Title of Invention

"A RELEASE PHARMACEUTICAL PREPARATION FOR COLON DELIVERY"

Abstract This invention relates to a release pharmaceutical preparation for colon delivery comprising a core containing a medicinal active ingredient as herein described along with an effervescent couple and mucoadhesive polymer, and a press-coated layer provided around said core comprising an enteric polymer, lipophilic and hydrophobic substances, wherein the said layer is 150-160% by weight based on the weight of said core and said lipophilic and hydrophobic substances are in the amount of 5 to 100% by weight based on a weight of the enteric polymer.
Full Text FIELD OF INVENTION
This invention relates to a Release Phramaceutical Preparation for Colon Delivery.
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical controlled to release a medicinal active ingredient at a targeted site in gastrointestinal tract, and more particularly to a pharmaceutical preparation for oral administration from which a medicinal active ingredient can be selectively delivered to any specific site in the intestinal tract.
Selective delivery of a medicinal active ingredient to a specific site in the
intestinal tract has been desired in drug therapies, for instance, a local
therapy for inflammatory disease in the intestinal tract such as
ulcerative colitis or Crohn's disease, or an oral administartive therapy
with a medicinal compound of a peptide which is apt to be decomposed
chemically or enzymatically in the intestinal tract, with a medicinal
compound of which the absorption site is
limited, or with other medicinal compound.
In order to efficiently realize the selective delivery of a medicinal active ingredient to a specific site in the intestinal tract, it is necessary to design a pharmaceutical preparation taking into account the physical and physiological environment in the human gastrointestinal tract and the traveling time of the pharmaceutical preparation through the intestinal tract. With respect to the physical and physiological environment in the gastrointestinal tract, it is recognized that the value of pH in the stomach is usually 1.8 to 4.5 in a healthy human and that the value of pH in the intestines is 6.5 to 7.5 and the pH does not essentially differ between the small intestine and the large intestine. According to the results of the widespread research of Davis et al., the residence time of a pharmaceutical preparation in the human stomach is 0.5 to 10 hours and further not only the inter-individual variation thereof is large, but also the residence time is considerably influenced, for example, by feeding, a size of the pharmaceutical preparation to be administered and the like. However, the traveling time of a pharmaceutical preparation through the small intestine is generally recognized to be 3.+-.1 hours and the inter- and intra-individual variation is relatively small (Journal of Controlled Release, 2, 27-38 (1985)).
With respect to a method by which a medicinal active ingredient can be selectively delivered to a specific site in the intestinal tract, hitherto various researches have been done. There have been proposed a pharmaceutical preparation wherein a sustained release pharmaceutical preparation is coated with an enteric coating (Annals of the New York Academy of Science, 618, 428-440 (1991)), a pharmaceutical preparation obtained by utilizing a technique for controlling the starting time of the release (Chemical & Pharmaceutical Bulletin, 40, 3036-3041 (1992)) and the like, as well as pharmaceutical preparations obtained by using known techniques such as an enteric pharmaceutical preparation and a sustained release pharmaceutical preparation.
However, every conventional method has a problem such as insufficient site-selectivity or poor practicality due to peculiarity of the material to be used. For example, in case of using the enteric pharmaceutical preparation, the release of a medicinal active ingredient starts abruptly at the upper small intestine resulting in consumption of almost of the medicinal active
ingredient by absorption or decomposition before the medicinal Active ingredient reaches the targeted site in the intestine, although the release of the medicinal active ingredient can be effectively suppressed in the stomach. In case of using the sustained release pharmaceutical preparation, a considerable amount of a medicinal active ingredient is released when the pharmaceutical preparation stays in the stomach and passes through the small intestine because the medicinal active ingredient is continuously released.
Further, in order to release a medicinal active ingredient at the large intestine, there has been recently developed a system utilizing the ecosystem of specific microorganisms in the large intestine. For example, in a pharmaceutical preparation wherein a composition containing a medicinal active ingredient is coated with a novel polymer having an azo group, or the composition containing a medicinal active ingredient is dispersed in the new polymer having an azo group to form a matrix type of pharmaceutical preparation (Science, 233. 1081-1084 (1986)). the polymer is decomposed in the large intestine by enterobacteria having azo-reductase activity and the medicinal active ingredient is thereby released at the large intestine However for practical use. there are still many problems to be solved, for example, regarding the safety of the polymer itself, the controllability of the decomposition rate thereof, and the like
Another major problem is incomplete disintegration of the drug delivery system in the large intestine because of high viscosity of the large intestinal contents, in order to immediately release the medicinal agent in the colon, an effervescent couple have been used as a disintegrating agent.
In case of prolonged release multiunit dosage forms it is desirable that the passage through the large intestine should be slow, for this purpose a mucoadhesive polymer is used.
OBJECTS OF THE INVENTION
An object of the present invention is to propose a release pharmaceutical preparation for colon delivery which obviates the above-mentioned problems in the conventional pharmaceutical preparations, and to provide a pharmaceutical preparation for oral administration of high practical use by which a medicinal active ingredient can be effectively released at a targeted site in the intestinal tract.
Another object of this invention is to propose a release pharmaceutical preparation for colon delivery using a mucoadhesive polymer to increase the colonic transit time and an effervescent couple to ensure immediate disintegration and release of the drug in the colon irrespective of its diseased condition.
DESCRIPTION OF THE INVENTION
According to this invention there is provided a release pharmaceutical preparation for colon delivery comprising:-
a) a core containing a medicinal active ingredient as herein described along with an effervescent couple and mucoadhesive polymer, and
b) a press-coated layer provided around said core comprising an enteric polymer, lipophilic and hydrophobic substances, wherein the said layer is 150-160% by weight based on the weight of said core and said lipophilic and hydrophobic substances are in the amount of 5 to 100% by weight based on a weight of the enteric polymer.
In accordance with the present invention, there is provided a pharmaceutical preparation for oral administration, which is controlled
to release a medicinal active ingredient at a targeted site in the intestinal tract comprising
(a) A core containing a medicinal active ingredient along with a novel effervescent couple and a mucoadhesive polymer
(b) A press-coated layer comprising an enteric polymer, said layer being provided around the core.
In the pharmaceutical preparation of the present invention, a lipophilic or hydrophobic substance may be included in the press-coated layer in order to control a dissolution rate of the layer in the intestine.
The pharmaceutical preparation of the present invention has the following characteristics: when the pharmaceutical preparation is orally administered, the release of a medicinal active ingredient does not occur at all during residence of the pharmaceutical preparation in the stomach and, after discharge from the stomach, until the preparation reaches a desirable targeted site in the intestine and thereafter, the release of the ingredient starts rapidly. In case of using a medicinal active ingredient as a drug required to be selectively delivered to a specific site in the intestinal tract, an excellent pharmaceutical preparation having high availability can be provided.
DETAILED DECSRIPTION
The present invention is based on the aspect that a press-coated layer comprising an enteric polymer starts to dissolve more slowly in the intestine than a film-coated layer comprsing the enteric polymer and that the starting time of dissolution of a medicinal active ingredient can be controlled by varying an amount of the press-coated layer.
In the pharmaceutical preparation of the present invention, the press-coated layer (b) comprising an enteric polymer is capable of suppressing the release of a medicinal active ingredient in the intestine until the pharmaceutical preparation reaches near the desirable targeted site. Namely, during residence of the pharmaceutical preparation in the stomach, the press-coated layer (b) does not dissolve and protects the core (a) so that the release of a medicinal active ingredient can be perfectly supressed, and after discharge of the pharmaceutical preparation from the stomach, the press-coated layer (b) graduallly dissolves, and therefore the release of a medicinal active ingredient is substantially suppressed in the intestine until the pharmaceutical preparation reaches near the desirable targeted site. At the target site the core tablets come in contact with the colonic fluid and the effervescent couple reacts vigorously to release more water and hence induces a chain reaction so that the actives or granules are immediately released in the colon without being affected by the colonic content viscosity.
In order to sufficiently exhibit the above-mentioned capacity in the pharmaceutical preparation of the present invention, it is desirable to determine the time required for dissolution of the press-coated layer (b) in the intestine so that it has sufficient acid resistance and does notdissolve during residence in the stomach, and after discharge from the stomach, the press-coated layer (b) can substantially suppress the release of a medicinal active ingredient until the pharmaceutical preparation reaches near the desirable targeted site in the intestine. It is desirable that the coating amount of the press-coated layer (b) is usually determined so that a medicinal active ingredient is not released in the stomach for a period of about 8 hours which is recognized as the maximum residence time of a pharmaceutical preparation in the stomach, and in case of targeting the upper large intestine.

