HARD CAPSULE FORMULA

Description

Technical Field

[0001] The present disclosure is related to a hard capsule formulation.Background

[0002] As a means for delivering a pharmaceutical agent to the intestine without the agent disintegrating in the stomach, a method has been known of applying an enteric coating ontoa coating film (i.e. onto the shell) of a hard capsule.

[0003] Recently, a hard capsule in which the film (outer shell film) itself of the hard capsule is acid-resistant has been developed and sold (for example, "DRCAPS ™< " from Capsugel). Such hard capsules are superior in that a further enteric coating does not necessarily have to be applied onto the coating film (outer shell) of the capsule.

[0004] These kinds of hard capsules having acid resistance are useful because the shelldoes not normally dissolve even in an acidic solution having a pH of 1.2 (in other words,because the hard capsule does not disintegrate in the stomach of a living organism). In particular, when filling a hard capsule with a substance such as a pharmaceutical agent or the like for which no problems would occur as long as the hard capsule does not disintegrate in the stomach (for example, garlic and the like which may cause a return smell), the anticipated effects can be achieved with no remarkable problems.

[0005] However, upon careful examination of hard capsule formulations, including hard capsules with acid resistance that do not achieve sufficient effects, the present inventors made the surprising discovery that even if the hard capsule does not disintegrate in the stomach, gastric acid may gradually penetrate through the hard capsule outer shell over time because the shell itself of the hard capsule is not waterproof. As a result, the present inventors discovered that, since a substance such as a pharmaceutical agent or the like that is filled within a hard capsule makes contact with an acid (gastric acid), the anticipated effects cannot be achieved when filling a hard capsule with a substance such as a pharmaceutical agent or the like (for example, proteins (royal jelly, milk proteins, etc.), enzymes (nattokinase (source Bacillus subtilis var.natto), coenzymes, etc.), and viable bacteria (lactic acid bacteria, bifidobacteria, etc.) whose components deteriorate (change, decompose, or die) upon contact with an acid.

[0006] WO 2007 / 098612 A1 relates to gelatin compositions with covalent attachments forming functionalized gelatin. The functional groups in the gelatin backbone confer a buffer capacity and resistance of said gelatin to gastric acid.

[0007] US Patent No. 5,849,327 relates to pharmaceutical compositions with polymeric beads and polysaccharides, where the dosage form has an enteric coating. WO 96 / 17599 A1 describes a coating for a drug or capsule wherein said coating is formed at least partly from seaweed and / or kelp extracts which is impervious to gastric acidity but denatures in the intestine. US 2007 / 148248 A1 is directed to film-forming compositions comprising a gastric resistant natural polymer, a film-forming natural polymer, and optionally a gelling agent. The film-forming composition is suitable for preparing soft or hard shell gelatin capsules. US 4601896 A describes capsules formed by a composition comprising a substantially homogeneous and gastric-fluid impervious composition. Collagen and / or elastin combined with procollagen are the basic components used in the preferred gastric protective coatings described in US 4601896A. WO 2013 / 067483 A1, published on May 10, 2013, discloses a hard capsule formulation of a hard capsule with acid resistance comprising magnesium stearate and a swelling agent.

[0008] United States Patent Application, Publication No. 2012 / 0288562 A1 assigned toCapsugel Belgium NV relates to acid resistant capsules.Summary

[0009] The scope of the invention is defined by the claims appended hereto.

[0010] Considering the above-described problems, an objective of the present disclosure is to create a hard capsule formulation that includes a pharmaceutical agent or the like whose components would deteriorate upon contact with an acid, in which the pharmaceutical agent or the like does not deteriorate due to gastric acid penetrating intothe outer shell of the hard capsule.

[0011] As a result of keen examination over a long period of time, the present inventors discovered that the above-mentioned problem could be solved by developing a hard capsule formulation having the features described below.

[0012] The hard capsule formulation of the present disclosure includes a hard capsule with acid resistance, wherein the hard capsule is not treated with an enteric coating and the hard capsule formulation includes an agent to inhibit invasion of gastric fluid and a pharmaceutical agent in the hard capsule, said agent being a water repellent agent selected from the group consisting of calcium stearate, magnesium stearate, and carnaubawax.

