. The test is carried as per USP monograph described method. The product filled was Acetaminophen.

Result-
Percentage drug release is as follows
Time in min 0.1 N HCL buffer 6.8 pH phosphate buffer
Innovation sample Control sample Innovation sample Control sample
0 0 0 0 0
10 80 70 80 10
20 90 85 90 20
30 95 95 95 25
40 95 95 95 30
50 - - - 40
60 - - - 48

As can be seen the innovation sample behaves same in both media. However control sample made with gelling agent works well in 0.1 N HCL buffer however does not comply in 6.8 pH Phosphate buffer.

DETAILS OF THE INVENTION:-

A hard capsule shell consists of Hypromellose , Water, Colouring agent, Antimicrobial agent, Surfactant but without any other film forming agent and gelling system. The Hypromellose is between 85 to 94%. The said Hypromellose having methoxy group between 28 to 30% and Hydroxypropyl group between 7.6 to 12%. The said Hypromellose has 2 % viscosity range between 4.5 to 15 cps when measured at 20 deg C. The said colouring agent between 0.1 to 10%. The said coloring agent is selected from the group comprising annatto, carotene, chlorophyll, cochineal, curcumin, red iron oxide, yellow iron oxide, titanium oxide, black iron oxide, caramel, riboflavin, quinazarine green, alizarin cyanine green, fast green, tartrazine, sunset yellow, quinoline yellow, erythrosine, eosin YS, toney red, ponceau 4R, carmoisine, indigo carmine, brilliant blue, orange G, resorcin brown, naphthol blue black, allura red, lakes salts of above water soluble colours and various possible combinations thereof. The said antimicrobial agent is between 0.1 to 3 %. The said surfactant is between 0.1 to 3 %.

The process of manufacturing capsule shell is as follows
(i) Dispersing Hypromellose in hot water
(ii) Adding required additives such as colouring agents, antimicrobial agents, surfactants etc.
(iii) Allowing the said dispersion to cool up to 15 deg C and remove foam / bubbles.
(iv) Pour the above composition in to dipping dish on capsule making machine.
(v) Pre heating the pins to temperature 80 to 110 deg C just before dipping.
(vi) Dipping the said preheated pins in dipping solution maintained between 15 to 25 deg C
(vii) Withdrawing the pins out of solution with a pre defined velocity-time profile. Distributing the wet picked mass around pin.
(viii) Subjecting the pins with wet material in oven type tunnel with temperatures between 110 and 65 deg C till the water content of wet film reduces to 50%.
(ix) Subject the film to hot blowing air having temperature between 30 to 45 deg C till the water content of film reduces to below 8 %.
(x) Remove the dried shell from pin , cut to appropriate size and join both cap and body parts
,CLAIMS:1. A hard hypromellose capsule comprises hypromellose having methoxygroup between 28 to 30% and hydroxypropyl group between 7,6 to 12%, water, colouring agent between 0.1 to 10%, antimicrobial agent between 0.1 to 10 % , surfactant between 0 to 10 % but without any film forming agent and gelling system of shell weight.
2. The capsule as claimed in 1 wherein colouring agent preferably between 0.001 to 6% or more preferably 01 to 5%, antimicrobial agent, preferably between 0.1 to 7 % or more preferably 0.01 to 3%, surfactant between, preferably 0.1 to 7 % or more preferably 0.01 to 3% of shell weight.
3. The capsule as claimed in claims 1 and 2 wherein the said colouring agent selected from the group comprising annatto, carotene, chlorophyll, cochineal, curcumin, red iron oxide, yellow iron oxide, titanium oxide, black iron oxide, caramel, riboflavin, quinazarine green, alizarin cyanine green, fast green, tartrazine, sunset yellow, quinoline yellow, erythrosine, eosin YS, toney red, ponceau 4R, carmoisine, indigo carmine, brilliant blue, orange G, resorcin brown, naphthol blue black, allura red, lakes salts of above water soluble colours and various possible combinations thereof.
4. The capsule as claimed in claims 1 to 3 wherein the capsule shell contains Hypromellose between 75 to 99% of shell weight.
5. The capsule as claimed in claim 4 wherein the said capsule shell contains hypromellose, preferably, between 85 to 95%, or more preferably, between 88 to 94% of the shell weight.
6. The capsule as claimed in claims 1 to 5 wherein the said capsule shell contains water between 2.5 to 9 of the shell weight.
7. A process for manufacturing of the hard hypromellose capsule of claims 1 to 6 comprises steps:
(i) Dispersing Hypromellose in hot water;
(ii) adding required additives such as colouring agents, antimicrobial agents, surfactants etc in step (i);
(iii) allowing the said dispersion step (ii) to cool up to 15 deg C and removing foam / bubbles;
(iv) Pouring the aqueous composition of step (iii) in to dipping dish on capsule making machine;
(v) pre heating the pins to temperature of 80 to 110 deg C just before dipping;
(vi) dipping the said preheated pins of step (v) in dipping solution maintained at temperature between 15 to 25 deg C;
(vii) Withdrawing the pins out of solution with a pre defined velocity-time profile and distributing the wet picked mass around pin;
(viii) subjecting the pins with wet material in oven type tunnel with temperature maintained between 110 and 65 deg C till the water content of wet film reduces up to 50%.
(ix) subjecting the film to hot blowing air having temperature between 30 to 45 deg C till the water content of film reduces up to below 8 %.
(x) removing the dried shell from pin, cutting the dried shell to appropriate size and joining both cap and body parts to form a capsule.

8. The process as claimed in claim 7 wherein the said hot water temperature is above 750.
9. The process as claimed in claims 3 and 4 wherein the said powder to water ratio is 15 to 25%.
10. The process as claimed in claims 3 to 5 wherein viscosity of said hypromellose polymer is 2%