can suppress the release of a medicinal active ingredient in the intestines for about 3+1 hours which is recognized as a general traveling time of a pharmaceutical preparation through the small intestine.
The pharmaceutical preparation of the present invention can be suitably designed so that when a dissolution test is carried out according to the dissolution test (paddle method; 37.degree. C; 100 rpm; 900 ml of dissolution fluid) of USP XXIV (refer to Example 1), release of a medicinal active ingredient is substantially suppressed for at least 10 hours in the first fluid (pH 1.2), and the release of the medicinal active ingredient is substantially suppressed for at least about 2 hours in the second fluid (pH 6.8) and thereafter the release of the medicinal active ingredient starts quickly. The time required to start the release of the medicinal active ingredient (hereinafter referred to as "lag-time") in the second fluid is set to meet the desired target-site in the intestinal tract. For example, in case that the pharmaceutical preparation of the present invention is designed to have the lag-time of about 2 hours, about 4 hours or about 7 hours, there can be obtained a pharmaceutical preparation wherein release of a medicinal active ingredient is intended to occur at the lower ileum, the ascending colon or the transverse colon. If the pharmaceutical preparation of the present invention is designed to have the lag-time being longer than about 7 hours, there can be obtained a pharmaceutical preparation wherein release of a medicinal active ingredient is intended to occur at the lower large intestine such as the descending colon or the sigmoid colon.
In the pharmaceutical preparation of the present invention, the core (a) is not particularly limited-^* only a medicinal active ingredient included in the core (a). The core (a) may comprise a medicinal active ingredient only. Or if required, various pharmaceutical additives such as an excipient and a disintegrant which are generally used in the art of pharmaceutical preparation, may be included in the core (a) as described below. The form of the core (a) may be a tablet, a granule, a pellet or the like.
The medicinal active ingredient to be included in the above-mentioned core (a) in the present invention is not particularly limited as long as it is orally administerable. Concrete examples of such medicinal active intredient include chemotherapeutic agents, antibiotics, respiratory
stimulants, antitussives, expectorants, antimalignanttumor agents, autonomic agents,
psychotropic agents, local anesthetics, muscle relaxants, agents affecting digestive organs,
antihistamines, toxicopetic agents, hypnotics, sedatives, antiepileptics, antipyretics,
analgesics, antiinflammatory agents, cardiotonics, antiarrhythmic agents, diuretics,
vasodilators, antilipemic agents, nutrients, tonics, alteratives, anticoagulants, agents for liver
disease, hypoglycemics, antihypertensives and the like.
The amount of a medicinal active ingredient to be included in the core (a) is not particularly limited and may be determined according to an effective dose of the medicinal active ingredient to be used, and the like. The amount is preferably about 0.2 to about 100 w/w %, more preferably 0.5 to 50 w/w %, based on a weight of the core (a).
In the core (a) and the press-coated layer (b) of the pharmaceutical preparation of the present invention, various additives such as an excipient, a binder, a disintegrant, a lubricant and an aggregation-preventing agent which are generally used in the field of pharmaceutical preparation may be included, if desired.
Most important excipients in the core tablet is an effervescent couple, responsible for the immediate release of the ingredients in the large intestine. Core tablets consist of an active drug and a large fraction, generally greater than about 20% by weight of the total tablet, of an effervescent couple, which typically comprises an acid source and a carbonate source. Typically but without limitation, a suitable dispersion-enhancing amount of the effervescent couple is about 1% to about 20% by weight of the dosage form.
Effervescent couple herein is an agent comprising one or more compounds which, acting together or individually, evolve a gas on contact with water. The gas evolved is generally oxygen or, most commonly, carbon dioxide. Preferred effervescent agents comprise an acid component and a base component that react in the presence of water to generate carbon dioxide gas. The acid component can comprise one or more acids and the base component can comprise one or more bases.
Preferably, the base component comprises an alkali metal or alkaline earth metal carbonate or bicarbonate and the acid component comprises an aliphatic carboxylic acid.
Non-limiting examples of suitable bases for use in a base component include carbonate salts (e. G., calcium carbonate), bicarbonate salts (e. g., sodium bicarbonate), sesquicarbonate salts, and mixtures thereof. Calcium carbonate is a preferred base.
Non-limiting examples of suitable acids for use in an acid component include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of such acids, acid salts of such acids, and mixtures thereof. Citric acid is a preferred acid.
In a preferred embodiment of the invention, where the effervescent couple comprises an acid component and a base component, the weight ratio of the acid component to the base component is about 1: 100 to about 100: 1, more preferably about 1: 50 TO about 50: 1, and still more preferably about 1: 10 TO about 10: 1. In A further preferred embodiment of the invention, where the effervescent couple comprises an acid component and a base component, the ratio of the acid component to the base component is approximately stoichiometric.
Because it is useful for a dosage form of the invention to be small enough to be comfortably swallowed whole, it is preferred that the drug loading in the dosage form be as high as possible, especially where the therapeutically effective dose is fairly high. In a particularly preferred embodiment, therefore, the amount of effervescent couple present, as a fraction of the total weight of the dosage form, is small enough to allow a therapeutically effective dose of the particular drug to be incorporated into a dosage form no greater than about 800 mg in total weight.
Typically, according to this embodiment, the amount of effervescent couple is not greater than about 20% by weight of the dosage form.
An effervescent couple as defined above is preferably present in a composition of the invention in an amount of about 1% to about 20%, more preferably about 2% to about 15% and still more preferably about 3% to about 10%, by weight of the composition. As indicated herein, the amount of the effervescent couple is not sufficient to provide substantial enhancement of disintegration of the composition, but in accordance with the invention surprisingly is sufficient to provide substantial enhancement of dispersion of primary particles of the composition in an aqueous medium. Preferably, such enhanced dispersion is
