Title of Invention

A STABLE CAPSULE WITH A HYDROPHILIC COMPONENT IN A HYDROPHOBIC MEDIUM

Abstract In various embodiments of the present invention, a capsule is provided including a hydrophobic inner layer and at least one hydrophilic outer layer. The hydrophobic layer may include a hydrophilic component such as an active pharmaceutical ingredient (API) which may be fully encapsulated, partially encapsulated or part of an adsorption complex. Such capsules experience no or minimal cracking or breaking in the outer layer.
Full Text

Field of the Invention
The present invention relates to stable pharmaceutical compositions having an active
pharmaceutical ingredient. More particularly, this invention relates to stable capsules with a
hydrophilic component in a hydrophobic medium.
Description of Related Art
Compositions in a capsule dosage form may include a fill material having one or more
active agents dissolved or suspended in an appropriate liquid or paste vehicle, encapsulated in
a gelatin shell, typically comprising gelatin together with a plasticizer. The fill material is
typically a pumpable liquid or paste. The earner for the fill material may be a single or a
multi-component system that should be compatible with the outer gelatin phase(s) of the
capsule.
Carrier mediums used in soft gelatin capsules fall into two general categories,
hydrophilic and lipophilic. Unfortunately, hydrophilic carriers cannot be used in certain
types of capsules such as when it may interact with the outer layers. Rather, in such capsules,
hydrophobic or lipophilic carrier mediums need to be used. Typical examples include
mineral oils (petroleum or petroleum-derived), vegetable oils {chiefly from seeds and nuts),
animal oils (usually occurring as fats; the liquid types include fish oils), edible oils (chiefly
vegetable oils as well as some special fish oils) arid triglycerides (preferably short chain
triglycerides). In some capsules with a hydrophobic carrier medium in a core phase, it has
been observed that an outer shell material may crack and/or break thereby causing
unacceptable leakage of the core material.
Accordingly, there is a need for a capsules containing hydrophilic compounds
wherein the shell material does not crack or break.
Summary
In several embodiments of the present invention, there is provided a capsule having a
hydrophobic inner layer and at least one hydrophilic outer layer. The hydrophobic layer may
include a hydrophilic component such as an active pharmaceutical ingredient (API) in a

therapeutically effective amount. The API may be fully encapsulated, partially encapsulated
or part of an adsorption complex. Such capsules experience minimal or no cracking or
breaking in the at least one outer layer. Another embodiment of the present invention
provides a seamless capsule having phenylephrine in a therapeutically effective amount. The
phenylephrine may be fully encapsulated or partially encapsulated or adsorbed onto a
complex.
Another embodiment of the present invention provides a package that may include a
dispenser or blister package and a seamless capsule. A seamless capsule may include a
hydrophobic inner layer and at least one hydrophilic outer layer. The hydrophobic layer may
include a hydrophilic ingredient such as an active pharmaceutical ingredient (API) in a
therapeutically effective amount. The API may be partially encapsulated, fully encapsulated
or is part of an adsorption complex. The package may contain drug facts attached thereto.
Another embodiment of the present invention provides for a method of stabilizing a
seamless capsule having a hydrophilic API in a hydrophobic inner layer. In one embodiment,
there is provided a method of preventing or minimizing migration of a hydrophilic ingredient
such as an API from a hydrophobic inner layer of a seamless capsule to an outer hydrophilic
layer of a capsule by including the steps of providing an API in a therapeutically effective
amount that is encapsulated, partially encapsulated or adsorbed and incorporating the API
into the hydrophobic inner layer of a seamless capsule.
In various embodiments, there is provided a capsule including a hydrophobic inner
layer and at least one hydrophilic outer layer. The hydrophobic inner layer may include a
hydrophilic component. The hydrophilic component experiences no or minimal migration to
the outer hydrophilic outer layer. The hydrophilic component may be an active
pharmaceutical ingredient which may be present in a therapeutically effective amount.
Brief Description of Accompanying Drnwings
Figure 1 is a cross section illustrating a capsule having an inner core layer and an outer shell
layer as provided by one embodiment of the present invention.
Figure 2 is a cross section illustrating a capsule having an inner core layer and an outer
coating layer and an outer film layer as provided by one embodiment of the present invention.