[0013] The agent to inhibit invasion of gastric fluid is an agent that contributes to substantially (completely, or partially) prevent an acidic solution (gastric fluid in a living organism) from invading into the hard capsule through the outer shell of the hard capsule and infiltrating into the materials filled within the hard capsule.

[0014] In one example, the agent to inhibit invasion of gastric fluid is a gelling agent and / or a water repellent agent. In other words, both a gelling agent and a water repellent agent can also be used. These agents are believed to contribute to the inhibitory effect through different mechanisms, and using both a gelling agent and a water repellent agent is thought to be even more useful. The gelling agent is believed to contribute to preventing an acidic solution (gastric fluid in a living organism) from infiltrating into the materials filled within the hard capsule by swelling. In contrast, the water repellent agent is believed to contribute to preventing an acidic solution (gastric fluid in a living organism) from infiltrating by the water repellent action thereof.

[0015] In one example of the hard capsule formulation, the gelling agent can be included as a powder. Such a gelling agent can be preferably selected from the group consisting of guar gum, pectin, (iota) type carrageenan, λ (lambda) type carrageenan, xanthan gum, locust bean gum, alginate, alginic acid, tamarind gum, glucomannan, agar,curdlan, gellan gum, and collagen. Such a gelling agent can be more preferably selected from the group consisting of guar gum, λ (lambda) type carrageenan, xanthan gum, andlocust bean gum.

[0016] In one example of the hard capsule formulation, the water repellent agent can be included as a powder. Such a water repellent agent can be preferably selected from the group consisting of calcium stearate, magnesium stearate, and carnauba wax.

[0017] In one example, the hard capsule formulation includes a pharmaceutical agent. In order to most effectively utilize the technology of the hard capsule formulation of the present disclosure, a pharmaceutical agent whose components deteriorate (change / decompose / die) upon contact with an acid can be used. Such pharmaceutical agents include, for example, proteins (royal jelly, milk proteins, etc.), enzymes (nattokinase (source Bacillus subtilis var.natto), coenzymes, etc.), and viable bacteria (lactic acid bacteria, bifidobacteria, etc.).

[0018] In the hard capsule formulation of the present disclosure, the amount of the gelling agent and water repellent agent to be used is not particularly limited. Under given conditions (the pharmaceutical agent(s), excipient(s), hard capsule, the capacities thereof, etc.), the gelling agent and water repellent agent can be included in an amount at which theeffect thereof is demonstrated at an anticipated level. For example, on a weight basis, the amount of the gelling agent and water repellent agent can be 25% or less, preferably 20% or less, more preferably 10% or less, and even more preferably 9% or less of the total weight of the materials filled within the hard capsule.

[0019] The hard capsule formulation disclosed herein can be used for any purpose as long as it is appropriate, but in particular, it can be used as a capsule for medical or health foodapplications.

[0020] The hard capsule to be used in the hard capsule formulation of the present disclosure can be manufactured by a method known to those skilled in the art, and a commercially available hard capsule can be also used. Any material can be used for the hard capsule, and among such materials, gelatin, hydroxypropyl methyl cellulose, and pullulan are preferable. The hard capsule can be manufactured by a method in which a molding pin is immersed into an aqueous solution (gel) in which the material of the hard capsule (and a gelling agent and / or a gelling adjuvant as desired) has been dissolved and then the molding pin is pulled out, and the hard capsule material is then gelled and dried.

[0021] Plasticizers, preservatives, dispersing agents, and other additives for improving the production of the hard capsule are known, and their appropriate use in the capsule of the present disclosure is within the scope of modifications that can be anticipated from those skilled in the art.