accompanied by substantial enhancement of rate of dissolution of the drug in the aqueous medium.
Another important excipients is a mucoadhesive polymer, Concrete examples of the
mucoadhesive polymers are sodium carboxy methyl cellulose, carbopols natural gums etc,
Concrete examples of the other excipient include a saccharide such as sucrose, lactose,
mannitol or glucose, starch, partially pregelatinized starch, crystalline cellulose, calcium
phosphate, calcium sulfate, precipitated calcium carbonate, hydrated silicon dioxide and the
like. Concrete examples of the binder include an oligosaccharide or a sugar alcohol such as
sucrose, glucose, lactose, maltose, sorbitol or mannitol; a polysaccharide such as dextrin,
starch, sodium alginate, carrageenan, guar gum, arable gum or agar; a natural polymer such
as tragacanth, gelatin or gluten; a cellulose derivative such as methylcellulose, ethylcellulose,
sodium carboxymethylcellulose or hydroxypropylmethylcellulose; a synthetic polymer such as
polyvinylpyrrolidone, polyvinylalcohol, polyvinylacetate, a polyethyleneglycol, polyacrylic acid
or polymethacrylic acid; and the like. Concrete examples of the disintegrant include calcium
carboxymethylcellulose, sodium carboxymethylstarch, corn starch, hydroxypropylstarch,
partially pregelatinized starch, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone,
calcium cross-linked carboxymethylcellulose and the like. Concrete examples of the lubricant
and the aggregation-preventing agent include talc, magnesium stearate, calcium stearate,
colloidal silicon dioxide, stearic acid, hydrated silicon dioxide, a wax, a hydrogenated oil, a
polyethyleneglycol, sodium benzoate and the like.
As an enteric polymer used for the press-coated layer (b), any film-formable polymer soluble in an aqueous medium of a pH of not less than 5 and insoluble in an aqueous medium of a pH of less than 5 can be used in the pharmaceutical preparation of the present invention. Examples of the enteric polymer include a cellulose derivative, a polyvinyl derivative, a maleic acid-vinyl compound copolymer, an acrylic copolymer and the like.
Concrete examples of the cellulose derivative include carboxymethylethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and the like. Concrete examples of the
polyvinyl derivative include polyvinyl alcohol phthalate, polyvinyl butylate phthalate, polyvinyl
acetoacetal phthalate and the like. Concrete examples of the maleic acid-vinyl compound
copolymer include poly(vinyl acetate, maleic acid anhydride), poly(vinyl butyl ether, maleic
acid anhydride), poly(styrene, maleic acid monoester), and the like. Concrete examples of the
acrylic copolymer include poly(ethyl acrylate, methacrylic acid), poly(styrene, acrylic acid),
poly(methyl acrylate, methacrylic acid, octyl acrylate), poly(methacrylic acid, methyl
methacrylate) (e.g. Eudragit L and Eudragit S, each being trade name, available from Rohm
Pharma, Germany), and the like.
Among these examples, carboxymethylethyicellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate and poly(methacrylic acid, methyl methacrylate) (Eudragit L and Endragit S) are preferably used as the enteric polymer, and particularly hydroxypropylmethylcellulose acetate succinate and poly(methacrylic acid, methyl methacrylate) (Eudragit L and Endragit S) are preferable, and more particularly hydroxypropylmethylcellulose acetate succinate is preferable.
The above-mentioned enteric polymers are different in various physical properties such as a
dissolution pH (enteric polymers may be somewhat different in a dissolution pH), a molecular
weight and a polymerization degree. However, any enteric polymer can be suitably used for
preparing a press-coated layer in the pharmaceutical preparation of the present invention by
selecting a kind and an amount of the enteric polymer, a compressing pressure of a press-
coated layer and the like so that the press-coated layer (b) is capable of suppressing release
of a medicinal active ingredient until the pharmaceutical preparation reaches near a desirable
targeted site in the intestine, namely can substantially suppress the release of a medicinal
active ingredient for any desired period of time (for example, at least 2 hours) in the second
fluid of the dissolution test in USP XXIV.
Thus, with respect to the above-mentioned preparation of the press-coated layer, there is no particular difficulty for a person skilled in the art to select a type or a grade of the enteric polymer and an amount thereof, a compressing pressure and the like so that a medicinal active ingredient can be released at a desired site in the intestinal tract, particularly a targeted site in between the upper small intestine and the lower large intestine.
For instance, a usually used enteric polymer in a commercially available form can be used for tabletting by means of a tabletting machine to obtain a pharmaceutical preparation of the present invention in a form of a tablet.
If an enteric polymer cannot be . used- - -for tabletting because of having a very small
particle size (e.g. in a form of a fine powder), the enteric polymer is once transformed to a
form of granules having a suitable particle size for tabletting and thereafter the granules are
tabletted together with a core tablet. Then, the pharmaceutical preparation of the present
invention in a form of a tablet can be obtained. For example, an acrylic enteric polymer is
which commercially available under the trade name of Eudragit S or Eudragit L generally has
a small particle size, and the acrylic enteric polymer can be used as it is, however, the acrylic
enteric polymer can be more suitably used in a form of granules prepared as described
above rather than as it is.
The press-coated layer (b) comprising an enteric polymer in the pharmaceutical preparation of the present invention may be a press-coated layer having a multiple layer, which is formed by press-coating a core containing a medicinal active ingredient with one kind of an enteric polymer and providing a further press-coated layer comprising the same or different kind of an enteric polymer around the layer. Additionally, the press-coated layer (b) may be formed by using two or more kinds of enteric polymers in admixture. Each of the above-mentioned press-coated layer having a multiple layer or that comprising two or more kinds of enteric polymers can be suitably used as the press-coated layer (b) in the pharmaceutical preparation of the present invention so long as the press-coated layer (b) is capable of suppressing the release of a medicinal active ingredient until the pharmaceutical preparation reaches near a desirable targeted site in the intestine, namely can substantially suppress the release of a medicinal active ingredient for any desired period of time (for example, at least 2 hours) in the second fluid of the dissolution test in USP XXIV.
