JP2005510477A - Drug delivery system with an anticonvulsant gap - Google Patents

Abstract

  The invention is an oxybutynin spaced drug delivery system comprising an immediate release composition and a timed pulse release composition, wherein a predetermined amount of oxybutynin is pulsed first, then at predetermined time intervals. To do the best treatment. The DDS is suitable for treating urinary incontinence by administration once or twice a day.

Description

  The present invention relates to an antispasmodic agent spaced drug delivery system that allows spaced drug delivery of oxybutynin. In the system, oxybutynin is first pulsed and then released at one or more predetermined time intervals.

  The oxybutynin hydrochloride or oxybutynin chloride (α-cyclohexyl-α-hydroxybenzeneacetic acid 4- (diethylamino) -2-butynyl ester hydrochloride) described in British Patent No. 940,540 and US Patent No. 4870074 is It is a muscular anticonvulsant with a mild anticholinergic, general analgesic and local anesthetic action. Relaxation on smooth muscle is based on antagonism of processes distal to the neuromuscular junction (papaverine-like effect) and anticholinergic activity with respect to muscarinic receptor blockade. Oxybutynin hydrochloride has been in clinical use for 20 years and has been noted to reduce symptoms associated with urination in patients with uninhibited neuropathic and reflex neuropathic bladder.

  Oxybutynin is rapidly absorbed from the gastrointestinal tract after oral administration and its pharmacological action begins within 1 hour. The action time of this agent is 3 to 6 hours. Its half-life is less than 2 hours. The usual dose in the management of incontinence is repeated doses of 5 mg tablets 2-4 times / day. This is difficult to achieve because it requires strict patient compliance and is also inefficient in cost.

An oxybutynin drug delivery system (drug delivery system, DDS) at an interval to eliminate the need for multiple doses in the treatment of urinary incontinence, eliminating the need for multiple doses in the treatment of urinary incontinence In order to do so, the concept of using DDS that first releases oxybutynin immediately and then pulses at one or more predetermined time intervals has never been known or even suggested in the art. Absent.
In addition, for optimal treatment of urinary incontinence, a spacey oxybutynin drug delivery system, in which a predetermined amount of oxybutynin is first pulsed and then a predetermined amount of oxybutynin is pulsed a predetermined number of times. To date, it has not been known or even suggested in the art.

  US Patent No. 3,247,066 ('066 patent) claims a non-toxic, insoluble, non-digestible film coating made of a ruptureable plastic that is inert to gastrointestinal fluids and disperses water. A controlled release dosage form comprising solid beads is described that contains a uniform dispersion of a drug encapsulated in a water-swellable colloid coated with a film coating that is permeable to. Here, the coating thickness and bead swellability indicate that when exposed to gastrointestinal fluid for a long period of time, water diffuses through the coating into the bead, resulting in swelling of the bead and cohesion of the coating. To the extent that the pressure rise exceeds, the coating surface ruptures and the drug is released from within the bead into the gastrointestinal fluid and diffuses. However, in the system disclosed and exemplified in the '066 patent, gelatin is used as the swellable colloid, and gelatin has only a low to moderate degree of swelling, so that the It does not swell as much as desired for pulsing at predetermined time intervals. Moreover, it does not suggest the use of anticonvulsants in the type of treatment that is the subject of the invention of this patent.

  US Patent No. 5,654,009 (the '009 patent) is for intramuscular or subcutaneous administration comprising a core portion containing a drug and a hydratable swellable polymer and a coating of biodegradable high molecular weight material surrounding the core. A delayed action formulation is disclosed. Water enters the core through the outer layer, causing the hydratable swellable polymer in the core to swell and rupture the outer membrane. This system claims an improvement over the prior art in that the outer membrane can be ruptured at a predetermined time. However, the system of the '009 patent does not imply or do not specifically mean that the drug can then be rapidly released as desired. Moreover, it does not suggest the use of anticonvulsants in the type of treatment that is the subject of the invention of this patent.

  US Patent No. 5840754 discloses a method for reducing the incidence of side effects in patients. The method is a tablet form of oxybutynin that delivers oxybutynin over a 24-hour period at a substantially controlled rate of release to control the plasma concentration of oxybutynin to the desired concentration and lower the maximum plasma concentration Consisting of administering a form of oxybutynin. The patent teaches those skilled in the art that pulsed release of oxybutynin may be undesirable.