[0022] In one example, the hard capsule formulation of the present disclosure includes a hard capsule, and an agent to inhibit invasion of gastric fluid and a pharmaceutical agent in the hard capsule. Herein, the hard capsule can be subjected to application of an enteric coating onto a coating film (i.e. an outer shell) of the hard capsule. However, in order to most effectively utilize the technology of the hard capsule formulation of the present disclosure, a hard capsule in which an enteric coating is not applied onto the outer shell ofthe hard capsule is preferably used. Further, in order to most effectively utilize the technology of the hard capsule formulation of the present disclosure, the hard capsule is preferably acid-resistant. Herein, acid resistance implies a property in which the hard capsule does not substantially dissolve (disintegrate) due to gastric fluid in a living organism (stomach). It is preferable that the hard capsule does not dissolve in the stomach but does dissolve in the intestine. Such a hard capsule with acid resistance is commercially available (for example, DRCAPS ™< from Capsugel). In one example, the agent to inhibit invasion of gastric fluid can be selected from the group consisting of guar gum, λ (lambda) type carrageenan, xanthan gum, locust bean gum, calcium stearate, magnesium stearate, and carnauba wax.

[0023] The scope of the present disclosure also includes arbitrary combinations of one or a plurality of the features described above.

[0024] In one example, a hard capsule formulation includes a pharmaceutical agent orthe like whose components deteriorate upon contact with an acid in a hard capsule, in which the pharmaceutical agent or the like can be prevented from deteriorating due togastric fluid that penetrates into the hard capsule shell.Brief Description of Drawings

[0025] FIG. 1 is a photograph of a cross-section of a hard capsule filled with only lactose. FIG. 2A is a photograph of a cross-section of a hard capsule filled with a mixed powder in which pectin ("GENU Pectin DD slow set-J" from Sansho Co., Ltd.) is mixed with lactose such that the pectin is 10% by weight relative to the lactose. FIG. 2B is a photograph of a cross-section of a hard capsule filled with a mixed powder in which pectin ("GENU Pectin DD slow set-J" from Sansho Co., Ltd.) is mixed with lactose such that the pectin is 25% by weight relative to the lactose. FIG. 2C is a photograph of a cross-section of a hard capsule filled with a mixed powder in which guar gum is mixed with lactose such that the guar gum is 10% by weight relative to the lactose. FIG. 2D is a photograph of a cross-section of a hard capsule filled with a mixed powder in which guar gum is mixed with lactose such that the guar gum is 25% by weight relative to the lactose. FIG. 2E is a photograph of a cross-section of a hard capsule filled with a mixed powder in which λ (lambda) type carrageenan is mixed with lactose such that the λ (lambda) type carrageenan is 10% by weight relative to the lactose. FIG. 2F is a photograph of a cross-section of a hard capsule filled with a mixed powder in which λ (lambda) type carrageenan is mixed with lactose such that the λ (lambda) type carrageenan is 25% by weight relative to the lactose. FIG. 3 is a photograph of a cross-section of a hard capsule filled with a mixed powder in which alginic acid is mixed with lactose such that the alginic acid is 10% by weight relative to the lactose. FIG. 4 is a schematic diagram of Example 1 and Example 2. Description

[0026] The terms used in the present specification are not intended to limit the present disclosure.

[0027] The term "include" as used in the present specification is intended to mean that the matters as described (members, steps, elements, or numbers, etc.) exist except when another understanding thereof is explicit from the context, and such terms do not exclude the existence of other matters (members, steps, elements, numbers, etc.).

[0028] Unless a different definition is given, all of the terms used herein (including technical terms and scientific terms) have the same meaning as those widely understood by those skilled in the art in the technical field to which the present disclosure belongs. Unless a different definition is explicitly given, the terms used herein should be interpreted with a meaning that is consistent with the meaning in the present specification and the related technical field, and they should not be idealized or interpreted with an excessively formal meaning.

[0029] Some of the examples of the present disclosure may be explained referring to schematic diagrams, but the schematic diagrams may be exaggerated in order to clearly explain such examples.

[0030] The present disclosure will now be explained in further detail below referring to examples.