Figure 3 is a schematic cross section illustrating one embodiment of the present invention of
the nozzle part of an apparatus which is suitable for producing seamless capsules.
Detailed Description
In one embodiment of the present invention, there is provided a capsule having an
encapsulated or partially encapsulated hydrophilic compound(s) in a hydrophobic carrier in
an inner layer. Such capsules do not experience cracks or breaks in surrounding outer
layer(s) that may have a hydrophilic carrier or phase. In another embodiment of the present
invention, there is provided a seamless microcapsule with encapsulated or partially
encapsulated hydrophilic APIs positioned in a hydrophobic earner in an inner layer or phase
and wherein the outer shell of the microcapsule does not experience breakage or cracking.
In several embodiments of the present invention, one useful capsule is a seamless
capsule. Such seamless capsules typically include at least one inner layer, defined as the
'core layer' and at lease one outer layer, defined as a shell layer.
The terms microcapsule and minicapsule are synonymous with each other and used
interchangeably throughout this specification.
Capsules may be formulated to disintegrate and/or dissolve directly in the buccal
cavity or in the GI tract or stomach area. In various embodiments, one useful capsule
includes a fast disintegrating capsule that disintegrates in the buccal cavity. In several
embodiments of the present invention, a fast disintegrating capsule may be designed to
disintegrate in the buccal cavity from about 1 second to about 60 seconds or from about 1
second to about 45 seconds or from about 1 second to about 30 seconds or from about 1
second to about 15 seconds. In one embodiment of the present invention, there is provided a
seamless capsule that disintegrates in the buccal cavity between about 1 second and 30
seconds. In several embodiments, the capsule will disintegrate in the buccal cavity without
any external forces such as biting on the capsule.
An embodiment of the present invention provides for a fast disintegrating capsule
with a single inner hydrophobic core layer and a single hydrophilic outer layer, wherein the
capsule is stable and docs not experience any cracking or breaking in the outer layer. This
type of capsule may be advantageous for several reasons. Depending on the materials
utilized in the capsule, a capsule having multiple hydrophilic or water soluble outer layers

may effect the desired disintegration performance of the capsule. For instance, a capsule with
a hydrophobic core layer and two or more outer water soluble layers may not disintegrate as
quickly as a capsule that has a single core layer and a single outer water soluble layer.
Additionally, having a single core hydrophobic layer and a single outer water soluble layer
may be advantageous from a manufacturing efficiency point of view.
An embodiment of the present invention is shown in Figure 1, wherein a multilayered
capsule includes an inner core layer and an outer shell layer. Other embodiments of the
present invention include capsules with more layers such as an additional layer between the
core and shell layer and/or an additional layer on the outside of the outer shell layer. Several
embodiments of the present invention provide for a capsule that has 2, 3, 4, 5 phases or
layers. The thickness of each layer may be adjusted by varying the ratio of the various
solutions. Suitable enteric agents include pectin, alginic acid, cellulose such as carboxyl
methylcellulose, celluloseacetate phthalate, and the like, Eudragit® which is one of an acrylic
copolymer and the like and combinations thereof.
In various embodiments of the present invention, an API that resides in an inner core
layer may be encapsulated or partially encapsulated by an appropriate means. Encapsulation
of drugs is known to'be useful for providing sustained release versions of certain APIs.
While it may be desirable in certain circumstances to provide for a sustained release product
so that API is released into the patient over an extended period of time, it would not be
desirable to encapsulate a drug if an immediate release product is desired. In vanous
embodiments of the present invention, there are provided capsules, such as seamless capsules
that are designed to disintegrate in the buccal cavity. It has surprisingly been found that
stable capsules can be provided by encapsulating or partially encapsulating the API contained
therein.
Partially encapsulating an API is advantageous since it minimizes or eliminates the
outer shell cracking issue while not creating an undesirable sustained release API. Another
embodiment of the present invention also provides for a seamless capsule containing an
encapsulated API wherein the encapsulated API is available for immediate release in the
patient. In such embodiments, the encapsulation is in an effective amount to minimize or
eliminate migration of the API to the outer shell. Alternatively, the encapsulation is in an
effective amount to minimize or eliminate the deformations in the outer shell such as cracks,

breaks and the like and combinations thereof. An API may be partially encapsulated, fully
encapsulated, partial adsorbates, full -adsorbates or combinations thereof.
While not wishing to be bound by any theory, it is believed that hydrophilic
compounds, sucli as hydrophilic active pharmaceutical ingredients (APIs), tend to migrate
from an inner layer or core phase which has a hydrophobic carrier medium to an hydrophilic
phase located outside of the core or inner hydrophobic layer. In several embodiments, the
hydrophilic phase or layer is an outer shell layer or a middle shell layer residing outside of
the core hydrophilic phase or layer. While not wishing to be bound to any particular theory,
it is believed that a partially or fully encapsulated or adsorbing an hydrophilic API reduces,
minimizes or eliminates the API's affinity to migrate to an outer layer or phase, thereby
reducing or eliminating the migration of the API to the outer shell and thereby reducing or
eliminating the cracking or breaking of the outer shell.
Several embodiments of the invention contemplate that APIs can be encapsulated,
partially encapsulated, adsorbed as a complex or partially adsorbed as a complex.
Encapsulation can be achieved using conventional procedures and can be performed using
water-insoluble as well as water soluble agents. Alternatively, it is possible to encapsulate a
release controlling substance, together with an API, within an encapsulating shell to provide
for controlled release of a taste-masked capsule.
for instance, an API may be encapsulated or partially encapsulated by first
granulating the API with a sufficient quantity of the desired encapsulation material. The wet
mass is passed through a mesh screen such as a 10 mesh screen to break up any lumps, if
necessary. The granules are dried over a forced air oven at 50 °C. The dried powder is
passed through a screen, such as a 40 mesh screen. The powder is then ready to be
incorporated into the core inner solution.
Suitable materials that can be used to encapsulate or partially encapsulate an API
include, but are not limited to, hydroxypropylcellulose, ethycellulose,
hydroxypropylmethylcclIulosc(Aquacoat®), ethylcellulose, methacrylates, acrylic co-
polymers such as Eudragit® (Butylmethacrylat-(2-Dimethylaminoethyl)methacrylat-
Methylmethacrylat-Copolymer (1:2:1)"), KOLLICOAT® , polyvinylpyrrolidone and
combinations thereof. The pharmaceutical composition can include other functional
components presented for the purpose of modifying the physical, chemical or taste properties
of the systemically active therapeutic agent. For example, the API can be in the form of a

