DESC:Technical Field
The present invention relates to suppository capsules suitable for rectal, vaginal and urethral administration.

Background of the Invention
Rectal route of administration is a preferred route for pediatric, geriatric and patients having difficulty in taking medication via oral route of administration such as for example cancer patients. Absorption of medication through the rectal route is faster for aqueous and alcoholic solutions and generally there is a quick onset. Administration through rectal route by-pass the first pass metabolism and hence it is helpful for drugs that have a high first pass metabolism. The rectal and vaginal route of administration has been used for local and systemic delivery of medication. Suppositories are solids for insertion into one of the several orifices of the body excluding the mouth. Rectal suppositories are used to deliver various medication including laxatives such as glycerin, analgesics, antipyretics such as acetaminophen and the like. Also, rectal suppository is preferred for drugs that cause gastric irritation and nausea.

Typically, suppositories are made from fats that melt at the temperature of the human body and release the drug that is dispersed or dissolved in it. Generally, suppository is cylindrical, or bullet shaped for convenience to administer into anal canal or vagina. Figure 1 shows a shape of suppository known in the art.

Despite various advantages of the suppository, it suffers from disadvantages such as difficulty in handling, patient discomfort, mucosal irritation, inconsistent and erratic absorption profiles of the drug from the rectum or vagina and/or requirement of low temperatures for storage. The dose of suppository cannot be adjusted as per the patient requirements and it cannot be extemporaneously prepared. Further, manufacture of suppository requires separate equipment that is capital intensive and occupies floor space.

Vaginal suppositories or pessaries are known in the art for delivery of active agents. Typically, vaginal suppositories are molded in the globular or oviform shape or compressed on a tablet press into modified conical shape. Compressed tablets weighing about 3 g are used as vaginal suppositories. The moisture level of vagina is sufficient to allow ready dissolution of a suppository if it is formulated to require minimum water for disintegration. The compressed suppository for vaginal use is usually diamond-shaped to ease insertion and to provide maximum surface area, which facilitates disintegration of the suppository and hastens dispersion of the drug in the vagina. Vaginal suppositories are usually used for local effects, as in the treatment of vaginitis or as a spermatocide. They can also be used for introducing drugs with systemic effects. Coatings have been applied to suppositories to protect them from fast disintegration, to act as lubricants, and to prevent coalescing of adjacent suppositories during storage.

The rectal suppository are available in different shapes such as cone shaped with rounded apex, bullet shaped, or torpedo shaped. It is known in the art that torpedo shaped suppository are the best form of suppositories. However, due to the lack of knowledge of the administration of torpedo shaped suppository with apex foremost or the base foremost, results in the less retention of the suppository in the rectum leading to poor drug delivery. Furthermore, administration of torpedo shaped suppository with apex foremost require pushing the suppository with the finger to the anal canal with a pressure that causes discomfort to patients, particularly to infants and old patients.

Capsules, especially soft capsules have been considered as alternative to the suppository. Soft gelatin suppositories of varying shapes, filled with either liquid or solid mixtures of the drug, are also known for rectal and vaginal use. Soft gelatin capsules are available in various sizes. Figure 2 shows a shape of soft gelatin suppository known in the art. However, the shape of the soft gelatin capsule suppository is similar to the torpedo shaped suppository and hence there occurs a problem of administration and retention of soft gelatin capsule in the rectum after application. In both the cases of torpedo shaped suppository and soft gelatin capsule suppository, the administration of the suppository with the broad end outside the body poses a problem of incomplete closure of the external anal sphincter and requires the patient to be in the lying position for some-time after administration of the suppository causing discomfort. Also, due to the incomplete closure of the external anal sphincter due to the reverse vermicular contraction during administration, there is a high possibility of falling of suppository after administration.

Hard capsule dosage form can be manufactured by filling the capsule shells on a capsule filling machine. The other advantages of the dosage form include ease of handling, extempore preparation and dose adjustment as per the patient requirements. Preparation of formulation with different release profiles such as immediate release, sustained release, extended release, site-specific release is possible with the hard capsule. However, the hard capsules commonly are cylindrical in shape with hemispherical ends and therefore have the problem of administration and retention in the anal canal as that of the suppository and also have an additional problem of opening of the capsule parts during administration. Research in the field of capsule technology, have provided a locking mechanism between the cap and body of the capsule that prevents breaking of capsule. US Patent 5769267 discloses a capsule with having a design that provides protection against reopening and bursting. The capsule is cylindrical in shape with the ends being hemispherical, flattened, box-shaped which makes it not suitable for rectal or vaginal delivery.