[0031] However, the present disclosure should not be construed as limited to the examples described herein.Examples Example 1

[0032] Each of the powders in Table 1, which are food additives or pharmaceutical additives, was filled without mixing with any other powder into a divided body part of an acid-resistant hard capsule from Capsugel (DRCAPS ™< , Size 1, colorless and transparent) up to an opening end surface of the body. Next, 100 µl of Japanese Pharmacopeia, First Solution (pH 1.2 solution) colored with Blue No. 1 was dropped thereon, and the penetrance (%) after 60 minutes was measured (refer to FIG. 4).

[0033] Penetrance is defined by the distance that the blue-colored solution penetrated relative to the body length (16.6 mm). In other words, if the blue-colored solution penetrated 4.15 mm, then the penetrance would be 25% (upon rounding up or down). If the penetrancewas smaller, this means that the penetration of an acidic solution was more largely inhibited (in terms of within a living organism, it means that the penetration of gastric fluid was morelargely inhibited).

[0034] In the present example, the penetrance was evaluated based on the followingstandards: Excellent: 10% or less Good: 11 % or more to 20% or less Acceptable: 21 % or more to 50% or less Unsuitable: 51 % or more

[0035] The powders used in the present example were gelling agents (also referred to asgelling agent powders when appropriate; gelling adjuvants were not used) and water repellent agents (also referred to as water repellent powders when appropriate). Normalexcipients were used as the comparative examples.

[0036] The results are shown in Table 1 TABLE 1 Test PowderProduct NamePenetrance (%)EvaluationGelling AgentspectinUNIPECTINE 400 from Unitec Foods Co., Ltd.8ExcellentpectinUNIPECTINE 3555 from Unitec Foods Co., Ltd..18GoodpectinGENU Pectin DF-2-J from Sansho Co., Ltd.10ExcellentpectinGENU Pectin LM-1 04AS-J from Sansho Co., Ltd.13GoodpectinGENU Pectin LM-104AS-FS-J from Sansho Co., Ltd.15GoodpectinGENU Pectin LM-102AS-J from Sansho Co., Ltd.17GoodpectinGENU Pectin BB rapid set-J from Sansho Co., Ltd.5ExcellentpectinGENU Pectin DD slow set-J from Sansho Co., Ltd.5Excellentxanthan gumInagel ASP Xanthan from Ina Food Industry, Co., Ltd.13Goodxanthan gumEchogum T / Keltrol T from DSP Gokyo Food & Chemical Co., Ltd..10Excellentxanthan gumVis Top D-3000-C from San-Ei Gen F.F.I., Inc.12Goodlocust bean gumLocust Bean Gum F from San-Ei Gen F.F.I., Inc.14Goodlocust bean gumMEYPRO-LBGFLEURM-175 from Sansho Co., Ltd.15Goodlocust bean gumGENU GUM RL-200-J from Sansho Co., Ltd.12Goodtamarind gumGlyloid 6C from DSP Gokyo Food & Chemical Co., Ltd..8ExcellentglucomannanRheolex RS from Shimizu Chemical Corp.10ExcellentglucomannanPropol A from Shimizu Chemical Corp.31Acceptableguar gumKT-0104 from DSP Gokyo Food & Chemical Co., Ltd..aExcellentcurdlanCurdlan from Takeda-Kirin Foods Corp.19GoodGelling Agentsgellan gumKelcogel from Sansho Co., Ltd.18Goodporcine collagenCollagel A from Gelita8Excellentκ (kappa) type carrageenanGelcarin GP812NF from FMC15Good (iota) type carrageenanGelcarin GP379NF from FMC15Goodsodium polyacrylatePanakayaku CP from Nippon Shokubai Co., Ltd.12GoodComparative Examplescorn starchNisshoku Corn Starch W from San-Ei Gen F.F.I., Inc.56Unsuitablecrystalline celluloseCrystalline Cellulose FD301 from Asahi Kasei Chemicals Corp.53UnsuitableWater Repellent Agentscalcium stearateTaiyo Chemical Industry Co., Ltd.4Excellentmagnesium stearateTaiyo Chemical Industry Co., Ltd.2Excellentcarnauba waxFreund Corp.3ExcellentComparative ExamplescyclodextrinCeldex B-100 from Nihon Shokuhin Kako Co., Ltd.52UnsuitablelactoseKanto Chemical Co., Inc.100Unsuitable