microencapsulation, ion-exchange resin complex, such as a sulfonated polymers, electro-
chemical melt, supercritical fluids, magnesium trisilicate, coacervation, or cyclodextrin
(cyclic-linked oligosaccharides) complexes. Useful sulphonated polymers include
polystyrene cross-linked with 8% of divinylbenzene such as Amberlite ®IRP-69 and IRP-64
(obtained by Rohm and Haas), Dow XYS-40010.00®, Dow XYS40013.00® (obtained from
the Dow Chemical Company).
Various embodiments of the present invention provide for an outer layer that includes
a water soluble layer. Useful materials for a water soluble outer, coating or shell layer
include, but are not limited to, gelatins, proteins, polysaccharides, starches, celluloses and
combinations thereof Useful materials for the water soluble outer coating or shell layers
include but are not limited to, albumin, pectin, guar gum, carboxyrnethyl starches,
carboxymethyl celluloses, carrageenan, agar and the like, hydroxypropylcellulose,
ethycellulose, hydroxypropylmethyl cellulose, such as Aquacoat®, polyvinyl alcohol,
polyvinyl pyrrolidone, pullulan and combinations thereof. When the material for forming the
coating layer contains protein or polysaccharide, useful amounts include an amount from
about 100 parts by weight to about one part by weight. Other useful materials in the outer,
coating or shell layer include an enteric material, a plasticizer, a preservative and a colorant
and the like and combinations thereof.
To adjust the hardness of the shell, a material that increases the hardness of the shell
material after hardening, such as sorbitol, can be added to the shell material along with the
plasticizer. Furthermore, by adding a thickening polysaccharide, a gelling agent, a proteolytic
agent or the like, it is possible to improve the long-term stability of the shell. The shell
material can be colored to any arbitrary color tone by a pigment, and flavorings, sweeteners,
souring agents or the like can be added. Sorbitol, thickening polysaccharides, gelling agents,
proteolytic agents and the like are added at 10% by mass or less with respect to the total
amount of the shell material, and preferably at 5% by mass or less.
Other useful materials in the water soluble phase include plasticizers, which include
polyhydric alcohols, such as sorbitol, glycerin, polyethylene glycol and the like and
combinations therof. A water-soluble polyvalent alcohol or water-soluble derivative thereof
may also be used in water soluble outer or coating layer. Useful examples of polyvalent
alcohol or water soluble derivatives thereof include but are not limited to, glycerin,

polyglycerin, sorbitol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene
glycol, ethylene oxide-propyiene oxide copolymer, oligosaccharide, sugar esfer, glycende,
sorbitan ester and the like. Useful preservatives and colorants include benzoic acid, para-
oxybenzoate, caramel colorant, gardenia colorant, carotene colorant, tar colorant and the like
and combinations thereof.
A film substance may be used on the water soluble outer or shell layer and may be
formed by treating a capsule with a film forming substance. Suitable film formers include
but are not limited to albumin, pectin, guar gum, carrageenan, agar and the like,
hydroxypropylcellulose, ethyccllulose, hydroxypropylmethyl cellulose, such as Aquacoat®,
pullulan and combinations thereof.
Useful amounts of additives include 2 parts by weight to 98 parts by weight, based on
100 parts by weight of gelatin in the coating layer. In order to inhibit oxygen-permeability of
the capsule of the present invention, sucrose may be contained in the coating layer, in
addition to the film-forming material and additives. When sucrose is not contained in the
coating layer, oxygen may permeate through the water-soluble gel layer to reach the content
and oxidize the unsaturated fatty acid and derivative thereof during a long storage period of
time. Oxidized unsaturated fatty acid and derivative thereof increase peroxide value (POV)
and deteriorate product quality. Sucrose efficiently inhibits the disadvantage. Sucrose maybe
contained in an amount of one part by weight to 100 parts by weight based on 100 parts by
weight of gelatin.
A water-soluble layer or phase may also contain an acid or an acid salt thereof, to
minimize or prevent the capsule from insolubilizmg. Useful acids or acid salt thereof include
a water-soluble organic acid, an inorganic acid, or an acid salt thereof (for example, sodium
salt). Suitable organic acid include acids having 2 to 6 carbon atoms, including, for example,
citric acid, malic acid, tartar acid, fumaric acid, lactic acid, butyric acid, succinic acid and the
like, an acid salt thereof (for example, sodium malate, potassium succinate, calcium citrate
and the like); and combinations thereof. Useful inorganic acids include phosphoric acid,
polyphosphoric acid, carbonic acid, an acid salt thereof (for example, dibasic sodium
phosphate) and combinations thereof. Useful amounts of an acid or acid salt thereof to a
water-soluble layer is generally from about 0.01 to about 50% by weight, or from about 0. 05
to about 20% by weight, based on 100% by weight of a water soluble layer or phase.

The inner or core solution or phase of a capsule may include a fatty acid such as a
unsaturated fatty acid or a derivative thereof. Suitable materials for the inner core include but
are not limited to, vegetable fats and oils, animal fats and oils and mineral oils and
combinations thereof. Suitable materials for the inner core include fish oils and a purified
malerial thereof, liver oils, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA),
arachidonic acid, prostaglandin and a derivative thereof, sucrose fatty acid ester, propylene
glycol fatty acid ester, glycerin fatty acid ester, long chain fatty acid triglyceride, medium
chain fatty acid triglyceride, ampho-ionic emulsifiers, lecithin, sesame oil, coffee oil,
rapeseed oil, brown rice oil, liquid paraffin and combinations thereof.
To prepare an emulsified core liquid, well-known conventional methods can be used
in which the main component, including an emulsifying agent, and an oil component are
emulsified using a homogenizer to obtain an oil-in-water emulsion. Other useful materials
for the core or inner phase include, but are not limited to, various types of a stabilizers for
unsaturated fatty acid or a derivative thereof including antioxidants, such as vitamin E,
vitamin C, fi- carotene, eucalyptol, menthol, flavorings, sweeteners, wheat germ oil and the
like and combinations thereof.
The core filler material can be in a liquid state when extruded from the multiple
nozzle as the core liquid, and the core liquid can remain a liquid after the formation of the
multilayer liquid drops, or alternatively can be a gel or solid after formation of the seamless
capsule. The core material may include a foodstuff, health food, flavoring, condiments,
pharmaceutical, aromatic agent, or the like, it is possible to include various additives such as
solvents (for example, edible oils), sweeteners, souring agents, flavorings, colorings,
thickeners (gelatinizing agents), stabilizers, and emulsifiers, or the like that are permitted in
terms of food production or pharmacology. When the core material is prepared in a liquid
state, it can take the form of a transparent solution, suspension, or a latex (cream) where the
main component is dissolved in a solvent. The method in which a core liquid filler material is
prepared can be any well-known method in the fields of food production or pharmaceutical
manufacturing. For example, to prepare a transparent core liquid, the main component and
additives are measured and mixed with a solvent such as a edible oil, and as needed heated
and agitated to produce a uniform solution.
Useful amounts of the inner or core phase is from about 10% to 95% by weight, or
from about 40% to about 90% by weight, based on the total weight of the capsule.

In several embodiments of the present invention, the seamless capsule may contain a
viscous liquid "which- is scarcely misciblc with water between an outer film and the inner or
core phase. The viscous liquid which is scarcely miscible with water may be liquid having a
viscosity of not more than 1000 cp at 100C. Examples thereof include emulsifiers, oils, resins
and the like and they may be used alone or in combination thereof. Examples of the
emulsifier include nonionic emulsifiers having HLB value of 2 to 8 such as sucrose fatty acid
ester, propylene glycol fatty acid ester, glycerin fatty acid ester (e.g. long chain fatty acid
triglyceride, medium chain fatty acid triglyceride, such as NeoBee®, etc.), ampho-ionic
emulsifiers such as lecithin or a mixture thereof. Examples of oils include vegetable fats and
oils, animal fats and oils and mineral oil of which solubility in 100 g of absolute alcohol at
150C is not more than 50 g, for example, sesame oil, coffee oil, rapeseed oil, brown rice oil.
liquid paraffin and combinations thereof. Further, dl-alpha-tocopherol, isobutylene polymers
(e.g. polybutylene, polybutene, etc.), resins (e.g. silicone resin, vinyl acetate resin, etc.),
silicon dioxide, such as Cab-o-sil®; and the like can be used. The viscous liquid maybe
present between the content and film in the case of producing the capsule. However, it is not
necessarily required that the viscous liquid is present between the content and film, and it
may be present in the content in the separate state.
The inner or outer layer may include other materials including APIs, foods, cosmetics,
flavors, industrial chemicals and the like.
Another embodiment of the present invention provides for a seamless microcapsule
with three layers, namely, the core layer, a middle layer and an outer shell layer. The middle
layer may be added to the microcapsule by a third injection nozzle. The middle layer may
provide for a more stable microcapsule. More particularly, the middle layer may provide for
additional protection for the shell layer and prevent or minimize migration of the core layer to
the outer shell layer.
An aspect of the present invention provides for a seamless capsule or capsule that
includes an encapsulated or partially encapsulated API in a therapeutically effective amount.
Useful APIs include antimicrobial agents, non-steroidal anti-inflammatory agents,
antitussives, decongestants, anti-histamines, expectorants, anti-diaherrals, H2-antagonists,
proton pump inhibitors, analgesics, stimulants and combinations thereof. Useful APIs
include diphenhydramine, dextromethorphan, phenylephrine, menthol, pseudoephedrine,
acetaminophen, ibuprofen, famotidine, guaifenesin, ketoprofen, nicotine, celecoxib,

valdecoxib. chlorpheniramine, fexofenadine, loratadine, desloratadine, cetirizine, ranitidine,
simethicone, and isomers, pharmaceutically acceptable salts andprodrugs thereof and -
combinations thereof.
Further useful active pharmaceutical ingredients include diphenhydramine,
dextromethorphan, phenylephrine, famotidine, ketoprofen, nicotine, valdecoxib,
chlorpheniramine, loratadine, desloratadine. cetirizine, famotidine; simethicone, and isomers,
pharmaceutically acceptable salts and prodrugs thereof and combinations thereof.
Useful amounts of phenylephrine include from about 1 milligram to about 60
mg, from about 1 mg to about 15 mg or from about 5 mg to about 10 mg or about 10 mg.
Various embodiments of the present invention provide compositions with at least two
API's.
Useful API's include, but are not limited to:
(a) antimicrobial agents such as triclosan, cetylpyridium chloride, domiphen bromide,
quaternary ammonium sails, zinc compounds, sanguinarine, fluorides, alexidinc, octonidine,
EDTA, and the like;
(b) non-steroidal anti-inflammatory and pain reducing agents such as aspirin,
acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, flurbiprofen sodium,
naproxen, tolmetin sodium, indomethacin, celecoxib, valdecoxib, parecoxib, rofecoxib and
the like;
(c) antitussives such as benzonatate, caramiphen edisylate, menthol,
dextromethorphan hydrobromide, chlophedianol hydrochloride and the like;
(d) antihistamines such as brompheniramine maleate, chlorpheniramine maleate,
carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate,
diphenylhydramine hydrochloride, azatadine maleate, diphenhydramine citrate,
diphenhydramine hydrochloride, dipbenylpyraline hydrochloride, doxylamine succinate,
promethazine hydrochloride, pyrilamine maleate, tripelennamine citrate, triprolidine
hydrochloride, acrivastine, loratadine, desloratadine, brompheniramine, dexbropheniramine,
fexofenadine, cetirizine, montelukast sodium and the like;
(e) expectorants such as guaifenesin, ipecac, potassium iodide, terpin hydrate and the
like;
(f) analgesic-antipyretics such salicylates, phenylbutazone, indomethacin, phenacetin
and the like;

(g) antimigraine drugs such as sumitriptan succinate, zolmitriptan, valproic acid
cletriptan hydrobromide and the like; '
(h) anti-gas and anti-diaherrals such as simethicone, loperamide,
(i) H2-antagonists, proton pump inhibitors such as ranitidine, famotidine, omeprazole
and the like; and
(j) central nervous system agents.
The amount of the API's in the formulation may be adjusted to deliver a
predetermined dose of the active agent over a predetermined period of time, which may
typically vary from 4 to 24 hours. Examples of doses containing specific pharmaceutically
active agents are set forth in Table 1.


Except as otherwise noted, the amount of API is designated as % by weight per
dosage form. Generally, the amount of the API used may be from about 0.01% to about 80%
by weight, or from about 0.1% to about 40% by weight, or from about 1% to about 30% by
weight, or from about 1% to about 10% by weight.
An "effective" amount or a "therapeutically effective amount" of an active ingredient
refers to a non-toxic but sufficient amount of the agent to provide the desired effect. The
amount of active agent that is "effective" will vary from subject to subject, depending on the

age and general condition of the individual, the particular active agent or agents, and the like.
Thus, it is not always possible to specify an exact "effective amount." However, an
appropriate "effective" amount in any individual case can be determined by one of ordinary
skill in the art using routine experimentation.
"Pharmacologically active"' (or simply "active"), refers to a compound that has
pharmacological activity and a "pharmacologically active" derivative of an active agent,
refers to a derivative having the same type of pharmacological activity as the parent
compound and approximately equal in degree. When the term "pharmaceutically acceptable"
is used to refer to a derivative (e.g., a salt) of an active agent, it is to be understood that the
compound is pharmacologically active as well. When the term "pharmaceutically acceptable"
is used to refer to an excipient, it implies that the excipient has met the required standards of
toxicological and manufacturing testing or that it is on the Inactive Ingredient Guide prepared
by the Food and Drug Administration.
By "pharmaceutically acceptable" such as in the recitation of a "pharmaceutically
acceptable excipient," or a "pharmaceutically acceptable additive," is meant a material that is
not biologically or otherwise undesirable, i.e., the material can be incorporated into a
pharmaceutical composition administered to a patient without causing any undesirable
biological effects or interacting in a deleterious manner with any of the other components of
the composition in which it is contained.
In various embodiments of the present invention, the dosage forms may be
administered orally. Oral administration may involve swallowing, so that the composition
with the API(s) enters the gastrointestinal tract, and/or buccal, lingual, or sublingual
administration by which the API enters the blood stream directly from the mouth.
Useful inactive ingredients that may be included in the various phases or solutions of
the capsule, may include but are not limited to, binding agents, filling agents, lubricating
agents, suspending agents, sweeteners, flavorings and flavor enhancer agents, taste-masking
agents, preservatives, buffers, wetting agents, anti-oxidants, colorants or coloring agents,
pharmaceutically acceptable carriers, disintegrants, salivary stimulating agents, cooling
agents, co-solvents (including oils), pH adjusting agents, effervescent agents, emollients,
bulking agents, anti-foaming agents, surfactants, soluble organic salts, permeabilizing agents,
glidants and other excipients and combinations thereof. Desirably, the agents are chemically
and physically compatible with the API.