In the press-coated layer (b) in the pharmaceutical preparation of the present invention, a lipophilic or hydrophobic substance (i.e. a substance having lipophilic property or hydrophobic
property, hereinafter referred to as "lipophilic/hydrophobic substance") can be suitably
included in addition to an enteric polymer in order to control a dissolution rate of the press-
coated layer (b), if required. As such lipophilic/hydrophobic substance, a substance which
exerts an effect to decrease a dissolution rate of the press-coated layer (b) in aqueous
medium at a pH of not less than 5, may be used alone or in admixture of at least two kinds of
substances. It is considered that the effect that a dissolution rate of the press-coated layer in
aqueous medium of a pH of not less than 5 is decreased, is exerted owing to either a function
that the lipophilic/hydrophobic substance prevents the enteric polymer from wetting with
water or a mechanism that the lipophilic/hydrophobic substance physically interacts with the
enteric polymer to form more tight press-coated layer.
The above-mentioned effect is varied depending on a physical property and an amount of a lipophilic/hydrophobic substance to be used and a kind of the enteric polymer to be used. For instance, generally, the more effect is exerted by using the substance having a lower melting point, and in case of using a metallic salt of a fatty acid as a lipophilic/hydrophobic substance, a multivalent metallic salt thereof exerts more intensive effect than a monovalent metallic salt thereof. Accordingly, the dissolution rate of a press-coated layer can be also controlled by using two or more kinds of the lipophilic/hydrophobic substances.
Examples of the above-mentioned lipophilic/hydrophobic substance suitably used are, for example, a fat and oil, a wax, a hydrocarbon, a higher alcohol, an ester, a higher fatty acid, a metallic salt of a higher fatty acid, other plasticizer and the like.
Concrete examples of the fat and oil include, for example, a vegetable fat and oil such as cacao butter, palm oil, Japan wax or coconut oil; an animal fat and oil such as beef tallow, lard, horse fat or mutton tallow; a hydrogrnated oil obtained from animals such as hydrogrnated fish oil, hydrogrnated whale oil or hydrogensted beef tallow; a hydrogensted oil obtained from plants such as hydrogensted rape seed oil, hydrogenated castor oil, hydrogenated coconut oil or hydrogenated soybean oil; and the like.
Concrete examples of the wax include, for example, a vegetable wax such as carnauba wax,
candelilla wax, bayberry wax, ouricury wax or esparto wax, an animal wax such as beeswax, white beeswax, spermaceti, shellac wax or wool wax, and the like.
Concrete examples of the hydrocarbon include, for example, paraffin, vaseline, microcrystalline wax and the like.
As the higher alcohol, a saturated linear alcohol is exemplified, and concrete examples thereof include, for example, a saturated linear monohydric alcohol having 12 to 30 carbon atoms such as lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol or melissyl alcohol.
Concrete examples of the ester Include, for example, an ester of a fatty acid such as myristyl
palmitate, stearyl stearate, myristyl myristate or behenyl behenate; a glycerine ester of a fatty
acid including a monoglyceride such as glyceryl monolaurate, glyceryl monomyristate,
glyceryl monostearate or glyceryl monooleate, a diglyceride such as glyceryl distearate or
glyceryl dilaurate, a triglyceride such as glyceryl trilaurate, glyceryl tristearate or glyceryl
triacetyl stearate; and the like.
As the metallic salt of a higher fatty acid, an alkali metal salt and an alkaline earth metal salt of a higher fatty acid are exemplified, and concrete examples of the metallic salt of a higher fatty acid include a calcium salt, a sodium salt, a potassium salt, a magnesium salt, a barium salt and the like, of the above-mentioned higher fatty acids. Among these metallic salts of a higher fatty acid, calcium stearate and magnesium stearate are preferable.
Concrete examples of the plasticizer include, for example, triacetin, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, diethyl phthalate, polyethyleneglycol, polysorbate and the like. Among these plasticizers, triacetin, triethyl citrate and acetyl triethyl citrate are preferable.
Among such lipophilic/hydrophobic substances, magnesium stearate, calcium stearate,
triacetin, lauric acid, capric acid, triethyl citrate, acetyl triethyl citrate and the like are
preferable. Particularly, magnesium stearate, calcium stearate, triacetin, lauric acid, capric
acid and triethyl citrate are preferable, and more particularly, magnesium stearate, calcium
stearate, triacetin and lauric acid are preferable.
The lipophilic/hydrophobic substance may be used alone or in admisture of two or more kinds of the above-mentioned substances.
A preferable combination of the enteric polymer and the lipophilic/hydrophobic substance in the press-coated layer of the pharmaceutical preparation of the present invention is, for example, a combination of a cellulose derivative and a higher fatty acid or a metallic salt thereof, a combination of a cellulose derivative and a plasticizer, and the like. In the more preferable combination, the enteric polymer is hydroxypropylmethylcellulose acetate succinate and the lipophilic/hydrophobic substance is magnesium stearate, calcium stearate, triacetin, lauric acid, or a mixture of magnesium stearate and calcium stearate.
An amount of the lipophilic/hydrophobic substance in the press-coated layer (b) is about 5 to about 100% by weight, preferably 20 to 60% by weight based on a weight of the enteric polymer.
The lag-time, the time required until the release of a medicinal active ingredient starts in the
intestine or in the second fluid (pH 6.8) of the dissolution test in USP XXIV, can be controlled
by varying a time required for dissolution of the layer (b) as below. For exmaple, if the amount
of the press-coated layer (b) is increased (or decreased), the time required for dissolution can
be prolonged (or reduced). In case that the coating amount of the press-coated layer (b) is
almost constant, the time required for dissolution can be varied by using one or more grades
of the enteric polymer having different polymerization degree or substitution degree, in the
press-coated layer.
Alternatively, the time required for the dissolution can be also prolonged by including a lipophilic/hydrophobic substance in the press-coated layer (b). Furthermore, if the mount of the lipophilic/hydrophobic substance to be included in the press-coated layer (b) is increased (or decreased), the time required for the dissolution can be prolonged (or reduced). Also, the time required for the dissolution can be varied accordingly to the kind of the lipophilic/hydrophobic substance to be used.