Hard capsules with different shapes are known in the art. For example, Pulvules which are known for oral delivery of Prozac. Pulvules have a tapering body and may not be suitable as a suppository as it may pose the problem of retention of the capsule in the anal canal.

There is a need to develop a capsule that facilitates ease of administration via the rectal and vaginal route that provides flexibility of dosing and also helps in retention of capsule in the rectum/vagina without causing discomfort to the patient after administration.

Summary of the Invention
In an aspect, the invention relates to a hard capsule suppository (100) comprising a body (102) having a closed end (104) and an open end (106), a cap (120) having an open end (124) and an arrowhead shaped closed end (122), and a skirt portion (126) below the arrowhead shaped closed end (122) of said cap.

In another aspect, the invention relates to a method for preparation of the hard capsule suppository (100). The method comprises preparing a polymer solution, dipping pins having shape of the body (102) and cap (120) of the hard capsule suppository (100) into the polymer solution; and drying the polymer solution coated on the pins.

Brief Description of the Drawings
Figure 1: shows a shape of a suppository known in the art.
Figure 2: shows a shape of a soft gelatin suppository known in the art.
Figure 3: shows an enlarged view of the hard capsule suppository of the present invention.
Figure 4: shows an enlarged view of the hard capsule suppository body of the present invention.
Figure 5: shows an enlarged view of the hard capsule suppository cap of the present invention.

Detailed description of the Invention
The invention relates to a hard capsule suppository (100) comprising a body (102) having a closed end (104) and an open end (106), a cap (120) having an open end (124) and an arrowhead shaped closed end (122) and a skirt portion (126) below the arrowhead shaped closed end (122) of said cap (120).

The arrowhead shaped closed end (122) of the cap (120) tapers from the open end (124) of the cap (120) to the closed end (122) of the cap (120) at an angle in a range of 60° to 80°. Preferably, the arrowhead shaped closed end (122) of the cap (120) tapers from the open end (124) to the closed end (122) of the cap (120) at an angle in a range of 70° to 75°. The arrowhead shaped closed end of the cap enables the hard capsule suppository (100) to move into the rectum or vagina with ease minimizing the force required to push the capsule into the rectum.

In an embodiment, the cap (120) and the body (102) can have equal length. In another embodiment, the cap (120) can have a shorter length than the body (102).

The diameter of the open end (106) of the body (102) of the hard capsule suppository (100) can be the same or greater than the closed end (104) of the body (102). The closed end (104) of the body (102) of the hard capsule suppository (100) provides a tight closure of the external sphincter of the anus reducing the possibility of expulsion. The closed end (104) of the body (102) of the hard capsule suppository (100) can be flat or grooved.

Figure 4 shows the body (102) of the hard capsule suppository (100) with the flat closed end (104). This enables easy administration of the hard capsule suppository (100) using a finger or an applicator. The closed end (104) can be grooved to enable to hold the capsule on a finger to provide ease of administration.

The skirt portion (126) of the cap (120) has an upper part (125) having a same diameter as that of the open end (124) of the cap (120).

In an embodiment, the arrowhead shape of the cap (120) tapers from the upper part (125) of the skirt (126). The arrowhead shape of the cap (120) tapers from the open end (124) of the cap (120) at a distance of 6.5 mm to 8 mm. Preferably, the arrowhead shape of the cap (120) tapers from the open end (124) of the cap (120) at a distance of 6.5 mm to 8.1 mm. The skirt portion (126) of the cap (120) has a diameter broader than open end (106) of the body (102) of the hard capsule suppository (100). Preferably, the skirt portion (126) of the cap (120) has a diameter of 7.5 to 8 mm and the open end (106) of the body (102) of the hard capsule suppository (100) has a diameter of 7.1 to 7.5 mm. The diameter of the skirt portion (126) of the hard capsule suppository (100) being broader than the arrowhead portion (122) of the cap (120) and the open end (106) of the body (102), retains the hard capsule suppository (100) in the rectum or vagina and prevents falling of the capsule from rectum or vagina. If the hard capsule suppository (100) slips out from the rectum, the skirt portion (126) of the hard capsule suppository (100) being broader than the body (102) of the hard capsule suppository (100) will be held in the rectum by the reverse vermicular contractions of internal and external anal sphincters. Further, the closed end (104) of the body (102) of the hard capsule suppository (100) provides a tight closure of the external sphincter of the anus reducing the possibility of expulsion.