[0037] As shown in Table 1, it is clear that penetration of the acidic solution was very remarkably inhibited when using a gelling agent or a water repellent agent compared to the comparative examples (normal excipients). The penetrance in the case of lactose, which was one comparative example, was 100%. This means that the acidic solution penetratedthe entire body length (16.6 mm).Example 2

[0038] The penetrance was measured according to the same method as in Example 1 upon mixing 10%, 25%, and 50% by weight of a certain powder (gelling agent or water repellent agent) into lactose which is popular for an excipient of a capsule (in Example 1, thepenetrance in the case of lactose was 100%).

[0039] in this example, the penetrance was evaluated based on the following standards: Rank AA: penetrance of 10% or less for a 10% mixtureRank A: penetrance of 10% or less for a 25% mixture Rank B: penetrance of 15% or less for a 25% mixture Rank C: penetrance of 50% or less for a 25% mixtureRank Unsuitable: anything other than the above

[0040] The results are shown in Table 2. TABLE 2Test PowderProduct Name% Mixed into LactosePenetrance (%)EvaluationpectinUNIPECTINE 400 from Unitec Foods Co., Ltd.1028B25115012pectinUTFC LM QS 400C from Unitec Foods Co., Ltd.10B25135011pectinGENU Pectin BB rapid set-J from Sansho Co., Lid.1012A259507pectinGENU Pectin DD slow set-J from Sansho Co., Ltd.1010AA257508xanthan gumEchogum T / Keltrol T from DSP Gokyo Food 8 Chemical Co., Ltd.,1019A256506xanthan gumVis Top D-3000-C from San-Ei Gen F.F.I., Inc.1023A258507locust bean gumGENU GUM RL-200-J from Sansho Co., Ltd.1025A259509tamarind gumGlytoid 6C from DSP Gokyo Food & Chemical Co., Ltd.,1016B2513506glutomannanRheolex RS from Shimizu Chemical Corp.1016B2514508guar gumKT-0104 from DSP Gokyo Food & . Chemical Co., Ltd.1010AA2595010aiginic acidDuck Acid from Kbun Food Chemifa Co,. Ltd,1059C25355029aiginic acidSnow Acid Algin G from Fuji Chemical Industry Co., Ltd.1047C25345027 (iota) type carrageenanGelcarin GP379NF from FMC1023B25155013λ (lambda) type carrageenanViscarin GP209NF from FMC108AA257508magnesium stearateTaiyo Chemical Industry Co., Ltd.1073B2514503

[0041] As shown in Table 2, it is clear that penetration of the acidic solution was very remarkably inhibited when using a gelling agent or a water repellent agent. When using only lactose (excipient) in the comparative example, the penetrance was 100% as is clear from Example 1. The results exhibited when using alginic acid were mediocre (anevaluation of "C").

[0042] As shown in Table 2, guar gum, λ (lambda) type carrageenan, and pectin (GENU Pectin DD slow set-J from Sansho Co., Ltd.) received a rank of AA. Xanthan gum and locust bean gum received a rank of A. Magnesium stearate, tamarind gum, glucomannan, and (iota) type carrageenan received a rank of B. Alginic acid received a rank of C.Comparative Example 3

[0043] Mixed powders were prepared by mixing into lactose 10% and 25% by weight of the three powders that were evaluated as Rank AA in Example 2 (i.e., guar gum, λ (lambda) type carrageenan, and pectin (GENU Pectin DD slow set-J from Sansho Co., Ltd.)), relative to the lactose. These mixed powders were filled into an acid-resistant hard capsule from Capsugel (DRCAPS ™< , Size 1, colorless and transparent). Similarly, mixed powders were prepared by mixing into lactose 10% by weight of the powder that was evaluated as Rank Cin Example 2 (alginic acid). This mixed powder was filled into the same type of hard capsule. Further, a comparative example was prepared by filling only lactose into the same type of hard capsule.