Examples of useful substantially water soluble earners or filling agents include, but
are not limited to, various starches, celluloses, carbohydrates compression sugars or soluble
fillers. More particularly, useful fillers include but are not limited to lactose, lactose
monohydrate, lactose anhydrous, sucrose, amylose, dextrose, mannitol, inositol, maltose,
maltilol, sorbitol, glucose, xylitol. erythritol, fructose, maltodextrins; microcrystalline
cellulose, calcium carboxy methyl cellulose; pregelatinized starch, modified starches, potato
starch, maize starch; clays, including kaolin and polyethylene glycols (PEG) including PEG
4000; or combinations thereof. Useful amount of fillers include the range of about 1 to about
99 weight percent, or about 25 to about 95 weight percent or about 40 weight percent to about
95 weight percent of the compositions of this invention.
Compositions of the present invention may include a sweetener. Useful sweeteners-
include, but are not limited to, sugars such as sucrose, glucose (corn syrup), dextrose, invert
sugar, fructose, and mixtures thereof; acid saccharin and its various salts such as the sodium
or calcium salt; cyclamic acid and its various salts such as the sodium salt; the dipeptide
sweeteners such as aspartame and alitamc; natural sweeteners such as dihydrochakone
compounds; glycyrrhizin; Stevia rebaudiana (Stevioside); sugar alcohols such as sorbitol,
sorbitol syrup, mannitol, xylitol and the like, synthetic sweeteners such as acesulfame-K and
sodium and calcium salts thereof and other synthetic sweeteners,, hydrogenated starch
hydrolysate (lycasin); protein based sweetening agents such as talin (thaumaoccous danielli)
and/or any other pharmacologically acceptable sweetener known by the stale of the art, and
mixtures thereof.
Suitable sugar alcohols useful as sweeteners include, but are not limited to, sorbitol,
xylitol, mannitol, galactitol, maltitol, isornalt (PALATINIT™) and mixtures thereof. The
exact amount of sugar alcohol employed is a matter of preference subject to such factors as
the degree of cooling effect desired. Thus, the amount of sugar alcohol may be varied in order
to obtain the result desired in the final product and such variations are within the capabilities
of those skilled in the art without the need for undue experimentation.
in another embodiment, a capsule is free of sugar. A sugar-free formulation has the
advantage that it can be administered easily to consumers with blood sugar disorders or to
diabetics in need of such preparations. Such sweeteners include, but are not limited to,
sucralose, acesulfame potassium, and aspartame which share properties such as absence of
bitter and metallic aftertastes.

In another embodiment, a capsule may include acesulfame K, aspartame, sucralosc
and combinations thereof. Acesulfame K is a commercial product of Nutrinova Nutrition
Specialties & Food Ingredient GmbH. Useful amounts of sucralose in a dosage form is
between about 0.002% to about 10% by total weight of the FDDF. However, this amount can
vary greatly depending upon the nature of the composition being sweetened. In one preferred
embodiment, the sweetener is a mixture of sucralose with acesulfame K.
One embodiment of the invention provides for a controlled or extended release
composition.
Optionally, one or more flavors such as those described in U.S. Patent No. 6,596,298
which is incorporated herein. Any amount of flavor can be used and will depend on
characteristics of the active pharmaceutical ingredient(s); preferred concentration of flavoring
is between about 0.01% to about 10% w/w of a composition.
Another embodiment of the present invention provides a kit having two or more
separate compositions having an API in capsules, including seamless capsules, and a means
for separately retaining said capsules, such as a container, divided bottle, or divided foil
packet. An example of such a kit is the familiar blister pack used for the packaging of
capsules and the like. Other embodiments contemplate articles of manufacture including
various packaging configurations, ranging from unit dose blister packs to multiple dose
packages such as bottles. To assist compliance, the kit may have directions for administration
and may be provided with a so-called memory aid.
In one embodiment, capsules are provided in blister packaging which is believed to
limit the amount of oxygen that may interact with the capsule and as such may also increase
or enhance the stability of the drug product containing the API. Another embodiment
contemplates a method of dispensing a capsule from a blister pack by forcing the drug
product through a foil back on a blister pack.
An embodiment of the present invention provides a method for producing the
encapsulated unsaturated fatty acid substance may be a conventional method for producing a
soft capsule. An example of the method for producing the capsule includes a method
containing steps of preparing a sheet for the coating layer mainly containing gelatin and a
sheet for the water-soluble gel layer containing an acid or an acid salt thereof, respectively,
laminating both sheets, drying to obtain a dried sheet and encapsulating unsaturated fatty acid
or the derivative thereof as the content with the dried sheet on a rotary filler to form a seamed