The dosage form of the pharmaceutical preparation of the present invention is preferably a tablet. The size of the pharmaceutical preparation is not particularly limited, however, the diameter thereof is preferably 4 to 16 mm, more preferably 6 to 12 mm.
The form of the core (a) is preferably a tablet. The size of the core (a) is not particularly limited, however, the diameter thereof is preferably 3 to 15 mm, more preferably 5 to 8 mm.
In the pharmaceutical preparation of the present invention, the thickness of the press-coated
layer (b) can be selected without any limitation so that the pharmaceutical preparation to be
obtained can have a desired lag-time. The thickness of the press-coated layer (b) is usually
determined to be 0.4 to 3 mm, preferably 0.5 to 1.5 mm. The coating amount of the press-
coated layer (b) corresponding to the above-mentioned thickness, varying according to the
size of a core tablet, is usually about 150 to about 600 w/w %, preferably 200 to 400 w/w %
based on a weight of the core (a).
The preparation of the core (a) can be carried out according to the usual procedure for the preparation, for example, as described in Remingtons Pharmaceutical Sciences, 17, (Mack Publishing Company, published in 1985). In case of preparing a tablet as a core, for example, the tablet can be obtained by tabletting a medicinal active ingredient alone, or if necessary, admixture with other suitable additives such as an in excipient, a binder and a lubricant which are usually used in the art of pharmaceutical preparation. If necessary, the above-mentioned medicinal active ingredient or mixture is granulated and, if required, sieved before the tabletting process to obtain a granulated particle of the desired range of particle size.
The above-mentioned granulated particle can be prepared according to a usual method such as a dry granulation or a wet granulation. As an example of the granulated particle, for instance, a granule can be prepared by firstly mixing a medicinal active ingredient and a pharmaceutical additive and secondly by granulating the obtained mixture by means of a oscillating granulating machine such as a sieve extruder, a roll extruder, a tornado mill, a screw extruder or alexander machine. A granule can be also prepared by granulating a medicinal active ingredient and a pharmaceutical additive in a form of powder by means of a mixing granulating machine such as a blender granulator or a pin granulator. A granule can
be also prepared according to tumbling granulation, i.e. by spraying a binder solution to a medicinal active ingredient and a pharmaceutical additive in a form of powder in a rotating dram or pan, or a granule can be prepared according to fluidizing granulation, i.e. by spraying a binder solution with fluidizing a medicinal active ingredient and a pharmaceutical additive in a form of powder in a fluidized-bed granulator.
Alternatively, the granulated particle can be prepared by coating an inert carrier substance
with a medicinal active ingredient and a binder. For instance, granules can be prepared by
spray-coating a solution containing a medicinal active ingredient and a binder onto an inert
carrier substance. Granulated particles can be prepared according to powder coating, i.e. by
firstly mixing an inert carrier substance and a medicinal active ingredient and, if required,
other pharmaceutical additive and secondly by coating the obtained mixture with spraying a
bindersolution.
As the above-mentioned inert carrier substance, for example, a crystalline of a saccharide or inorganic salt such as lactose, cellulose or sodium chloride, a spherical particle and the like can be used. Concrete examples thereof include Avicel SP (trade name, available from Asahi Chemical Industry Co., Ltd., Japan, spherical particle of crystalline cellulose). Nonpareil NP-5 and Nonpareil NP-7 (each being trade name, available from Freund Industrial Co., Ltd., spherical particle of crystalline cellulose and lactose) and the like.
Thus obtained granulated particle can be used for tabletting to prepare a core tablet.
The press-coating to form the press-coated layer (b) around the core (a) is carried out according to a usual method in this field, for instance, a compression molding method such as a press-coating method or a dry coating method, and the like. For example, the press-coated layer can be formed by press-coating the core (a) with an enteric polymer alone, or if necessary, in admixture with a lipophilic/hydrophobic substance and/or other suitable additives such as an excipient, a binder, a lubricant and a fluidizing agent. If necessary, the above-mentioned polymer or mixture is granulated and, if required, sieved according to a usual method before the press-coating process. Then, the press-coated layer is provided on the core. The press-coating can be suitably carried out by means of a press-coating machine
or a tabletting machine generally used, under the conditions such that the compressing pressure is, for instance, 200 to 1200 kg/cm.sup.2 and the compressing rate is 1 to 20 mm/minute.
An amount of the additives such as an excipient and a disintegrant optionally added in the core (a) and the press-coated layer (b), a concentration of a binder in the binder solution and a solvent to be used can be determined without any limitation so long as it is within a scope based on the usual knowledge of a person skilled in the art of pharmaceutical preparation.
The present invention is more specifically described and explained by means of the following Examples and Experimental Examples. It is to be understood that the present invention is not limited to the Examples, and various changes and modifications may be made in the invention without departing from the spirit and scope thereof.
EXAMPLE1
Diltiazem hydrochloride (300 g) and corn starch (100 g) were mixed together. The mixture was granulated according to a wet granulation method using a binding solution (180 g) of polyvinylpyrrolidone (trade name: Kollidon 30, available from BASF) (90 g) dissolved in ethanol (90 g). The obtained granules were dried and sieved to obtain granules for tabletting (585 g). A part of thus obtained granules for tabletting (530 g), calcium carbonate(IOOg), monosodium citrate(120g), calcium carboxymethylcellulose (trade name: ECG-505, available from Gotoku Chemical Co., Ltd.) (40 g) and magnesium stearate (10 g) were mixed together. The mixture was tabletted by means of a rotary tabletting machine (16 station rotary from cadmech) to obtain a plain tablet (a core tablet) having a diameter of 6 mm and a weight of 70 mg.
The obtained plain tablet was press-coated with a mixture of powder of hydroxypropylmethylcellulose acetate succinate, calcium stearate and magnesium stearate (the mixing ratio, by weight (w/w) (hereinafter referred to as "the mixing ratio"), 8:1:1) in a coating amount of 200 mg per tablet by means of a press-coating machine to obtain a