  The present inventors have made a space drug delivery system (hereinafter referred to as “spaced DDS”) for oxybutynin or a pharmaceutically acceptable salt thereof. And (a) an immediate release composition that immediately releases oxybutynin or a pharmaceutically acceptable salt thereof; and (b) oxybutynin or a pharmaceutically acceptable salt thereof, Further, a spaced DDS has been found that consists of a timed pulse release composition that is adjusted to release at predetermined time intervals. Surprisingly, this Spaced DDS is suitable for twice / day or once / day treatment of urinary incontinence.

  Conventionally, there is no literature suggesting the use of such a spaced DDS with a programmed pulsed release of oxybutynin for twice / day or once / day treatment of urinary incontinence.

  The present invention is a Spaced DDS for twice / day or once / day treatment of oxybutynin, which is an antispasmodic agent spaced drug delivery system (hereinafter "antispasmodic agent spaced drug delivery system"). Anticonvulsant-Spaced DDS "). That is, in this spaced DDS, oxybutynin is first released and then pulsed once or twice with a predetermined time interval.

  More particularly, the present invention provides an anticonvulsant capable of providing a programmed delivery or release of a predetermined amount of oxybutynin with a predetermined number of pulses at predetermined time intervals, particularly for optimal treatment of urinary incontinence. It aims to provide a drug-spaced DDS.

The present invention discloses a novel concept regarding the spaced DDS for oxybutynin. The Spaced DDS of the present invention can be administered to a patient in a single dose to deliver oxybutynin in spaced timed pulses to maintain a therapeutically effective oxybutynin plasma concentration for 12-24 hours. it can. The patient is obviated from having to take multiple doses during this time.
In particular, the present invention provides an anticonvulsant-spaced DDS comprising an immediate release composition that instantaneously pulses oxybutynin and one or more timed pulsed release compositions that pulse release oxybutynin at predetermined time intervals. provide.

More specifically, the present invention is an anticonvulsant drug delivery system (anticonvulsant-spaced DDS) with an interval,
(a) an immediate release composition comprising oxybutynin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient;
(b) a timed pulsed release composition that pulses oxybutynin or a pharmaceutically acceptable salt thereof at approximately a predetermined time, and optionally,
(c) a timed release composition in accordance with the definition of (b) above, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is substantially predetermined when different from the timed pulse release composition described in (b) One or more compositions that sometimes pulse release.

  The spaced DDS of the present invention contains a therapeutically effective amount of oxybutynin in a twice / day or once / day treatment. The amount of oxybutynin hydrochloride present is preferably in the range of about 2.5 mg to 30 mg, more preferably in the range of about 5 mg to 15 mg.

  The amount of oxybutynin may be the same for the immediate release composition and the timed pulse release composition. For example, in an example of a particular embodiment of a spaced DDS containing 15 mg oxybutynin hydrochloride, a first timed pulsed release composition in which 5 mg is released in an immediate release composition and 5 mg releases 5 mg at a first predetermined time And 5 mg may be included in the second timed pulsed release composition that releases 5 mg at a second predetermined time.

  The amount of oxybutynin may be different for immediate release compositions and timed pulsed release compositions. For example, in an example of a particular embodiment of a spaced DDS containing 10 mg of oxybutynin hydrochloride, a first timed pulsed release where 2.5 mg is released in an immediate release composition and 4 mg releases 4 mg at a first predetermined time In the composition, and 3.5 mg may be included in the second timed pulsed release composition that releases 3.5 mg at a second predetermined time.

  Spaced DDS can be designed to release oxybutynin first as a pulse and then at predetermined time intervals to provide optimal therapy. The number of pulses in oxybutynin release can also be selected to optimize treatment. Thus, the spaced DDS of the present invention provides the ease and freedom in achieving the desired oxybutynin plasma concentration for optimal therapy.

  Immediate release compositions are well known in the art, and immediate release compositions in the spaced DDS of the present invention can be obtained by known techniques. Similarly, timed pulsed release compositions can be obtained by known methods, but it is preferred to obtain such compositions in accordance with the preferred embodiments of the invention described below.