capsule; and another method for producing a seamless capsule by using an instrument
equipped with some nozzles arranged concentrically.
Seamless microcapsules may be manufactured by any acceptable machinery such as
the seamless minicapsulc production machine, such as the Spherex, manufactured by Freund
Corp., Japan as shown in Figure 2. Highly spherical uniform, seamless capsules may be
produced by such machinery. A useful manufacturing process for seamless capsules,
including seamless microcapsules, includes mixing the components of the core in one
container and the components of the shell(s) in another container. The shell(s) materials are
heated to provide a fluid medium. The core and shell(s) materials are then pumped separately
to at least two fluid nozzles submerged in an organic carrier medium. The capsules formed
are allowed to cooled and stiffen. They are then denatured and separated for further
handling. Additional solutions may be injected to form a three or more system
microcapsule. The core solution and the shell solution must be different. The principle of
seamless mini capsule formulation is the utilization of surface tension. In particular, when
two different solutions contact each other, surface tension works to reduce the contact area of
the solution resulting in a spherical shape.
Suitable methods for producing seamless capsules are disclosed in US5,330,835 and
US 6,531,150, US2004/0051192, US5,478,508 which are incorporated herein in their
entirety.
FIG. I schematically shows a cross-sectional view of a capsule ( 20 ), with an inner
core material ( 21 ) with a coating layer ( 23 ). FIG. 2 schematically shows a cross-sectional
view of a capsule ( 15 ), with an inner core material ( 11 ), a coating layer ( 10 ) and a film
layer (14).
FIG. 3 is a schematic cross section illustrating one embodiment of the present
invention which is suitable for producing a seamless capsule. The inner core material ( 4 ) of
the capsule supplied to the nozzles is extruded from an annular end of an inner nozzle (called
the first nozzle) (1 ), the material for forming the water-soluble gel layer ( 5 ) is extruded
from an annular end of an intermediate nozzle (called the second nozzle) ( 2 ) and optionally
a film-forming materia] for a coating layer ( 6 ) is extruded from an annular end of an outer
nozzle (called the third nozzle) ( 3 ), simultaneously, to make a three-phase composite jet
stream, followed by releasing the jet stream into a cooling solution ( 8 ) to obtain the

encapsulated unsaturated fatty acid substance ( 7 ) of the present invention in a form of the
seamless-capsule
In the method of the present invention, since all of the loading materials are liquid, the
encapsulation process can be easily performed by adequately vibrating the jet stream with a
vibration means to readily release the jet stream, and thereby a particle size of the resulting
capsules may be controlled uniformly.
The encapsulated unsaturated fatty acid substance ( 7 ) produced by the method of the
present invention may be used in any way of an undried form remaining moisture in the
coating layer, or a dried form.
The capsule of the present invention may be formed into a desirable particle size of
0.1 mm to 20 mm, preferably 0.3 to 8 mm. The water-soluble outer layer ( 12 ) may have a
thickness from about 0.001 to about 5.00 mm, or from about 0.01 to 1 mm.
EXAMPLES

The formulations in Table 2 are mixed to prepare the respective layers. The materials
are extruded through each one of a double and triple nozzle, respectively, arranged

concentrically and released into a cooling solulion (vegetable oil) to produce capsules in form
of a double and triple structure, respectively. The resulting capsules are spherical and about 8
mm in diameter.

The API, phenylephrine, is partially encapsulated by granulating phenylephrine with
the encapsulating materials listed in Table 3. The wet granulation mass is passed through a
10 mesh screen. The granules are dried over a forced air oven at 50 °C. The dried powder is
passed through a 40 mesh screen and the powder is then mixed into the core solution.
While the invention has been described in detail and with reference to specific
examples thereof, it will be apparent to one skilled in the art that various changes and
modifications can be made therein without departing from the spirit and scope thereof of the
invention.

The applicant confirms that the biological material used in the process of this invention is not procured from India, and has rather been procured from country outside India.



WE CLAIM

1. A capsule comprising a hydrophobic inner liquid core and at least one
hydrophilic outer shell layer, said hydrophobic inner liquid core comprises
a hydrophilic active pharmaceutical ingredient in a therapeutically effective
amount mixed into said liquid core; said active pharmaceutical ingredient
is fully encapsulated, partially encapsulated or part of an adsorption
complex and said wherein said hydrophobic inner liquid core comprises a
material selected from the group consisting of fish oils and a purified
material thereof, liver oils, eicosapentaenoic acid, docosahexaenoic acid,
arachidonic acid, sucrose fatty acid ester, propylene glycol fatty acid ester,
glycerin fatty acid ester, long chain fatty acid triglyceride, medium chain
fatty acid triglyceride, ampho-ionic emulsifiers, lecithin, sesame oil, coffee
oil, rapeseed oil, brown rice oil, liquid paraffin and combinations thereof
wherein said pharmaceutical ingredient is phenylephrine encapsulated,
partially encapsulated or adsorbed with a material selected from the group
consisting of cellulose, sulphonated polymers, acrylic co-polymers,
trisilicates, polystyrenes, cyclodextrins and combinations thereof.
2. The capsule as claimed in claim 1, wherein said capsule is a seamless
capsule.
3. The capsule as claimed in claim 2, wherein said capsule has a diameter
from about 2 mm to about 10 mm.
4. The capsule as claimed in claim 1, wherein said at least one hydrophilic
outer shell layer is a single layer.