pharmaceutical preparation of the present invention in a form of a press-coated tablet having
a diameter of 9 mm and a weight of 270 mg.
With respect to thus obtained pharmaceutical preparation of the present invention, a dissolution test (paddle method) was carried out with the first fluid of the test in USP XXIV (pH 1.2) and the second fluid of the test in USP XXIV (pH 6.8) according to the description of the dissolution test in USP XXIV. The dissolution test was carried out using 900 ml of the dissolution fluid at 37.degree. C. and at the rotation speed of 100 rpm.
As it is clear from the dissolution pattern of diltiazem hydrochloride being a medicinal active ingredient, in the first fluid, the medicinal active ingredient was not released at all for long time (at least 15 hours), which means that the acid resistance of the pharmaceutical preparation was maintained sufficiently. In the second fluid, the medicinal active ingredient was quickly released after the lag-time of about 3 hours in a pulsatile dissolution pattern.
EXAMPLE2
The plain tablet containing diltiazem hydrochloride obtained in Example 1 was press-coated
with a mixture of powder of hydroxypropylmethylcellulose acetate succinate (trade name:
AQOAT (AS-LF), available from The Shin-etsu Chemical Co., Ltd.) and calcium stearate (the
mixing ratio, 8:2) in a coating amount of 200 mg per tablet by means of a press-coating
machine (Correct 18HUK-DC Type, made by Kikusui Seisakusho Ltd.) to obtain a
pharmaceutical preparation of the present invention in a form of a press-coated tablet having
a diameter of 9 mm and a weight of 270 mg.
With respect to thus obtained pharmaceutical preparation of the present invention, a
dissolution test was carried out with the second fluid of the test in USP XXIV under the same
conditions in Example 1. In the second fluid, the medicinal active ingredient was quickly
released after the lag-time of about 10 hours.
EXAMPLE3
5-Aminosalicylic acid (300 g) and guar gum(IOOg) were mixed together. The mixture was granulated according to a wet granulation method using a binding solution (180 g) of polyvinylpyrrolidone (trade name: Kollidon K30, available from BASF) (90 g) dissolved in ethanol (90 g). The obtained granules were dried and sieved to obtain granules for tabletting (585 g). A part of thus obtained granules for tabletting (530 g), calcium carbonate (lOOg), monosodium citrate (120g), calcium carboxymethylcellulose (trade name: ECG-505, available from Gotoku Chemical Co., Ltd.) (40 g) and magnesium stearate (10 g) were mixed together. The mixture was tabletted by means of a rotary tabletting machine to obtain a plain tablet (a core tablet) having a diameter of 6 mm and a weight of 70 mg.
The obtained plain tablet was press-coated with a mixture of powder of
hydroxypropylmethylcellulose acetate succinate (trade name: AQOAT (AS-LF), available
from The Shin-etsu Chemical Co., Ltd.), calcium stearate and magnesium stearate (the
mixing ratio, 8:1:1) in a coating amount of 200 mg per tablet by means of a press-coating
machine (Correct 18HUK-DC Type, made by Kikusui Seisakusho Ltd.) to obtain a
pharmaceutical preparation of the present invention in a form of a press-coated tablet having
a diameter of 9 mm and a weight of 270 mg.
With respect to thus obtained pharmaceutical preparation of the present invention, a
dissolution test was carried out with the second fluid of the test in USP XXIV under the same
conditions in Example 1. In the second fluid, the medicinal active ingredient was quickly
released after the lag-time of about 3 hours.
EXAMPLE4
The plain tablet containing 5-aminosalicylic acid obtained in Example 3 was press-coated with a mixture of powder of hydroxypropylmethylcellulose acetate succinate (trade name: AQOAT (AS-LF), available from The Shin-etsu Chemical Co., Ltd.), triacetin and hydrated silicon dioxide (the mixing ratio, 8:1:1) in a coating amount of 200 mg per tablet by means of a press-coating machine (Correct 18HUK-DC Type, made by Kikusui Seisakusho Ltd.) to
obtain a pharmaceutical preparation of the present invention in a form of a press-coated tablet having a diameter of 9 mm and a weight of 270 mg.
With respect to thus obtained pharmaceutical preparation of the present invention, a
dissolution test was carried out with the second fluid of the test in USP XXIV under the same
conditions in Example 1. In the second fluid, the medicinal active ingredient was quickly
released after the lag-time of about 3 hours.
EXAMPLE 5
The plain tablet containing 5-aminosalicylic acid obtained in Example 3 was press-coated
with a mixture of powder of Eudragit L (trade name, available from Rohm Pharma.
poly(methacrylic acid, methyl methacrylate)) and calcium stearate (the mixing ratio, 8 2) in a
coating amount of 350 mg per tablet by means of a press-coating machine (Correct 18HUK-
DC Type, made by Kikusui Seisakusho Ltd ) to obtain a pharmaceutical preparation of the
present invention in a form of a press-coated tablet having a diameter of 11 mm and a weight
of 420 mg.
With respect to thus obtained pharmaceutical preparation of the present invention, a
dissolution test was carried out with the second fluid of the test in USP XXIV under the same
conditions in Example 1. In the second fluid, the medicinal active ingredient was quickly
released after the lag-time of about 4 hours