The preferred anticonvulsant of the present invention -spaced DDS is
(a) an immediate release composition comprising oxybutynin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient;
(b) Oxybutynin or a pharmaceutically acceptable salt thereof, a swelling agent that swells and absorbs at least twice the volume when absorbing unbound water in the environment, and optionally a water-soluble compound to enhance the osmotic effect And a coating surrounding the core, the coating containing a coating agent selected to determine the amount of oxybutynin or a pharmaceutically acceptable salt thereof that is ruptured at approximately a predetermined time to release the pulse. A timed pulsed release composition, and
(c) a timed release composition according to the definition of (b) above, if desired, and oxybutynin or a pharmaceutical thereof at a time different from the timed pulse release composition described in (b) and at almost a predetermined time. A composition (one or more) that releases a pharmaceutically acceptable salt,
including.

  A preferred timed pulsed release composition of the present invention comprises a core comprising oxybutynin or a pharmaceutically acceptable salt thereof, a swelling agent, and optionally a water-soluble compound for enhancing permeability, and a coating surrounding the core. Where the coating ruptures or explodes as the liquid swells around the core, releasing oxybutynin or a pharmaceutically acceptable salt thereof as a pulse at approximately a predetermined time. The preferred timed pulsed release composition coatings of the present invention burst in a reliable manner. A total of 36 tablets were placed in an aqueous medium at 37 ± 0.5 ° C. using a USP type I or type II apparatus (rpm selected from about 50 rpm to about 100 rpm (number of revolutions per minute)). When subjected to the dissolution test, 36 tablets ruptured or exploded and pulsed release of oxybutynin or its pharmaceutically acceptable salt at approximately a predetermined time. Moreover, of the 36 tablets, 36 ruptured within about ± 50% from the predetermined time.

  The term “pulsed release” refers to normal tablets and capsules that do not have the design features of slow, long-term, controlled or delayed release of therapeutically active substances. Refers to release characteristics when tested in vitro. For example, in certain embodiments where the predetermined pulse release time is about 4 hours, “pulsed release of oxybutynin or a pharmaceutically acceptable salt thereof” at 37 ± 0.5 ° C. in acetate buffer at pH 4.5, When the tablet was subjected to USP dissolution test using USP type II apparatus (50 rpm), less than 10% of the active ingredient was released in 3 hours and 45 minutes, and 2 hours after film rupture or explosion (dissolution test) Approximately 6 hours after the start) over 70% of the active ingredient is released.

The swelling agent used in the preferred composition of the present invention is selected from hydrophilic polymers. The hydrophilic polymer may be of plant, animal, mineral or synthetic origin. Swellable polymers suitable for use in the present invention are (A) C _1-4 alkyl cellulose (eg, methyl cellulose, ethyl cellulose, etc.); hydroxy C _1-4 alkyl cellulose (eg, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.); Hydroxy C _1-4 alkyl C _1-4 alkyl cellulose (for example, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, etc.); Carboxy C _1-4 alkyl cellulose (for example, cellulose derivatives such as carboxymethyl cellulose, carboxyethyl cellulose, and alkali salts thereof: ( B) Vinylpyrrolidone polymers (such as polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone or Crospovidon); (C) Copolymers of vinylpyrrolidone and vinyl acetate (D) Rubber of plant, animal, mineral or synthetic origin (i) Agar, alginate, carrageenan, farseleran obtained from sea, (ii) Guar gum, gum arabic, tragacanth gum, caraya gum, locust bean gum obtained from terrestrial plants , (Iii) microbial polysaccharides such as dextran, gelatin gum, ramsan gum, welan gum, xanthan gum and (iv) synthetic or semi-compatible gums such as propylene glycol alginate and hydroxypropyl guar gum, and modified starches such as sodium starch glycolate The swelling agent used in the present invention is preferably a combination of the above-mentioned agents, and often the combination of the two agents provides controlled swelling, whereby the delivery system can be used for a predetermined time after taking. The coating or core is released by rupture or explosion.

  The swelling agent used in the present invention may contain one or more swellable hydrophilic polymers. The amount or composition ratio of the polymer can vary considerably. However, there is a sufficient amount of material in the core to take up a swelling pressure that exceeds the adhesion of the coating surrounding the tablet or core when water is taken up. Preferably, the polymer is used in a dry state or in a form having substantial capacity for water uptake. Examples of swellable hydrophilic polymers that can be used in the timed pulsed release composition of the present invention include vinylpyrrolidone polymers such as povidone, or crosslinked polyvinylpyrrolidones such as crospovidone; microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropyl Cellulose and cellulose derivatives such as cellulose, hydroxypropylmethylcellulose, carboxyalkylcellulose or crosslinked carboxyalkylcellulose and alkali salts thereof; sodium starch glycolate, starch and starch derivatives, ion exchange resins and mixtures thereof. Preferably, the swelling agent used is one that swells well but does not form a strong gel and can be selected from the group consisting of, for example, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, and sodium starch glycolate.