[0044] These filled hard capsules prepared above were immersed for two hours in a pH 1.2solution (Japanese Pharmacopeia, First Solution) colored with Blue No. 1 at 37°C and subsequently removed. The hard capsules were then cut in half in the longitudinal axis direction with a sharp scalpel to expose a cross-section thereof. The hard capsules wereexamined to observe how the blue-colored acidic solution penetrated through the hard capsule outer shell into the capsule contents and the extent of penetration (or in other words, whether or not penetration was inhibited).

[0045] Photographs of the cross-sections are shown in FIGS. 1, 2, and 3.

[0046] FIG. 1 is a photograph of a cross-section of a hard capsule filled with only lactose. As shown in this figure, when the hard capsule was filled with only lactose, the blue-colored acidic solution penetrated deep within the hard capsule, and extensive contact between thefilled powder and the acidic solution occurred.

[0047] FIGS. 2A-2F show photographs of cross-sections of hard capsules filled with mixed powders in which guar gum, λ (lambda) type carrageenan, or pectin (GENU Pectin DD slow set-J from Sansho Co., Ltd.) is mixed with lactose such that the guar gum, λ (lambda) type carrageenan, or pectin is 10% or 25% by weight relative to the lactose. As shown in these figures, even when only 10% of these powders were included, the blue-colored acidic solution surprisingly penetrated only close to the shell of the hard capsules. Further, the majority of the interior of the hard capsules was dry, and contact between the filled powder and the acidic solution was largely blocked (inhibited).

[0048] FIG. 3 is a photograph of a cross-section of a hard capsule filled with a mixed powder in which alginic acid is mixed with lactose such that the alginic acid is 10% by weight relative to the lactose. In this case, contact between the filled powder and the acidicsolution was blocked (inhibited) to some degree.Comparative Example 4

[0049] Mixed powders were prepared by mixing into lactose 10% and 25% by weight of the three powders that were evaluated as Rank AA in Example 2 (i.e., guar gum, λ (lambda) type carrageenan, and pectin (GENU Pectin DD slow set-J from Sansho Co., Ltd.)), relativeto the lactose. These mixed powders were filled into an acid-resistant hard capsule from Capsugel (DRCAPS ™< , Size 1, colorless and transparent). Further, a comparative example was prepared by filling only lactose into the same type of hard capsule.

[0050] These filled hard capsules prepared above were immersed for two hours in a pH 1.2 solution (Japanese Pharmacopeia, First Solution) at 37CC (in contrast to Example 3, the solution was not colored with Blue No. 1) and subsequently removed. The hard capsules were then cut in half in the longitudinal axis direction with a sharp scalpel to expose across-section thereof.

[0051] One drop of a two-color coloration indicator called Bromophenol Blue (BromophenolBlue: one type of acid base indicator used at a pH between 3.0 and 4.6; it becomes yellow when the pH of an aqueous solution is 3.0 or less, and it becomes blue-purple when the pH of an aqueous solution is 4.6 or more; this change is reversible) was dropped onto the exposed cross-section of each hard capsule.

[0052] In the results thereof, when the hard capsules were filled with the mixed powders prepared by mixing into lactose 10% and 25% by weight of the three powders that wereevaluated as Rank AA in Example 2 (i.e., guar gum, λ (lambda) type carrageenan, and pectin (GENU Pectin DD slow set-J from Sansho Co., Ltd.)), relative to the lactose, the inside of the filled materials became blue-purple and thus the filled materials had a pH of 4.6 or more. Thus, it was understood that in these hard capsules, any influence by penetration of the acidic solution was effectively prevented. When the hard capsule was filled with only lactose as the comparative example, the inside of the filled materials became yellow, and thus influence by penetration of the acidic solution was apparent.Comparative Example 5

