WO2006043284A1

WO2006043284A1 - A process for manufacturing neutraceutical, pharmaceutical cellulose derivatives capsule

Info

Publication number: WO2006043284A1
Application number: PCT/IN2005/000014
Authority: WO
Inventors: Sunil Mundra; Basanta Kumara Behera
Original assignee: Sunil Mundra; Basanta Kumara Behera
Priority date: 2004-10-21
Filing date: 2005-01-12
Publication date: 2006-04-27

Abstract

The present invention relates to a process for manufacturing neutraceutical pharmaceutical cellulose derivative capsule. In the present invention of manufacturing cellulose derivative capsule the conventional preheating of pins to facilitate gelatin is avoided, which reduces the manufacturing cost. This invention provides a counter flow movement of air in a specially designed enclosure over the pins such that the pins initially encounter relatively humid air and as they dry, they encounter increasingly dry air, which does the drying of capsules. This type of drying ensures the elimination of defects such as wrinkles, starred ends, corrugations, etc. At the end, the capsule bodies and caps are removed, trimmed and joined into prelock position.

Description

A PROCESS FOR MANUFACTURING NEUTRACEUTICAL, PHARMACEUTICAL CELLULOSE DERIVATIVE CAPSULE

FIELD OF TECHNOLOGY

The present invention relates generally to a process used in the manufacture of pharmaceutical capsules. More particularly the present invention relates to a process for manufacturing neutraceutical, pharmaceutical cellulose derivative capsules. The capsule of the present invention in particular is related for the use in drug delivery systems.

DESCRIPTION OF RELATED ART

Capsules presently in general, use for drug delivery inside the body, are made of gelatin and the process and technology involved in manufacturing such capsules is well developed. Hard capsules which are made of gelatin comprise plastisizers such as poly vinyl pyrrolidone, glycerin etc. These capsules have 13 to 15 percent of moisture content. These capsules are very sensitive to temperature, as even slight loss of moisture will make the capsules brittle. After the mad cow disease in Europe, many people are skeptical about consuming gelatin capsules, since gelatin is essentially derived from animal bones. Efforts have since been made for other viable, effective alternatives to satisfy the consumers. In this direction, capsules made of cellulose derivative were invented. In U.S. Patent 5,756,123, which is hereby given as reference, it was claimed that the capsules comprising Hydroxy Propyl Methyl Cellulose (HPMC), Carrageenan and Potassium or Calcium Ions in suitable ratios. In this connection, therefore, compositions of cellulose derivative based capsules are also well known. Gross MaId et al. (1998) developed manufacturing pharmaceutical capsules by using thermo gelling cellulose ether composition. In this process pins are heated pre-dip and post-dip to facilitate gelation. During such process, counter flow air is applied to provide drying from the inside. The main drawbacks of this process are: (a) the machinery used is expensive, (b) the formation of wrinkles, (c) starred ends, (d) corrugations etc., due to improper drying. Yamamotel has made an attempt to provide an alternate and better manufacturing method for the preparation of cellulose, especially HPMC based capsules wherein the above described problems were not completely solved.

Ogura et al. (U.S. Patent 5,264,223 and 5,431 ,917) have helped Shionogi Qualicaps in manufacturing and marketing HPMC capsules as an alternate to gelatin capsules. However, manufacturing of HPMC based capsules by Shionogi Qualicaps was mainly restricted to capsulesize 1 and trials are made on various capsule filling machines. Hofliger and Karg GKF1000, Harro Hofliger KFM1, Shionogi Qualicaps LIQFIL super 80 gave satisfactory results on capsule size 1 at about 36000 to 80000 capsules per hour. The defect rate was about less than 0.001 to 0.03 percent. However, capsule size beyond 1 did not show any satisfactory results for better marketing. Besides this, due to huge cost of the machine and the tedious manufacturing process, the manufacturer was not in a position to supply at a reasonable price to developing countries and even on occasion to developed nations.

SUMMARY OF THE INVENTION

The primary object of this invention is to invent a process for manufacturing neutraceutical, pharmaceutical cellulose derivative capsule which is unique.