  Alkaline salts of cross-linked carboxyalkyl cellulose, ie, sodium carboxymethyl cellulose (also known as croscarmellose sodium or Ac-Di-Sol) are commercially available as Nymcel ZSX, Pharmacel XL, Primellose or Solutabo (all are registered trademarks). Yes. The amount of swelling agent that can be used depends on the nature and amount of the other components in the core and the composition and thickness of the coating at the time of rupture desired for the timed pulsed release coating. In general, croscarmellose sodium as the polymeric swelling agent is in an amount ranging from about 1 to about 95%, preferably from about 2 to about 40%, more preferably from about 5 to about 20% by weight relative to the core. Used in

  Vinylpyrrolidone polymer or polyvinylpyrrolidone (PVP), also known as Povidone, is a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidone groups, with a molecular weight of 2500- Polymers of various molecular weights ranging from 3,000,000 daltons are obtained. PVP is commercially available as Kollidon (registered trademark BASF), Plasdone and Peristone (registered trademark General Aniline). PVP is classified into various grades based on the viscosity as an aqueous solution. Various grades of PVP available include PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-60, PVP K-90 and PVP K-120. is there. In the above nomenclature, the K-value is a value calculated from the viscosity of the aqueous PVP solution compared to the viscosity of water. Crospovidone or cross-PVP, which is a synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidone, can also be used as the swellable hydrophilic polymer. It is marketed as Kollidon CL and Polyplasdone XL and has a molecular weight of over 1,000,000 daltons. Crospovidone can be used as a swellable hydrophilic polymer in an amount ranging from about 2 to about 5% by weight of the core. A vinyl pyrrolidone polymer that can be used as a preferred swellable hydrophilic polymer is PVP K-30 (molecular weight of about 50,000 daltons). It may be used in an amount ranging from about 0.5 to about 5% by weight of the core, preferably from about 1 to about 2%.

  Sodium starch glycolate, which is a carboxymethyl ether of starch, can also be used as a polymeric swelling agent. It has a molecular weight between 500,000 and 1,000,000 daltons and is commercially available as Bxplotab and Primojel. Sodium starch glycolate can be used in amounts ranging from about 0.5 to about 40%, preferably from about 2 to about 40%, more preferably from about 2 to about 10%, by weight of the present hammeini, core.

  The core in the timed pulsed release composition preferably includes a wicking agent. As used herein and in the claims, the phrase “wicking agent” has a broader definition than conventional wicking agents and includes any pharmaceutical excipient. Such excipients include any pharmaceutical excipient that provides water entry into the core via any suitable mechanism, preferably the capillary action typical of conventional wicking agents. Materials that can be used as wicking agents in timed pulsed release compositions include colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, sodium lauryl sulfate, microcrystalline cellulose, low molecular weight polyvinylpyrrolidone, bentonite, silicic acid Although aluminum, magnesium, etc. are mentioned, it is not limited to these. The anticonvulsant-spaced DDS timed pulsed release composition of the present invention can be optimized for a reliable burst mode without the use of a wicking agent. However, it has been found that the use of a wicking agent makes the burst mode optimization work easier.

  The microcrystalline cellulose (MCC) used as a wicking agent in a preferred embodiment is formed of microcrystalline, chained, approximately 250 glucose molecular chains, which are primarily non-hydrolyzed from a pure cellulose raw material by hydrolysis with mineral acids. It can be obtained by removing the amorphous part. MCC has an average molecular weight of about 36,000 daltons and can be obtained in various grades. Each grade differs in bulk density, particle size (particle size) and moisture content. It is commercially available as Vivapur, Avicel, Vivacel, Emcocel, Fibrocel and Tabulose (all are registered trademarks). More preferred for use in timed pulsed release compositions on Avicel® PH 101 (average particle size 50 μm, ie # 60 sieve (based on ASTM, American Society for Testing and Materials)) The remaining particles are 1% or less, the particles remaining on the # 200 sieve (according to ASTM definition) are 30% or less, and the water content is 5%. ] And Avicel® PH 102 [average particle size is 100μm, ie no more than 8% particles remain on # 60 sieve (based on ASTM, American Society for Testing and Materials), # 200 sieve (according to ASTM definition) ) More than 45% of the particles remaining on it, and the water content is 5%. ].