The hard capsule suppository (100) can be made into any desired size such as 000, 00, 0, 1, 2, 3, 4 or 5 to accommodate different doses of drugs. Figure 3 shows a hard capsule suppository (100) of size 0.

In an embodiment, the invention relates to a hard capsule suppository (100) having a locking mechanism to secure the cap (120) with the body (102). As shown in Figure 4, the open end (106) of the body (102) has a lock groove (108) and an air channel (110) for engaging the body (102) with the cap (120).

As shown in Figure 5, the cap (120) comprises an open end (124) for receiving the open end (106) of the body (102), an arrowhead shaped closed end (122) and a skirt portion (126) below said arrowhead shaped closed end (122). The skirt portion (126) of the cap (120) has an outer surface (134) and an inner surface (136). The outer surface (134) of the skirt portion (126) has plurality of circular or oval shaped pre-lock grooves (130) in proximity to the open end (124). A final lock groove (132) is present on the outer surface (134) of the skirt portion (126) and above the said pre-lock grooves (130) extending along the circumference of the cap (120) such that the lock groove (108) of the body (102) and the final lock groove (132) of the cap (120) engages the body (102) with the cap (120).

The arrowhead shaped cap (120) is shorter in length than the body (102). The body taper and body dimensions are such as to accommodate the body (102) into the cap (120) such that an elastic frictional fit is provided in the pre-locked position.

In another embodiment, the invention relates to a hard capsule suppository (100) comprising powders, non-aqueous liquids or semisolids filled in said capsule.

When liquid to be filled is thin (low viscosity), the hard capsule suppository (100) is sealed by applying band across the point where cap (120) and body (102) overlap to avoid leakages. The band seal also serves as tamperproof mechanism. The hard capsule suppository (100) is inserted in rectum or vagina from head or cap side of the suppository capsule so that there is no obstruction at the joint and insertion is smooth. The hard capsule suppository (100) of the present invention can also be heat sealed between the cap (120) and the body (102) region.

Also, the drug can be either physically or chemically bonded with the shell material. This type of hard capsule suppository (100) has the advantage of formulating two or more drugs that are chemically incompatible, also the empty capsule shell serves as a carrier of the drug which can be helpful for local and/or systemic drug delivery.

The hard capsule suppository (100) is filled either on the commercial capsule filling machine or extemporaneously dispensed as per the patient requirement. The commercial capsule filling machine is employed with minor modifications for accommodation of the arrowhead shaped cap and does not require separate equipment for its manufacture as in case with suppository thus saving capital cost and floor space. Unlike suppository and soft capsule suppository, hard capsule suppository (100) is not required to be stored at low temperature.

In an embodiment, the hard capsule suppository (100) has better disintegration than soft gelatin capsules available in the market.

In an embodiment, the formulation of the hard capsule suppository (100) also can advantageously provide a controlled release of drug in comparison to the suppository and soft gelatin capsule. As the shape of the capsule of the present invention helps in retention of the capsule in the anal canal, the controlled release profile reduces the dosing frequency and increases patient compliance to the dosage regimen which further reduces the discomfort caused to the patient.

Thus, the hard capsule suppository (100) of the present invention can be easily administered via rectal or vaginal route with substantial improvement in retention of hard capsule suppository (100) in the rectum/vagina reducing the discomfort caused to the patient after administration. The arrowhead shape of the cap (120) also reduces the force required for administration in the rectal canal and enables the hard capsule suppository (100) to pass through the anal canal with less force of insertion with arrowhead cap (120) foremost. The hard capsule suppository (100) of the present invention provides adjustment of dose of the medicament being filled in the suppository capsule.

The invention also relates to a method for preparation of the hard capsule suppository (100). The method comprises preparing a polymer solution, then dipping pins having shape of the body (102) and cap (120) of hard capsule suppository (100) into the polymer solution and drying the polymer solution coated on the pins.