It is another object of the invention to invent a process for manufacturing cellulose, preferably HPMC based neutraceutical and pharmaceutical capsules which are totally free from defects such as wrinkles, starred ends, corrugations etc. It is another object of the invention to invent a process for manufacturing neutraceutical and pharmaceutical capsules of any suitable and desired size depending upon the end use. In the present invention of manufacturing cellulose derivative capsule the conventional preheating of pins to facilitate gelatin is avoided, which reduces the manufacturing cost. This invention provides a counter flow movement of air in a specially designed enclosure over the pins such that the pins initially encounter relatively humid air and as they dry, they encounter increasingly dry air, which does the drying of capsules. This type of drying ensures the elimination of defects such as wrinkles, starred ends, corrugations, etc.

Accordingly, the present invention comprises A process of preparing neutraceutical and pharmaceutical capsule, method comprising 78.5 to 96 percent by weight of Hydroxyl Propyl Methyl Cellulose^' (HPMC), 0.04 to 0.7 percent by weight of a gelling agent, preferably carrageenan, most preferably kappa carrageenan, 1 to 8 percent of water, 0.25 to 3.5 percent by weight of cations of first and second group of elements of the periodic table as cooling agent, optionally containing other known agents such as coloring agents and other known fillers characterized in that the said capsule composition is prepared from a novel aqueous HPMC solution prepared by mixing components A and B, as herein described, to obtain clear and shining capsule wherein the preheating step of a conventional process is avoided under controlled moisture levels.

Accordingly, the present invention further comprises a process of manufacturing neutraceutical and pharmaceutical capsules comprising the steps of:

(a) precooling the pin bars in the Precooling section

(b) greasing or oiling the pins in Greasing section

(c) dipping the pins in the novel cellulose solution prepared by mixing the components of A and B in any ratio, preferably in 1 :1 ratio;

(d) drying the coated pin bars wherein the immediate surrounding working areas of the manufacturing machine into different chambers to remove or trap the moisture; (e) positioning the pin bar so the corresponding capsule bodies and caps face each other in Table section;

(f) removing the said capsule bodies and caps from a modified gripper; and

(g) trimming and joining the capsule body and cap into prelock position.

Other advantages and features of the invention will become more clearly apparent from the following description of the embodiments of the invention given as non- restrictive example only and represented in the accompanying drawings.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

Figure 1 illustrates the process of preparation of the capsules using the conventional method (Prior art).

Figure 2 illustrates the method of preparation of the capsules according to the present invention.

Figure 3A illustrates position of the stripper on the pin body just below the capsule as practiced in the prior art.

Figure 3B is the side view of the conventional stripper consisting pivot and a spring.

Figure 4A illustrates the position and the process of removing the capsule according to the present invention.

Figure 4B is the side view of the stripper according to the present invention showing the gripping face and the pivot.

DETAILED DESCRIPTION OF THE INVENTION A preferred embodiment of the present invention will now be explained with reference to the accompanying drawings. It should be understood however that the disclosed embodiment is merely exemplary of the invention, which may be embodied in various forms. The following description and drawings are not to be construed as limiting the invention and numerous specific details are described to provide a thorough understanding of the present invention, as the basis for the claims and as a basis for teaching one skilled in the art how to make and/or use the invention. However in certain instances, well-known or conventional details are not described in order not to unnecessarily obscure the present invention in detail.

A process for manufacturing cellulose, preferably HPMC based neutraceutical and pharmaceutical capsules, has been disclosed here. The capsules of different sizes as known in the art are 0', 00' and 000' being manufactured according the present invention, consists of a capsule body and a capsule cap.

The conventional process for manufacturing the neutraceutical and pharmaceutical capsules is incorporated herein for reference and also to understand the present invention in more vivid manner. In the conventional process the pin bars are preheated in pre-heating section followed by greasing or oiling the preheated pin bars in the greasing section. A cellulose solution is prepared ready for use. However the granular size of HPMC used for making hard capsules by earlier workers (Yamamotel Patents 5,264,223 & 5,431 ,917; Ogura et al., 1998, AAPS 1997) was "0" to "100" mesh. The second drawback was that only Potassium Chloride was used as auxiliary chemical agent for gelation. The hard capsules obtained by such formulation did not give satisfactory result in the high speed-filling machine. This was mainly due to the uneven thickness of capsule film, mainly caused by over size granules of HPMC.