  The wicking agent preferably comprises a mixture of microcrystalline cellulose (MCC) and colloidal silicon dioxide. In a preferred embodiment of the present invention prepared by a granulation method, MCC is added intragranularly or extragranularly. Here, the MCC is present intragranularly in an amount ranging from about 30 to about 90% by weight relative to the core, more preferably from about 40 to about 60% by weight. Preferably, the total amount is present with the colloidal silicon dioxide in an amount ranging from about 1 to about 10 weight percent, more preferably from about 2 to about 5 weight percent.

Water-soluble compounds suitable for inducing osmotic properties, ie osmotic agents (osmagents), are generally timed pulses when the drug itself does not exert sufficient osmotic pressure to absorb liquid sufficiently from the surroundings. Used in the core of the release composition. Osmogens that may be present in the core of a timed pulsed release composition include all pharmaceutically acceptable, pharmacologically non-toxic water-soluble compounds, and pharmacies such as the United States Pharmacopoeia. And those described in Remington's The Science and Practice of Pharmacy, 20th edition, Lippincott Williams and Wilkins, Philadelphia (2000). Pharmaceutically acceptable water-soluble salts of inorganic or organic acids, or highly water-soluble non-ionic organic compounds (eg, carbohydrates such as sugars or amino acids) are generally preferred. Examples of substances used to induce osmotic pressure include magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate Inorganic acid salts such as sodium dihydrogen phosphate and potassium dihydrogen phosphate;
Organic acid salts such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate; mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose Carbohydrates such as lactose, rafinose; water-soluble amino acids such as glycine, leucine, alanine or methionine; urea and the like, and mixtures thereof. The amount of osmogen used will vary depending on the particular osmogen used and will range from about 1 to about 60% by weight of the core.

In addition to the above components, the core of the timed pulsed release composition may optionally include pharmaceutically acceptable excipients (eg, binders, disintegrants, lubricants, etc.). Examples of commonly used binders include sugars such as starch, gelatin, sucrose, glucose, dextrose, molasses and lactose; cellulose derivatives such as gum arabic, sodium alginate, methylcellulose, ethylcellulose, carboxymethylcellulose; and polyvinylpyrrolidone, Veegum , Polymers such as polyethylene glycol and waxes. Examples of lubricants that can be used in timed pulsed release compositions include talc, magnesium stearate, calcium stearate, aluminum stearate, stearic acid, hydrogenated vegetable oil, colloidal silicon dioxide, polyethylene glycol, carboxyalkyl cellulose and Examples thereof include cellulose derivatives such as alkali salts, and mixtures thereof. Hydrophobic or water-insoluble lubricants are preferred because they reduce the water absorption of the core but hydrophilic or water-soluble lubricants do not. A more preferred lubricant is colloidal silicon dioxide. A mixture of colloidal silicon dioxide and magnesium stearate can be used as a suitable lubricant. In a more preferred embodiment, microcrystalline cellulose and colloidal silicon dioxide are used in combination as a wicking agent, in which case the colloidal silicon dioxide also acts as a lubricant. Colloidal silicon dioxide is commercially available as Aerosil® (Degussa-Huls, Nippon and Fischer GmbH). A preferred colloidal silicon dioxide lubricant is Aerosil® 200 (approximate outer surface area: about 200 ² / g). Colloidal silicon dioxide can be used in an amount of about 0.5 to about 5 weight percent based on the core.