5. The capsule as claimed in claim 1, wherein said capsule disintegrates in
the buccal cavity between about 1 and 30 seconds.
6. The capsule as claimed in claim 1, wherein said active pharmaceutical
ingredient is encapsulated or partially encapsulated with an acrylic
copolymer.
7. The capsule as claimed in claim 1, wherein the ratio of the encapsulation
or adsorption material to active pharmaceutical ingredient is from about
10 to 1 to 1 to 10.
8. The capsule as claimed in claim 1, wherein the ratio of the encapsulation
or adsorption material to active pharmaceutical ingredient is from about 3
to 1 to 1 to 3.
9. The capsule as claimed in claim 1, wherein said at least one hydrophilic
outer shell layer comprises a material selected from the group consisting
of albumin, pectin, guar gum, carboxymethyl starch, carboxymethyl
cellulose, carrageenan, agar, hydroxypropylcellulose, ethycellulose,
hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone,
pullulan and combinations thereof.
10.The capsule of claim 1, wherein said phenylephrine is encapsulated,
partially encapsulated or adsorbed with a material selected from the group
consisting of hydroxypropylcellulose, ethycellulose,

hydroxypropylmethyIcelIulose, methacrylates, butylmethacrylat-(2-
dimethylaminoethyl)methacrylat-methylmethacrylate-cop- olymer (1:2:1),
polyvinylpyrrolidone, magnesium trisilicate, polystyrene cross-linked with
8% of divinylbenzene and combinations thereof.




ABSTRACT


TITLE : "A STABLE CAPSULE WITH A HYDROPHILIC COMPONENT IN A
HYDROPHOBIC MEDIUM"
In various embodiments of the present invention, a capsule is provided including
a hydrophobic inner layer and at least one hydrophilic outer layer. The
hydrophobic layer may include a hydrophilic component such as an active
pharmaceutical ingredient (API) which may be fully encapsulated, partially
encapsulated or part of an adsorption complex. Such capsules experience no or
minimal cracking or breaking in the outer layer.

Documents:

03647-kolnp-2007-abstract.pdf

03647-kolnp-2007-claims.pdf

03647-kolnp-2007-correspondence others 1.1.pdf

03647-kolnp-2007-correspondence others.pdf

03647-kolnp-2007-description complete.pdf

03647-kolnp-2007-drawings.pdf

03647-kolnp-2007-form 1 1.1.pdf

03647-kolnp-2007-form 1.pdf

03647-kolnp-2007-form 2.pdf

03647-kolnp-2007-form 3.pdf

03647-kolnp-2007-form 5.pdf

03647-kolnp-2007-gpa.pdf

03647-kolnp-2007-international publication.pdf

03647-kolnp-2007-international search report.pdf

03647-kolnp-2007-pct request form.pdf

03647-kolnp-2007-priority document.pdf

3647-KOLNP-2007-(09-04-2012)-ABSTRACT.pdf

3647-KOLNP-2007-(09-04-2012)-AMANDED CLAIMS.pdf

3647-KOLNP-2007-(09-04-2012)-CORRESPONDENCE.pdf

3647-KOLNP-2007-(09-04-2012)-DESCRIPTION (COMPLETE).pdf

3647-KOLNP-2007-(09-04-2012)-DRAWINGS.pdf

3647-KOLNP-2007-(09-04-2012)-FORM-1.pdf

3647-KOLNP-2007-(09-04-2012)-FORM-2.pdf

3647-KOLNP-2007-(09-04-2012)-FORM-3.pdf

3647-KOLNP-2007-(09-04-2012)-OTHERS.pdf

3647-KOLNP-2007-CANCELLED PAGES.pdf

3647-KOLNP-2007-CORRESPONDENCE.pdf

3647-KOLNP-2007-EXAMINATION REPORT.pdf

3647-KOLNP-2007-FORM 18.pdf

3647-KOLNP-2007-FORM 26.pdf

3647-KOLNP-2007-GRANTED-ABSTRACT.pdf

3647-KOLNP-2007-GRANTED-CLAIMS.pdf

3647-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

3647-KOLNP-2007-GRANTED-DRAWINGS.pdf

3647-KOLNP-2007-GRANTED-FORM 1.pdf

3647-KOLNP-2007-GRANTED-FORM 2.pdf

3647-KOLNP-2007-GRANTED-FORM 3.pdf

3647-KOLNP-2007-GRANTED-FORM 5.pdf

3647-KOLNP-2007-GRANTED-SPECIFICATION-COMPLETE.pdf

3647-KOLNP-2007-INTERNATIONAL PUBLICATION.pdf

3647-KOLNP-2007-PETITION UNDER RULE 137.pdf

3647-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

abstract-03647-kolnp-2007.jpg


Patent Number 256316
Indian Patent Application Number 3647/KOLNP/2007
PG Journal Number 23/2013
Publication Date 07-Jun-2013
Grant Date 31-May-2013
Date of Filing 27-Sep-2007
Name of Patentee MCNEIL-PPC, INC
Applicant Address 199 GRANDVIEW ROAD, SKILLMAN, NJ 08558, U.S.A
Inventors:
# Inventor's Name Inventor's Address
1 NEEMA MAHESH KULKARNI 16 WILKESHIRE BOULEVARD, RANDOLPH, NJ 07869
2 KANJI MADHAVJI MEGHPARA 60 STOCKTON COURT, MORRIS PLAINS, NJ 07950
PCT International Classification Number A61K 9/00
PCT International Application Number PCT/US2006/009526
PCT International Filing date 2006-03-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/666,051 2005-03-29 U.S.A.