The greased pin bars are dipped into this prepared cellulose solution. It was also known to practice double dipping whenever necessary to maintain the desired thickness of the capsule. The coated pin bars are subjected to spinning in spinning section to achieve the desired shape and size, preferably having uniform thickness throughout the capsule body and capsule cap. Drying of the coated pin bars at specific temperature for specific duration is carried out in the kilns. As shown in figure 1 , the capsules are preferably dried in upper drying kiln first and the second drying process in the lower drying kiln. Elevators transport the capsules among the kilns whenever required. In Table section, the dried pin bars are positioned in such a manner so the capsule bodies and capsule caps face each other. Finally the capsule bodies and capsule caps are removed from the grippers, trimmed and joined together into prelock position (Automatics).

According to the present invention, it is found that by making certain changes in the manufacturing process in the conventional method as explained below, the problems associated with prior art are eliminated. The problems with the prior art as explained earlier are,

(1) Machine not compatible to manufacture capsules of the desired size;

(2) Capsule shell could not be properly dried causing different moisture levels in the shell (quality of the capsules are affected);

(3) Deshaping of the capsules because of use of improper grippers;

(4) Formation of wrinkles, starred ends and corrugations etc., on the surface of the capsule;

(5) Excess manufacturing cost.

In order to practice the present invention there is no need of bringing any major structural amendments in the existing machinery. However few changes as discussed below suffice to sort out the problems of the prior art. According to the present invention, no preheating of pin bars is required for manufacturing neutraceutical and pharmaceutical capsules. Earlier practice related to preheating in the dipper area by Chisholms heated particle method is avoided completely. This eliminates the preheating arrangement of the machinery. Also power is saved which in turn reduces the manufacturing cost. This also helps in maintaining the proper air-conditioning system. Instead the pin bars are pretreated, cooled and the temperature is maintained between 20 to 30 degree Celsius, preferably between 23 to 27 degree Celsius, most preferably at 25 degree Celsius before dipping into cellulose solution.

According to one of the embodiments of the present invention, the capsules are manufactured from an aqueous solution of thermogelling HPMC composition using a newly formulated cellulose auxiliary agent and hardening agent. To get even better results, the newly formulated auxiliary agent and hardener are pretreated and mashed with suitable solvent for developing clearness and shine in the capsule as compared to the capsules manufactured in the conventional manner. In the present invention, HPMC having more than "100" mesh size and less than "1000" mesh size is used as base material for aqueous gel. Besides, according to the present invention, cations of monovalent and or divalent and or trivalent are used for proper formulation. The newly formulated auxiliary salt and or mixture of salts can be used for aqueous solution of thermogelling HPMC composition and can bring perfect stability in any size of HPMC based capsules and can also bring total compatibility in automatic machine, without any alternation of pin size and structure, as the new catalytic auxiliary salt and or mixture of salts can help in overcoming the problem of jamming in the automatic capsule filling machine. In the conventional capsule-making machine, there exists a problem of jamming during filling; the general reasons are attributed to the formation of over size of the capsules or extra thickness of the film at the time of formation and improper heating techniques. According to the practice of the present invention, the conventional jamming problem can be overcome by the use of specially formulated aqueous HPMC solution and drying of the film in desired time as explained herein. The HPMC solution of the present invention is sufficiently viscose to achieve uniform thickness in a single dip of the pin bars. The pin bars taken out from dip gets instantly dried in the prevailing conditions such that the solution does not drop or flow out thereby assuring the uniform thickness for the capsules. The present invention is also related to a novel cellulose auxiliary agent and a process to prepare the same. This is the agent used in preparing the aqueous solution of the HPMC capsules of the present invention. The cellulose auxiliary agent is prepared by mixing the components A and B. The component A is formulated by taking nitrate and or nitrite of alkali metal, preferably potassium solution in the concentration range of 0.01 to 0.75 molar mixed with an oxide of a divalent cation, preferably calcium in a ratio ranging from 0.01 :20 to 20:0.01. An aqueous acidified solution is added to this mixture and a pH is maintained in the range of 0 to 6.5. Generally aqueous citric acid solution is preferred to maintain the pH. The solution is continuously stirred for a period of about 6 hours. The resultant mixture is then filtered through 41 -Whatman filter paper. The residue obtained is kept in an oven and temperature is maintained preferably at 60 degree C for a period of about 6 hours or till such time that the residue is completely dried and gains a constant weight.