  The coating surrounding the core is substantially drug impermeable and does not release a substantial amount of drug until it ruptures or explodes after a predetermined time after taking the delivery system. Coating agents that can be used in the present invention are selected from water-insoluble polymers, hydrophobic compounds, hydrophilic non-polymeric compounds and hydrophilic polymers (which may be of vegetable, animal, mineral or synthetic origin) Is done. Suitable coating agents include, among others, cellulose acetate phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose and the like, carrageenan and mixtures thereof; methacrylic acid and methacrylic acid esters [ For example, anionic and cationic polymers of methacrylic acid, copolymers of methacrylate, copolymers of acrylate and methacrylate, copolymers of ethacrylate and methyl methacrylate, etc.], polyvinyl acetate phthalate, wax (eg beeswax, carnauba wax) Etc.), glyceryl monostearate, stearic acid, palmitic acid, glyceryl monopalmitate, cetyl alcohol, etc., or mixtures thereof It is below. The term “coating agent” as used herein and in the claims encompasses plasticizers contained in coating compositions and is known to those skilled in the art. The plasticizer may be a low molecular weight compound or may itself be a polymer. A preferred coating agent is a mixture of at least two coating agents. The time (time) at which oxybutynin or a pharmaceutically acceptable salt thereof is released from the timed release composition will vary depending on the change in the ratio of the two or more coating agents. The coating agent is preferably a combination of a water-insoluble polymer and a water-soluble compound selected from a water-soluble plasticizer and a water-soluble polymer. In a preferred embodiment of the invention, a mixture of ethylcellulose and hydroxypropylmethylcellulose (HPMC) in the mixture is used as the coating agent. It is preferable to mix ethyl cellulose and hydroxypropyl methyl cellulose and use them in a proportion suitable to cause the coating to open after a predetermined time from oral administration of the delivery system. The preferred ratio of the two polymers used, ethylcellulose: hydroxypropylmethylcellulose, is a ratio of ethylcellulose: hydroxypropylmethylcellulose of about 0:20 to about 20: 0, more preferably about 4: 1 to about 2: 1.

  A more preferred embodiment of the present invention provides an immediate release composition that releases oxybutynin or a pharmaceutically acceptable salt thereof within 30 minutes after oral administration; A first timed pulsed release composition, oxybutynin or a pharmaceutically acceptable salt thereof that pulses at approximately a predetermined time during 6 hours, is pulsed at approximately a predetermined time between 6 and 10 hours after oral administration. A spaced DDS comprising a second timed pulsed release composition. In a particularly preferred embodiment, the amount of oxybutynin released at 0 hours, 3-6 hours and 6-10 hours is 33.33% by weight of the total amount of oxybutynin in the spaced DDS at each of these releases. In another preferred embodiment, the amount of oxybutynin released at 0 hours, 3-6 hours, and 6-10 hours is 25%, 40% by weight and the total amount of oxybutynin in the spaced DDS, respectively, at each of these releases. 35% by weight.

  In a particularly preferred embodiment of the invention, the core of the timed pulsed release composition contains the ingredients listed in Table 1 below and optionally other pharmaceutical excipients.

  The core of the timed pulsed release composition of Table 1 above is a coating consisting of a coating agent comprising a mixture of coating agent ethylcellulose: hydroxypropylmethylcellulose (weight ratio 4: 1 to 2: 1, most preferably 3: 1). It may be surrounded. In order to pulse release oxybutynin or a pharmaceutically acceptable salt thereof at about 4 hours, the coating agent can be added in an amount of about 12-15% by weight based on the core. Alternatively, the coating agent can be added in an amount of about 18-22% by weight relative to the core to pulse release oxybutynin or a pharmaceutically acceptable salt thereof at about 8 hours. In a highly preferred embodiment, the spaced DDS for oxybutynin or a pharmaceutically acceptable salt thereof is an immediate release composition, a first timed pulse release composition that provides a pulse release at 4 hours, an 8 hour A second timed pulsed release composition that provides pulsed release.

The anticonvulsant space DDS of the present invention can be prepared by methods well known to those skilled in the art. Timed pulsed release compositions can be prepared in the form of coated tablets, coated pellets or coated granules by methods known to those skilled in the art. Immediate release compositions can be prepared in accordance with conventional methods, as separate physical components of the system, eg, separate or physically distinct particles, granules, beads or tablets. Alternatively, the immediate composition can be formed in a layer connected to the timed pulsed release composition as a layer surrounding the laminated or timed pulsed release coating. When the composition is present as a layer or coating on the timed pulsed emission core, it is formed by methods known to those skilled in the art such as, for example, powder layering or compression coating. Alternatively, the active ingredient (s) may be dissolved in a suitable solvent and sprayed onto the coated core to form an immediate release layer.
The following examples are for purposes of illustration and are not intended to limit the scope of the invention.

Example 1
The anticonvulsant space DDS of the present invention was prepared as described in Table 2 below.

  The core of the immediate release tablet, the core of the tablet that releases oxybutynin at a predetermined time (4 hours), and the core of the tablet that releases oxybutynin at a predetermined time (8 hours) are in accordance with the methods described herein. Prepared. Oxybutynin hydrochloride, Avicel PH 101, lactose monohydrate, and croscarmellose sodium were sifted using a suitable sieve and mixed with a rapid stirring granulator. After the dry mixed powder was granulated using 10% starch paste, the lump was wet crushed through a Fitzmill (crush granulator). The granules thus obtained were dried to a moisture content of 3-4%. The dried granules were then ground in a Fitzmill through a 1.55 mm screen and the granules were screened with # 16 sieves (according to American / Materials Testing Institute (ASTM) standards). These oxybutynin hydrochloride granules were then mixed with Avicel PH 102, colloidal silicon dioxide and magnesium stearate, and the resulting smooth mixture was tableted with a rotary tableting machine using a circular tableting punch.

  The core of the immediate release tablet was not coated, but the tablet core for releasing the drug at predetermined time intervals was coated using the coating composition described in Table 3 below.

  Tablets were coated in a normal coating pan with ethylcellulose and HPMC E50 in a mixture of dichloromethane and methanol. Tablets that release oxybutynin at a predetermined time of about 4 hours could be obtained by coating the tablets to increase 13-14% by weight of the core weight. In addition, a tablet that releases oxybutynin at a predetermined time of about 8 hours could be obtained by coating the tablet so as to increase 20% by weight of the core weight.

  By encapsulating one immediate release tablet, one tablet releasing oxybutynin at a predetermined time of about 4 hours, and one tablet releasing oxybutynin at a predetermined time of about 8 hours in a hard gelatin capsule, The spasm drug Spaced DDS was obtained.

Example 2
The anticonvulsant space DDS of the present invention was prepared according to the formulation shown in Table 4 below.

  The core of the immediate release tablet, the core of the tablet releasing oxybutynin at a predetermined time (4 hours), and the core of the tablet releasing oxybutynin at a predetermined time (8 hours) are according to the method described in Example 1. Prepared.

  The core of the immediate release tablet was not coated, but the tablet core for releasing the drug at predetermined time intervals was coated with the coating composition described in Table 5 below.

  Tablets were coated in a normal coating pan with ethylcellulose and HPMC E50 in a mixture of dichloromethane and methanol. Tablets that release oxybutynin at a predetermined time of about 4 hours could be obtained by coating the tablets to increase 13-14% by weight of the core weight. In addition, a tablet that releases oxybutynin at a predetermined time of about 8 hours could be obtained by coating the tablet so as to increase 20% by weight of the core weight.

One immediate release tablet, one tablet releasing oxybutynin at a predetermined time of about 4 hours, and one tablet releasing oxybutynin at a predetermined time of about 8 hours were encapsulated in a hard gelatin capsule. The capsules were subjected to a dissolution test using a USPII type apparatus (rpm = 50) at 37 ± 0.5 ° C. in an acetate buffer (pH 4.5). The release profile of oxybutynin is recorded and shown in Table 6.

Example 3
The bioavailability of the anticonvulsant drug DDS (oxybutynin hydrochloride 10 mg TR capsule) of the present invention and a commercially available long-term release tablet of oxybutynin hydrochloride (sustained release preparation) (Ditropan XL, 10 mg tablet) was studied. The formulation was subjected to a single dose, open label, randomized control and two-way crossover pharmacokinetic study with a 14-day washout period.

  An oxybutynin hydrochloride capsule (10 mg) (SPARC, Mumbai) was used as a reference product, and Ditropan XL tablets (10 mg) (Alza Corporation, USA, Lot no. TF 332, expiration date: May 2002).

  The pharmacokinetic assessment was performed by measuring plasma concentration of oxybutynin hydrochloride by blood sampling. Blood samples were obtained before and after administration of the test and reference products at the following time points. 2, 4, 5, 6, 7, 8, 9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 14, 24, 36 and 48 hours.

  Six healthy male volunteers participated in the study and all completed the two-way crossover study. Subjects fasted overnight before dosing and 4 hours after dosing. Water intake was also prohibited from 2 hours before dosing to 2 hours after dosing. Standard meals were given at 4 and 8 hours after dosing and at appropriate times thereafter. During both periods, the meal plan was the same.