[0053] Commercially available placenta (porcine or equine) was filled into size #1 acid resistant capsules from Capsugel (DRCAPS ™< ) with either 100% placenta (porcine or equine), or 60 wt% placenta (porcine or equine) with 40 wt% gellan gum, banded, and submitted to acid resistance testing at pH 1.2, followed by dissolution testing at pH 6.8 (n=6). After two hours of the acid resistance test, the 100% placenta (porcine or equine) capsule lost titer due to degradation by the acid, and the filled powder was dissolved by thepermeated acid through the shell. The cut capsule showed a dark brown gelled residue. In comparison, the 60 wt% placenta (porcine or equine) with 40 wt% gellan gum capsules showed 67% titer against the initial formulation, and the capsule interior after cutting open was intact. The 60 wt% placenta (porcine or equine) with 40 wt% gellan gum capsules disintegrated as expected within 8 minutes at pH 6.8.Comparative Example 6

[0054] Commercially available Nattokinase (source Bacillus subtilis var.natto) dry enzyme powder was filled into size #2 acid resistant capsules from Capsugel (DRCAPS ™< ) with either 100% dry powder enzyme, or 81 wt% dry powder enzyme powders with 9 wt% gellan gum and 9 wt% pH neutralizer (anhydrous tetrasodium pyrophosphate), banded, and submitted to acid resistance testing at pH 1.2, followed by dissolution testing at pH 6.8 (n=6). After two hours of the acid resistance test, the 100% dry enzyme powder was dissolved by the permeated acid through the shell. The cut capsule showed complete dissolution and damage of the dry powder enzyme. In comparison, the 81 wt% dry powder enzyme powders with 9 wt% gellan gum and 9 wt% pH neutralizer (anhydrous tetrasodium pyrophosphate) showed the capsule interior after cutting open the dry powder enzyme was visually intact. The 81 wt% dry powder enzyme powders with 9 wt% gellan gum and 9 wt% pH neutralizer (anhydrous tetrasodium pyrophosphate) disintegrated as expected within 12-24 minutes at pH 6.8.

Claims

1. A hard capsule formulation comprising: a hydroxypropyl methyl cellulose hard capsule with acid resistance, wherein said hard capsule is not treated with an enteric coating; and as materials filled within said capsule: 1) an excipient and an agent to inhibit invasion of gastric fluid, wherein said agent to inhibit invasion of gastric fluid comprises a water repellent agent selected from the group consisting of calcium stearate, magnesium stearate, and carnauba wax and optionally a gelling agent, wherein the amount of said water repellent agent and gelling agent, when present, is from 9% to 25% of the total weight of the materials filled within the hard capsule; and 2) a pharmaceutical agent.

2. The hard capsule formulation as claimed in claim 1, wherein said agent to inhibit invasion of gastric fluid comprising the water repellent agent further comprises a gelling agent.

3. The hard capsule formulation as claimed in claim 2, wherein said gelling agent is selected from the group consisting of guar gum, pectin, (iota) type carrageenan, λ (lambda) type carrageenan, xanthan gum, locust bean gum, alginate, alginic acid, tamarind gum, glucomannan, agar, curdlan, gellan gum, and collagen.

4. The hard capsule formulation as claimed in claim 2, wherein said gelling agent is selected from the group consisting of guar gum, λ (lambda) type carrageenan, xanthan gum, and locust bean gum.

5. The hard capsule formulation as claimed in claim 1, wherein said pharmaceutical agent is proteins, enzymes, or viable bacteria.

6. A method of inhibiting acid penetration in an HPMC hard capsule with acid resistance, comprising adding a water repellent agent selected from the group consisting of calcium stearate, magnesium stearate, and carnauba wax, and optionally a gelling agent to an excipient material filled within the capsule, wherein the amount of water repellent agent and gelling agent, when present, is from 9% to 25% of the total weight of the materials filled within the hard capsule.

7. The method as claimed in claim 6, further comprising adding a gelling agent selected from the group consisting of guar gum, pectin, (iota) type carrageenan, λ (lambda) type carrageenan, xanthan gum, locust bean gum, alginate, alginic acid, tamarind gum, glucomannan, agar, curdlan, gellan gum, and collagen.

8. The method as claimed in claim 6 or 7, wherein said pharmaceutical agent is proteins, enzymes, or viable bacteria.

9. Use of calcium stearate, magnesium stearate, and carnauba wax for inhibiting acid penetration in a hydroxypropyl methyl cellulose hard capsule with acid resistance.