WE CLAIM;
1. A release pharmaceutical preparation for colon delivery
comprising: -
a) a core containing a medicinal active ingredient as herein described along with an effervescent couple and mucoadhesive polymer, and
b) a press-coated layer provided around said core comprising an enteric polymer, lipophilic and hydrophobic substances, wherein the said layer is 150-160% by weight based on the weight of said core and said lipophilic and hydrophobic substances are in the amount of 5 to 100% by weight based on a weight of the enteric polymer.
c) A release pharmaceutical preparation as claimed in claim 1 wherein said effervescent couple, comprises an acid source and a base source and present, for example, in an amount of 1% to 20% by weight of the dosage form.

2. A release pharmaceutical preparation as claimed in claim 2 wherein said base comprises carbonate salts (e.g. calcium carbonate), bicarbonate salts (e.g. sodium bicarbonate), sesquicarbonate salts and mixture thereof.
3. A release pharmaceutical preparation as claimed in claim 2 wherein said acid comprises citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of such acids, acid salts of such acids, and mixtures thereof.


4. A release pharmaceutical preparation as claimed in claim 1 wherein said mucoadhesive polymer comprises at least one member selected from the group consisting of sodium carboxymethylethylcellulose, guar gum, carbopol).
5. A release pharmaceutical preparation as claimed in claim 1 wherein said enteric polymer comprises at least one member selected from the group consisting of carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate and poly (methacrylic acid, methyl methacrylate).
6. A release pharmaceutical preparation as claimed in claim 1 wherein comprising a lipophilic or hydrophobic substance in the press-coated layer, said substance being at least one member selected from the group comprising a plasticizer, a higher fatty acid and a metallic salt of a higher fatty acid.
7. A release pharmaceutical preparation as claimed in claim 7 wherein said lipophilic or hydrophobic substance comprises at least one member selected from the group consisting of magnesium stearate, calcium stearate, triacetin, lauric acid, capric acid, triethyl citrate and acetyl triethyl citrate.