  Subjects were fasted overnight for study, then once orally administered oxybutynin hydrochloride capsules (10 mg) (test product) and Ditropan XL tablets (10 mg) (reference product) at room temperature with water (240 ml).

  Plasma concentrations of oxybutynin in samples taken at various time points were measured and averaged from 6 volunteers. The data is shown in Table 7 below. The plasma concentration with respect to the time coordinate axis is shown in FIG.

  Although the present invention has been described with reference to specific embodiments, this is merely for purposes of illustration and should not be construed as limiting the scope of the invention.

Figure 3 represents the plasma concentration profile over time comparing the oxybutynin hydrochloride space DDS dosage form of the present invention to a commercially available Ditropan XL tablet.

Claims (14)

An anticonvulsant, space drug delivery system,
(a) an immediate release composition comprising oxybutynin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient;
(b) a timed pulsed release composition that pulses oxybutynin or a pharmaceutically acceptable salt thereof at approximately a predetermined time, and optionally,
(c) a timed release composition in accordance with the definition of (b) above, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is substantially predetermined when different from the timed pulse release composition described in (b) Drug delivery systems comprising one or more compositions that sometimes pulse release. An anticonvulsant, space drug delivery system,
(a) an immediate release composition comprising oxybutynin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient;
(b) Oxybutynin or a pharmaceutically acceptable salt thereof, a swelling agent that swells and absorbs at least twice the volume when absorbing unbound water in the environment, and optionally a water-soluble compound to enhance the osmotic effect And a coating surrounding the core, the coating containing a coating agent selected to determine the amount of oxybutynin or a pharmaceutically acceptable salt thereof that is ruptured at approximately a predetermined time to release the pulse. A timed pulsed release composition, and optionally,
(c) a timed release composition in accordance with the definition of (b) above, and oxybutynin or a pharmaceutically acceptable product thereof at a substantially different point in time from the timed pulse release composition described in (b) One or more compositions that pulse release salt;
Drug delivery system including   The anti-convulsant drug-spaced drug delivery system of claim 2, wherein the swelling agent is selected from the group consisting of crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, and sodium starch glycolate.   The space drug delivery system for anticonvulsants according to claim 2, wherein the coating agent is a composition containing at least two types of coating agents.   The antispasmodic drug of Spaced Drug Delivery according to claim 4, wherein the coating agent is a mixture of a water-insoluble polymer, a water-soluble polymer, and a water-soluble compound selected from a water-soluble plasticizer and a water-soluble polymer. system.   The anticonvulsant drug-spaced drug delivery system according to claim 5, wherein the coating agent comprises a mixture of ethylcellulose and hydroxypropylmethylcellulose.   The anti-convulsant drug-spaced drug delivery system according to claim 2, wherein the swelling agent is croscarmellose sodium.   3. The anticonvulsant, space drug delivery system of claim 2, wherein the timed pulsed release composition also contains a wicking agent.   9. The anticonvulsant space drug delivery system of claim 8, wherein the wicking agent is selected from microcrystalline cellulose, colloidal silicon dioxide and mixtures thereof. 3. The anticonvulsant, space drug delivery system of claim 2, wherein the core contains the ingredients listed in the table below and optionally other pharmaceutically acceptable excipients.

  11. The anticonvulsant according to claim 10, wherein the film surrounding the core contains a coating agent comprising a mixture of ethylcellulose and hydroxypropylmethylcellulose (weight ratio of ethylcellulose: hydroxypropylmethylcellulose = about 4: 1 to about 2: 1). Spaced drug delivery system.   12. The anti-convulsant drug-spaced drug delivery according to claim 11, wherein the coating agent is used in an amount of about 12 to 15% by weight based on the core so that the predetermined release time is about 4 hours. ·system.   12. The anti-convulsant drug-spaced drug delivery according to claim 11, wherein the coating agent is used in an amount of about 18-22% by weight based on the core so that the predetermined release time is about 8 hours. ·system. A spaced drug delivery system of the anticonvulsant according to claim 2,
(a) an immediate release composition comprising oxybutynin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient;
(b) a first timed pulsed release composition that pulses oxybutynin or a pharmaceutically acceptable salt thereof after about 4 hours; and
(c) A drug delivery system comprising a second that pulses oxybutynin or a pharmaceutically acceptable salt thereof after about 8 hours.

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