Component B is formulated by mixing calcium hydroxide, sodium hydroxide, calcium citrate and potassium bicarbonate in a suitable ratio, preferably in 3:2:10:5 ratio in the presence of distilled water. This is filtered through 41- whatman filter paper and the residue is air dried till a constant weight is obtained.

The components A and B are mixed in any ratio preferably in 1:1 to prepare the cellulose auxiliary agent. The capsule forming agent consists of the cellulose auxiliary agent prepared as above in 0.05 to 0.3 parts by weight and is used in preparing the aqueous solution of the HPMC capsules.

It is necessary to minimise or remove water vapor from the manufacturing surroundings to avoid deforming the capsules made of cellulose more drastically than capsules made of gelatin. A direct stream of air, preferably hot air if passed over the capsules may cause shifting of gel before it becomes firm. Besides passing air over the exterior of the pins may cause wrinkles on the body of the capsule. These wrinkles are formed due to improper drying as both the interior and exterior parts of the capsules are not properly and uniformly exposed for drying. Care is to be taken during drying process so that uniform drying is ensured both within the capsule film and the wall surfaces of the capsule. None of the prior arts provide any effective method for drying the capsules. With continuous efforts, the inventors of the present invention have evolved an effective method of drying that is explained as hereunder. The removal of moisture from different sites of the machine is carried out by dividing the immediate surrounding area of the machine into different chambers and provides by special arrangement for moisture trapping and outlets. Controlling humidity in the immediate surrounding of capsule manufacture sites helps in acquiring rapid firming of the cellulose film and also supports both inside out and outside out drying. A capsule manufacturing machine with the proviso of drying the cellulose film from all the sides by enclosing the immediate surrounding of the said cellulose film and with a provision to control humidity of air surrounding the pins is proved to be energy efficient.

The present invention does not use plates with air blowing directly over the pins, but uses a fully enclosed drying tunnel (kiln) properly insulated with 0 to 60 density ceramic insulation pads. The inner temperature of the kiln is maintained by heating elements (0 - 350 watts) placed directly under the deck of the kiln and radiant elements overhead in the drying tunnel. The temperature inside the kiln is maintained just above the thermal gel point of the base material formulated with mixing HPMC and auxiliary agent including hardening agent for capsule formation. Air for drying is passed through the kiln in counter flow to the direction of the motion of the pins. The foremost purpose of introduction of air inside the kiln is to remove moisture rather than drying the pins. A special type of dehumidifier (Bryair India, 0-5000 CFT) traps the removed moisture. This dehumidifier is used for exhausting of desired amount of moisture from the immediate and or specific sites of capsule manufacturing process.

According to the existing art, the bars are heated at the time of dipping by providing isolated heating elements below the bars and radiant heaters are provided about the bars to allow uniform and specific heating of bars or some part of the bars in order to bring homogeneity in temperature distribution among bars. According to the present invention, the preheating of the Bars is avoided and the drying process of pins includes providing counter flow movement of air through a specially designed enclosure over the pins such that the pins initially encounter relatively humid air and, as they become drier, they encounter increasingly dried air.

In the conventional machine, there is a possibility of damage at the open end of the capsule at the time of removal. According to the present invention, a gripper with raised ridges longitudinal to the axis of the pins or the rows of teeth is proposed for the better or improved grip of the cellulose based capsules of the invention.

Removal of the capsules from the pin mold is one of the most critical exercises, both in hard gelatin and HPMC capsules. The hard gelatin capsules are separated from the pins by a device, generally, known as stripper. The stripper moves over the dipped length to a position beyond the capsule part. It then closes over the necked pin and moves along the length of the pin until it is in perfect touch with the edge of the capsule and subsequently pushes the capsule part off the pin.

Figures 3a and 3b show a prior art stripper, generally used in a Calton type machine in manufacturing gelatin capsules. The stripper body has two parts namely pivot and spring. The main function of these two parts is to give smooth movement to stripper and helps in perfect grabbing of pin, during its movement.

The HPMC based capsules are found to be less rigid than gelatin or earlier cellulose derivative capsules of an equivalent shape, size and wall thickness. Also, it is essential that for perfect release from the pin when contacted by the stripper cheek. The HPMC based capsule has tendency to adhere to the pin while releasing, under stripper pressure the capsule gets deformed and may break also, instead of releasing, smoothly. A further complication in stripping cellulose-based capsules is the relative low moisture content. Whereas moisture can aid capsule removal in the gelatin process, cellulose capsules become soft at even modest moisture levels. Thus stripping must always be accomplished under dry capsule conditions. As with gelatin, dry capsules make capsule removal more difficult. Increasing lubrication to aid stripping also poses problems since the cellulose gel is very prone to movement during and immediately after dip. Excess lubrication, or even lubricants with particularly slippery characteristics, has a tendency to cause uneven capsule walls.

Keeping in view the aforesaid problems the present invention involved in modifying the design of the stripper (Figures 4a and 4b) to grip perfectly the capsule part prior to sliding it off the pin. The stripper has opposed gripping faces having raised ridges or rows of teeth suitably designed (not shown) to grip the capsule surface without any damage. The stripping process is preferably carried out in the temperature range of 20 to 25 degree Celsius, most preferably at 22 degree Celsius.

To summarize, the practice of the present invention is as follows: The pin bars are precooled in the precooling section to about 25 degree Celsius. Greasing or oiling of the cooled pins is done in the Greaser Section. The pins are dipped into the cellulose solution prepared according to the present invention as explained herein above. The coated pins are subject to spinning in the spinning section. Drying is carried out by minimizing or removal of moisture from the surroundings by using the dehumidifier. Pin bars are positioned in Table Section such that the corresponding Capsule bodies and capsule caps face each other. At the end, in automatics section the capsule bodies and caps are removed, trimmed and joined into prelock position. To practice the present invention, the conventional caltron machine also can be used for the manufacturing of different sizes of the capsules.

The above explanation, does not however limit the scope of the present invention as the modifications and or changes which are known to the person skilled in the art which might have not been referred also falls within the scope of the present invention. It will also be obvious to those skilled in the art that other control methods and apparatuses can be derived from the combinations of the various methods and apparatuses of the present invention as taught by the description and the accompanying drawings and these shall also be considered within the scope of the present invention. Further, description of such combinations and variations is therefore omitted above. It should also be noted that the host for storing the applications include but not limited to a computer, printer or a multi function device.

Although the present invention has been fully described in connection with the preferred embodiments thereof with reference to the accompanying drawings, it is to be noted that various changes and modifications are possible and are apparent to those skilled in the art. Such changes and modifications are to be understood as included within the scope of the present invention as defined by the appended claims unless they depart therefrom.

Claims

1. A process of preparing neutraceutical and pharmaceutical capsule, method comprising 78.5 to 96 percent by weight of Hydroxyl Propyl Methyl Cellulose (HPMC), 0.04 to 0.7 percent by weight of a gelling agent, preferably carrageenan, most preferably kappa carrageenan, 1 to 8 percent of water, 0.25 to 3.5 percent by weight of cations of first and second group of elements of the periodic table as cooling agent, optionally containing other known agents such as coloring agents and other known fillers characterized in that the said capsule composition is prepared from a novel aqueous HPMC solution prepared by mixing components A and B, as herein described, to obtain clear and shining capsule wherein the preheating step of a conventional process is avoided under controlled moisture levels.

2. A process of preparing neutraceutical and pharmaceutical capsules comprising the steps of: i. precooling the pin bars in the precooling section at the temperature ranging from 20 to 30 degree Celsius, most preferably at 25 degree

Celsius; ii. greasing or oiling the pins in greasing section; iii. dipping the pins in the novel cellulose solution prepared by mixing the components of A and B in any ratio, preferably in 1:1 ratio; iv. drying the coated pin bars wherein the immediate surrounding working areas of the manufacturing machine into different chambers to remove or trap the moisture; v. positioning the pin bar so the corresponding capsule bodies and caps face each other in table section; vi. removing the said capsule bodies and caps from the pins; and vii. trimming and joining the capsule body and cap into prelock position.

3. A process as claimed in any of the preceding claims wherein the component A is a residue prepared by mixing nitrate and or nitrite salt solution of potassium and calcium oxide in the ratio ranging from 0.01 :20 to 20:0.01 followed by the addition of an acid, preferably citric acid to maintain the pH between 0 and 6.5, stirring the resultant solution for about 6 hours to obtain the residue (component A), filter off the residue and subjected to drying in an oven till a constant weight is obtained.

4. A process as claimed in any of the preceding claims wherein the component B is also a residue, the process for preparation of component B comprises the steps of; i) mixing calcium hydroxide, sodium hydroxide, calcium citrate and potassium bicarbonate in a suitable ratio, preferably in 3:2:10:5 ratio in the distilled water; ii) filtering the solution of the step (i), preferably through 41 Whatman filter paper; iii) washing the residue; and iv) air drying the residue till a constant weight of component B is obtained.

5. A process for the preparation of a novel cellulose auxiliary agent wherein the components A and B prepared as described in the preceding claims are mixed in a desired ratio, preferably in 1:1 ratio.

6. A process for the preparation of a novel HPMC composition used as gelatinizing agent (dipping solution) for the preparation of the capsules, is prepared by mixing the cellulose auxiliary agent, hardening agent and HPMC in a predetermined ratio.

7. A process as claimed in claim 5, wherein the cellulose auxiliary agent is present in 0.05 to 0.3 parts by weight of the final gelatinizing agent.

8. A process as claimed in any of the preceding claims wherein the preheating of pin bars is avoided.

9. A process as claimed in any of the preceding claims wherein the pin bars are cooled before greasing or oiling.

10. A process as claimed in any of the preceding claims wherein the pin bars are cooled to a temperature before dipping such that to ensure the desired thickness for the capsule body and capsule pins.

11. A process as claimed in any of the preceding claims wherein the thickness of capsule body and capsule cap is controlled by regulating the time from dipping the capsules in HPMC base aqueous mixture and the time for subjecting the same to counter current of dry and hot air.

12. A process as claimed in any of the preceding claims wherein counter flow of hot air is passed basically to minimize the moisture level in the surroundings rather than drying the capsule bodies and caps.

13. A process as claimed in any of the preceding claims wherein the removal of moisture from different sites of the machine is carried out by dividing the immediate surrounding area of the capsule manufacturing machine into different chambers and providing means for moisture trapping and removing.

14. A process as claimed in claim 12, wherein the moisture is trapped by a dehumidifier.

15. A process as claimed in claims 11 to 13, wherein the hot air is not blown directly over the pin bars but instead the area is enclosed by drying tunnel (kiln) properly insulated with 0 to 60 density insulation pads, the inner temperature of the kiln is maintained by heating elements (about 350 watts) placed directly under the deck of the kiln and radiant elements overhead in the drying tunnel.

16. A process as claimed in claim 14, wherein the temperature inside the kiln is maintained just above the thermal gel point of the base material formulated with mixing HPMC and auxiliary chemical for gelatin.

17. A process as claimed in any of the preceding claims wherein the drying is carried out such that the moisture level in the capsule film and in the walls of the capsule is maintained at a uniform level.

18. A process as claimed in any of the preceding claims wherein the gripping face of the gripper is provided with raised ridges rather than rows of teeth.

19. A process as claimed in the claim 17 wherein the raised ridges of the gripper are constructed longitudinal to the axis of the pins so as to grip the cellulose based capsule firmly.

20. A process as claimed in any of the preceding claims wherein the possibility of damage to the open end of the capsule is minimized.

21. A process as claimed in the preceding claims wherein the capsule body is removed from the pins at a temperature ranging from 20 to 25 degree Celsius.

22. A process as claimed in the previous claims wherein the temperature is most preferably maintained at 22 degree Celsius.

23. A process for the preparation of neutraceutical and pharmaceutical capsules is substantially as herein described particularly with reference to the accompanying drawings.