The polymer for preparation of hard capsule suppository (100) can be selected from natural or synthetic polymers selected from gelatin, polysaccharides, cellulose, pullulan, seaweed extract, maltol extract, galactomannan extract, or combination thereof known in the art for preparing hard capsule.

The polysaccharide can be selected from gellan gum, starch or combination thereof. The cellulose is selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose hydroxyethyl methyl cellulose, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose, cotton cellulose, or combinations thereof. The seaweed extract can be selected from carrageenan, red seaweed, brown seaweed, funoran algae, red algae, brown algae, green algae, kelp, other marine plants, or combinations thereof. The maltol extract can be selected from larch bark, pine needles, chicory and roasted malt, or combinations thereof. The galactomannan extract can be selected from mannan, locust bean gum, carob, carob gum, carob bean gum, guar gum, tragacanth gum, or combinations thereof.

The polymer solution can also include other known additives known required for preparing hard capsules.

The pins are made of stainless steel and have the shape and desired size of the body (102) and cap (120). The hard capsule suppository (100) can be made into any size as desired which includes but is not limited to size 000, 00, 0, 1, 2, 3, 4 or 5.

In an embodiment, the method of preparation comprises, preparing a gelatin sol, HPMC sol or required polymer system of controlled viscosity suitable for making hard capsule suppository (100) and dipping the pins to form caps (120) and bodies (102) simultaneously. The pins are rotated to distribute the sol uniformly during which time gelatin or HPMC or polymer system solidifies or sets or gels by a blast of cool air. The pins are moved through series of controlled air drying kilns for the gradual and precisely controlled removal of water. The cap (120) and body (102) of the hard capsule suppository (100) is removed from the pins and trimmed to length by knives. After being trimmed to exact length, the body (102) and cap (120) sections are joined. Thickness of the wall of hard capsule suppository (100) is controlled by viscosity of the polymer solution and the speed and time of dipping. Other matters critical to the final dimensions are mold pin dimensions, precise drying and machine control relating to cut lengths. Precise control of drying conditions is essential to the ultimate quality of the cast film.

The method is advantageous as there is no manual intervention thereby ensuring product consistency and reproducibility. The method can be easily scaled to large scale production. Unlike the preparation of suppository and soft capsules the method is fast, not messy and can be used with heat sensitive drugs or active ingredients. Also, as the drug can be filled into the hard capsule suppository after its preparation, release of the drug from the capsule suppository is assured unlike suppository where the active may interact with the suppository base and hamper the drug release.

Example
Disintegration Studies
The disintegration time of the hard capsule suppository (100) was compared with that of commercially available soft gelatin capsule suppository, Susten 200 containing progesterone 200 mg. Disintegration is defined as the state in which no residue of the tested dosage form remains on the screen of the apparatus.

Hard capsule suppository (100) of the present invention (green cap and milky white body) was made from gelatin. The arrowhead shaped closed end (122) of the cap (120) tapered from the open end (124) to the closed end (122) at an angle of 72.7°. The arrowhead shape of the cap (120) tapered from the open end (124) of the cap (120) at a distance of 8.1 mm. The capsule size was size ‘0’. The hard capsule suppository (100) was manually filled with 100 mg of drug (indomethacin).

The disintegration of the hard capsule suppository (100) was determined by a disintegration apparatus (THERMONIK, Tablet Disintegration Test Machine, B.P. Standard. (CAMPBEL ELECTRONICS BOMBAY). The disintegration time was determined in distilled water and in phosphate buffer pH 6.8 and 7.2 (prepared as per Indian Pharmacopoeia) to mimic the rectal pH. The test was carried out in 800 ml of media for 90 minutes at the temperature of 37° C ± 0.5°C. Discs were used to keep the capsules submerged in the media.

Table I below shows the results of the disintegration studies.

Table I: Disintegration time of hard capsule suppository (100) and commercially available soft gelatin capsule suppository
Time (min.) Hard gelatin capsule suppository (100) Soft gelatin capsule suppository
pH- 6.8 pH- 7.2 Distilled Water pH- 6.8 pH- 7.2 Distilled Water
0 Without disc-Capsule floated on surface. Without disc- Capsule settled to bottom.
With disc- Capsule stuck to disc. With disc- Capsule stuck to disc
5-20 Without disc:
Capsule remained floating, swelled and softened, and dissolved within 15 mins.

The medium turned greenish and hazy. Without disc: Capsule swelled and softened and was stuck to tube; and dissolved in 20 mins. With and Without disc: Capsule softened to a matrix; stuck to the inner edge of glass tube / disc. Capsule dissolved in 10 mins.

The medium turned greenish and hazy.
Without disc- Capsule softened, rised up and floated in about 10 mins, on medium.

The medium turned hazy.
With disc- Capsule softened and stuck to the disc.

The medium turned hazy.

With disc:
Capsule swelled, softened and stuck to disc. Capsule dissolved in 6 mins.

The medium turned greenish and hazy.

With disc: Capsule softened, and soft capsule mass was stuck to the disc. The capsule dissolved in 10 mins.

The medium turned greenish and hazy.
30-90 Capsule in all the six tubes dissolved completely and medium was hazy greenish. Without disc-Soft capsule mass was floating.

Over a period of time up to 90 mins a creamy mass floating was observed. The medium was hazy.

The mass floated on the medium and media became turbid
With disc- at 90 mins, a flat soft creamy mass was still stuck, the medium was hazy.

As observed from Table I, it can be seen that the hard capsule suppository (100) of the present invention disintegrated and dissolved in 6-20 mins without leaving behind any residue. Thus, the hard capsule suppository (100) passes the disintegration test.

While the soft gelatin capsule suppository did not completely dissolve within 90 minutes of the test. This indicates that the hard capsule suppository (100) had better disintegration than the soft gelatin capsule suppository.

The superior disintegration of the hard capsule suppository (100) is an indication that the capsule would release its contents completely with the rectum (rectal pH is 6.7-7.2) thereby providing higher bioavailability of the drug at the site for absorption. Also, the shape of the hard capsule suppository (100) facilitates easy administration with minimal discomfort. This makes the hard capsule suppository (100) a suitable carrier for local as well as systemic delivery of the drugs.
The foregoing description of the disclosure has been set merely to illustrate the invention and is not intended to be limiting. Since modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to a person skilled in the art, the invention should be construed to include everything within the scope of the disclosure.
,CLAIMS:
1. A hard capsule suppository (100) comprising:
a body (102) having a closed end (104) and an open end (106);
a cap (120) having an open end (124) and an arrowhead shaped closed end (122);
a skirt portion (126) below the arrowhead shaped closed end (122) of said cap.

2. The hard capsule suppository (100) as claimed in claim 1, wherein the arrowhead shaped closed end (122) of the cap (120) tapers from the open end (124) to the closed end (122) of the cap at an angle in a range of 60° to 80°.

3. The hard capsule suppository (100) as claimed in claim 2, wherein the arrowhead shaped closed end (122) of the cap (120) tapers from the open end (124) to the closed end (122) of the cap at an angle in a range of 70° to 75°.

4. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the cap (120) is shorter in length than the body (102).

5. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the open end (106) and closed end (104) of the body (102) has a same diameter.

6. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the open end (106) of the body (102) has a diameter greater than the closed end (104).

7. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the closed end (104) of the body (102) of the capsule (100) is flat or grooved.

8. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the skirt portion (126) of the cap (120) has an upper part (125) having a diameter as that of the open end (124).

9. The hard capsule suppository (100) as claimed in claim 1 wherein the arrowhead shape of the cap (120) tapers from the open end (124) of the cap (120) at a distance of 6.5 mm to 8 mm.

10. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the size of the hard capsule suppository is 000, 00, 0, 1, 2, 3, 4 or 5.

11. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the open end (106) of the body (102) comprises a lock groove (108) and an air channel (110).

12. The hard capsule suppository (100) as claimed in any one of the preceding claims, wherein the skirt portion (126) comprises an outer surface (134) and an inner surface (136); the outer surface (134) comprises plurality of circular or oval shaped pre-lock grooves (130) in proximity to the open end (124); a final lock groove (132) on the outer surface (134) of the skirt portion (126) and above the pre-lock grooves (130) and extending along the circumference of the cap (120).

13. The hard capsule suppository (100) as claimed in any one of the preceding claims comprising powders, non-aqueous liquids or semisolids filled in said capsule.

14. A method for preparation of a hard capsule suppository (100), the method comprising,
preparing a polymer solution;
dipping pins having shape of the body (102) and cap (120) of the hard capsule suppository (100) as claimed in claim 1 into the polymer solution; and
drying the polymer solution coated on the pins.