Documents:

147-del-2005-Abstract-(11-03-2011).pdf

147-del-2005-abstract.pdf

147-del-2005-Claims-(11-03-2011).pdf

147-del-2005-claims.pdf

147-del-2005-Correspondence-Others-(11-03-2011).pdf

147-del-2005-correspondence-others.pdf

147-del-2005-correspondence-po.pdf

147-del-2005-Description (Complete)-(11-03-2011).pdf

147-del-2005-description (complete).pdf

147-del-2005-form-1.pdf

147-del-2005-form-18.pdf

147-del-2005-form-2.pdf

147-del-2005-form-26.pdf

147-del-2005-GPA-(11-03-2011).pdf

147-del-2005-petition-138.pdf


Patent Number 248830
Indian Patent Application Number 147/DEL/2005
PG Journal Number 35/2011
Publication Date 02-Sep-2011
Grant Date 29-Aug-2011
Date of Filing 24-Jan-2005
Name of Patentee JAMIA HAMDARD (HAMDARD UNIVERSITY)
Applicant Address HAMDARD NAGAR, NEW DELHI-110 062, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 MOHD AQIL JAMIA HAMDARD (HAMDARD UNIVERSITY), HAMDARD NAGAR, NEW DELHI-110 062, INDIA
2 ROOP K KHAR JAMIA HAMDARD (HAMDARD UNIVERSITY), HAMDARD NAGAR, NEW DELHI-110 062, INDIA
3 FARHAN JALEES AHMAD JAMIA HAMDARD (HAMDARD UNIVERSITY), HAMDARD NAGAR, NEW DELHI-110 062, INDIA
PCT International Classification Number A61K 9/46
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA