JP2009514989A - Modified release loxoprofen composition - Google Patents

Abstract

The present invention relates to a modified release composition comprising loxoprofen or a salt or derivative thereof that effectively delivers a drug in a pulsed or sustained manner for the treatment of pain and / or inflammation.
The composition can include a first loxoprofen element and one subsequent loxoprofen element, wherein the first loxoprofen element includes an immediate release element and the subsequent loxoprofen element includes a modified release element. Composition.
[Selection figure] None

Description

Cross-reference of related applications This application takes advantage of US Provisional Application No. 60/679517 filed on May 9, 2005 and US Application No. 11/372857 filed on March 10, 2006. Claiming the benefit of US Provisional Application No. 60/106726, filed on Nov. 2, 1998, as well as PCT Application No. PCT / US99 / 25632, filed Nov. 1, 1999. Same as US Pat. No. 6,730,325, which is a continuation of US application Ser. No. 09 / 5,636, filed on May 8, 2000, which is also a continuation application, currently US Pat. No. 6,228,398. This is a continuation of US application Ser. No. 09/850425, filed on May 7, 2001, and is similar to US Pat. No. 6,902,742. Continuation of US Application No. 10 / 354,834 filed Jan. 30, 2003 in current US Pat. No. 6,793,936, which is a continuation application of US Application No. 10/331754 filed on May 30 A part of US Application No. 11/372857, filed on Mar. 10, 2006, which is a continuation-in-part of US Application No. 10 / 87,689 filed on Apr. 19, 2004 It is a continuation application.
The present invention relates to novel compositions and dosage forms for the treatment of pain and inflammation. In particular, the present invention relates to novel compositions and dosage forms for delivery of loxoprofen or a salt or derivative thereof, and therapeutic methods using them.

  Loxoprofen is a prodrug of a phenylpropionic acid-based non-steroidal anti-inflammatory drug (NSAID). In the case of oral administration, it is metabolized to trans-OH form in the body (mainly liver and kidney) and exhibits potential anti-inflammatory activity. Loxoprofen is rapidly absorbed by the gastrointestinal tract located in the inflamed area and functions as an anti-inflammatory analgesic that is associated with skeletal muscle and joint injury or applied to pain and inflammation resulting from surgery. Loxoprofen is particularly useful for pain and inflammation caused by chronic arthritis, rheumatism, low back pain and traumatic injury.

Loxoprofen exhibits a white crystalline powder that is white or slightly yellowish. The chemical name for loxoprofen, sometimes referred to as loxoprofen sodium, is monosodium 2- [4- (2-oxocyclopentylmethyl) phenyl] propionate dihydrate. The empirical formula of loxoprofen is C ₁₅ H ₁₇ NaO ₃ .2H ₂ O, and the molecular weight is 304.31. The structural formula of loxoprofen is shown below:

  Loxoprofen is reported, for example, in US Pat. No. 6,248,350 “External preparation containing loxoprofen” which describes an anti-inflammatory sedation patch containing loxoprofen and is incorporated herein in its entirety. Conventional loxoprofen tablets such as LOXONIN® (Sankyo Corporation, Japan) are orally administered three times a day for the treatment of pain and inflammation.

  Loxoprofen has a high therapeutic value for the treatment of pain and inflammation associated with skeletal muscle disorders, joint disorders or due to surgery. If loxoprofen must be administered orally three times a day, strict patient compliance is an important factor in the efficacy of loxoprofen. In addition, such frequent administration often requires the attention of medical personnel, leading to increased costs associated with loxoprofen treatment. Thus, there is a need in the art for a loxoprofen composition that overcomes the above and other challenges associated with using conventional dosage forms of loxoprofen for the treatment of pain and inflammation.

  The purpose of many modified release formulations is to provide a substantially sustained release of the drug compound. Indeed, the specific purpose of these formulations is to minimize the fluctuations in plasma concentration levels often associated with conventional frequent dosing schedules. Another purpose of the modified release formulation is to speed up the onset of action by minimizing the time between administration of the drug and reaching a therapeutically effective plasma concentration. Another purpose of the modified release formulation is to maintain a therapeutically effective plasma concentration between doses. However, it is difficult to achieve two or all three of the above objectives of conventional formulations. Thus, combining at least two different release profiles results in minimal variation in plasma concentration levels and / or rapid onset of action and / or therapeutically effective plasma concentrations between doses A modified release composition or formulation that achieves a plasma profile that maintains is desirable.

  Conventional frequent dosing schedules that regularly administer immediate release (IR) dosage forms result in a typical pulsed plasma profile. In such cases, the peak plasma drug concentration is seen after administration of each IR dose, and a period of low drug concentration is observed between successive administration time points. Such a regimen and the resulting pulsed plasma profile that accompanies it may have certain pharmacological and therapeutic effects that are effective for certain drug therapies. For example, drug disappearance periods due to a decrease in plasma concentration of the active ingredient between peaks are believed to reduce and prevent patient tolerance to various drugs.

  For certain drugs, the therapeutic and pharmacological effects inherent to the pulse system are lost or reduced as a result of the constant or nearly constant plasma concentration level achieved by the zero order release drug delivery system. That is, although it is desirable to reduce the need for frequent administration, modified release compositions or formulations substantially mimic the release of frequent IR dosage regimens.

  A typical example of a drug that can cause resistance in a patient is methylphenidate. Methylphenidate, or α-phenyl-2-piperidine acetate methyl ester, is a stimulant that acts on the central nervous system and respiratory system and is primarily used in the treatment of attention deficit passive disorder (ADHD). After absorption from the gastrointestinal tract (GIT), the drug effect lasts 3-6 hours after oral administration for conventional IR tablets, or about 8 hours after oral administration for sustained release formulations. The total dose is typically 5-30 mg per day with the exception of 60 mg / day. In conventional dosing schedules, methylphenidate is typically administered twice daily, before breakfast and twice before lunch. The last dose is preferably administered several hours before bedtime. Side effects associated with methylphenidate treatment include insomnia and increased patient tolerance.

  WO 98/14168 (Alza Corp.) teaches dosage forms and methods of administering methylphenidate at a sustained, constant and increasing rate. The disclosed dosage forms comprise a plurality of beads comprising a hydrogel matrix that increases the active ingredient coated with varying amounts of release rate controlling material. The appropriate combination of active ingredient dose, as well as the number and thickness of coating layers, can be selected to provide a gradual release profile in which the plasma concentration of the active ingredient increases continuously over a desired period of time. The purpose of WO 98/14168 is to increase the constant rate of increase in order to specifically avoid the blood levels (specified by peaks and minimums) becoming inconsistent in relation to conventional treatment with immediate release drugs. Is to release the dosage form. As a result, the formulation does not deliver the active ingredient in a pulsed or bimodal manner.

  WO 97/03672 (Chiroscience Ltd.) discloses that methylphenidate exhibits a therapeutic effect when administered in the form of a racemic mixture or in the form of a single isomer (such as the RRd-threoenantiomer). In addition, WO 97/03673 (Chiroscience Ltd.) discloses sustained release formulations containing d-threomethylphenidate (dtmp). The present disclosure teaches the use of a composition comprising a coating wherein dtmp is passed to achieve sustained release and to achieve a serum level (of active ingredient) of at least 50% cmax over a period of at least 8 hours. As noted above, the formulation does not deliver the active ingredient in a pulsed or bimodal manner.

  Shah et al., J. Cont. Rel. (1989) 9: 169-175 show that some hydroxypropyl methylcellulose ethers can produce a bimodal release profile when compressed into a solid dosage form with a therapeutic agent. Note, however, that the polymer from one feed produced a bimodal profile, but the same polymer from a different source with almost the same product characteristics produced a non-bimodal profile. ing.

  Giunchedi et al., Int. J. Pharm (1991) 77: 177-181 discloses the use of a multiple-unit formulation of a hydrophilic matrix for the pulsed release of ketoprofen. Giunchedi et al. Teach that ketophan disappears rapidly from the blood after administration (plasma half-life of 1-3 hours) and that sustained pulses of the drug may be more useful than constant release depending on the treatment. The disclosed composite unit formulation comprises four identical hydrophilic matrix tablets placed in a gelatin capsule. In vivo studies show two peaks in the plasma profile, but the disappearance period is not fully specified and the variation between the peak and the minimum is small.

  Conte et al., Drug Dev. Ind. Pharm, (1989) 15: 2583-2596 and European Application No. 0274734 (Pharmidea Srl) teach the use of tri-layer tablets to deliver ibuprofen in sustained pulses. The three-layer tablet is composed of a first layer containing an active ingredient, a third layer containing an active ingredient, and a protective layer (second layer) of a semipermeable material sandwiched between the first layers. The protective layer and the third layer are covered with an impervious envelope. The first layer dissolves upon contact with the dissolving solution, but the third layer is effective only after the protective layer has collapsed or ruptured. In the tablet, the first part of the active ingredient must be released quickly. This approach must also provide a semi-permeable layer between the first and third layers to control the relative rate of delivery of the two parts of the active ingredient. Moreover, when the semipermeable layer ruptures, an uncontrolled release of the active ingredient in the second part occurs.

  US Patent Application No. 5,158,777 (ER Squibb & Sons Inc.) includes a combination of entero-coated or delayed release coated captopril in a pH stable core with other captopril applicable for immediate release after administration. Disclosed is a formulation. In order to form a pH stable core, a chelating agent such as disodium edetate or a surfactant such as polysorbate 80, each alone or in combination with a buffering agent. There are captopril quantities available for immediate release after oral administration in this composition, as well as captopril quantities that are otherwise pH stabilized to be released in the colon.

  U.S. Pat. Nos. 4,728,512, 4,794,001 and 4,904,476 (American Home Products Corp.) relate to preparations that provide three different releases. The preparation is a group of 3 spheroids containing the active drug substance: Group 1 spheroids are uncoated and immediately disintegrate to release the initial dose of drug substance upon ingestion; Group 2 spheroids are pH sensitive capsules Coated to provide a second dose; the third spheroid group is coated with a pH independent coating to provide a third dose. This preparation is designed for sustained release of pharmaceutical substances that are extensively presystemically metabolized or have a rapid elimination half-life.

  US Pat. No. 5,837,284 (Mehta et al.) Discloses a methylphenidate dosage form with immediate release and delayed release particles. This delayed release particle is brought about by the use of ammonio methacrylate pH independent polymer in combination with several fillers.

  The present invention is a composition comprising a population of loxoprofen-containing particles, wherein the composition is delivered orally to the patient and then loxoprofen or a salt or derivative thereof is pulsed or sustained in the patient. For delivery, it relates to a modified release coating, a modified release matrix material or a composition comprising them together. As used herein, “loxoprofen” includes the specific compounds described above and all pharmaceutically acceptable salts and derivatives thereof. The present invention also relates to a dosage form comprising the composition and a method for treating pain and / or inflammation comprising the step of providing the dosage form.

  Other objects and advantages of the present invention will be apparent to those skilled in the art from the following "invention," which illustrates and describes preferred embodiments of the invention and is merely illustrative of the best modes for carrying out the invention. It will be readily apparent from the detailed description. Naturally, the invention may be in other different forms, and some of these details may be modified in various obvious aspects, including and without departing from the invention.

  The efficacy of a pharmaceutical compound in the prevention and treatment of a disease state depends on a variety of factors including the rate and duration of the compound delivered to the patient from the dosage form. The combination of delivery rate and duration exhibited by any dosage form in the patient's body can be described as an in vivo release profile and, depending on the pharmaceutical compound administered, referred to as the plasma profile in the plasma. It will be related to the concentration and duration of the pharmaceutical compound. Because pharmaceutical compounds have varying pharmacokinetic properties such as biocompatibility, absorption and elimination rates, the release profile and resulting plasma profile is an important factor in considering the design of effective drug treatments .

  The release profile of the dosage form may be shown differently in the rate and duration of release and may be continuous or pulsed. Sustained release profiles include those in which the amount of one or more pharmaceutical compounds is sustainedly released at a constant rate or at various rates between doses. A pulsed release profile includes a release profile in which at least two separate amounts of one or more pharmaceutical compounds are released over different rates and / or different time periods. For any given pharmaceutical compound or combination of compounds, the release profile of any dosage form provides the patient with a plasma profile associated therewith. Where two or more dosage form elements have different release profiles, the dosage form release profile as a whole is a combination of the individual release profiles and can generally be described as “multimodal”. A release profile of a two-element dosage form, each element being a different release profile, can be described as “bimodal”, and a three-element dosage form release profile, wherein each element Can be described as “trimodal”.

  Similar to the variables that can be applied to the release profile, the associated patient's plasma profile may exhibit and persist at a constant or varying blood plasma concentration level of the pharmaceutical compound during the duration of action. Or a pulse may be sufficient. Sustained plasma profiles include plasma profiles of all rates and durations that exhibit a maximum single plasma concentration. A pulsed plasma profile includes a plasma profile in which at least two high blood plasma concentration levels of a pharmaceutical compound are separated at a low blood plasma concentration level, and is generally described as “multimodal” can do. A pulsed plasma profile showing two peaks may be described as “bimodal” and a plasma profile showing more than two peaks may be described as “trimodal”. Depending, at least in part, on the pharmacokinetics of the pharmaceutical compound contained in the dosage form, as well as the release profile of the individual elements of the dosage form, a multimodal release profile can produce a sustained or pulsed plasma profile when administered to a patient. Bring.

In one aspect, the present invention provides a multiparticulate modified release composition that delivers loxoprofen in a pulsed fashion.
In another aspect, the present invention provides a multiparticulate modified release composition containing loxoprofen that produces a plasma profile that is substantially similar to the plasma profile that results from administration of three IR dosage forms given sequentially.

  In yet another aspect, the present invention provides a multiparticulate modified release composition that substantially mimics the pharmacological and therapeutic effects produced by administration of three IR dosage forms of loxoprofen given sequentially.

In yet another aspect, the present invention provides a multiparticulate modified release composition that delivers loxoprofen in a sustained manner.
In yet another aspect, the present invention provides a multiparticulate modification that is immediately released upon administration of a first loxoprofen moiety and that subsequent portions of one or more loxoprofen are released after an initial time delay. A release composition results.

  In yet another aspect, the invention provides a multiparticulate modified release composition that is rapidly acting and has a pharmaceutically effective plasma concentration level of loxoprofen of about 12 hours to about 24 hours.

In another aspect, the present invention provides a solid oral dosage form comprising a multiparticulate modified release composition of the present invention for administration once a day or twice a day.
In another aspect, the present invention further provides a method for treating pain and / or inflammation comprising the step of providing a solid oral dosage form of the present invention.

  In one aspect of the invention, a pharmaceutical composition is provided having a first element comprising active ingredient-containing particles and at least one subsequent element comprising active ingredient-containing particles, each subsequent element being released. Unlike the first element, the rate and / or duration is at least one of the elements comprises loxoprofen-containing particles. Loxoprofen-containing particles may be coated with a modified release coating. Alternatively or additionally, the loxoprofen-containing particles may comprise a modified release matrix material. After oral delivery, the composition delivers loxoprofen in a pulsatile manner. In one aspect, the first element provides an immediate release of loxoprofen and one or more subsequent elements provide a modified release of loxoprofen. In such embodiments, the immediate release element functions to accelerate onset of action by minimizing the time between administration and reaching a pharmaceutically effective plasma concentration level, and 1 Or more subsequent elements function to minimize fluctuations in plasma concentration levels and / or maintain a pharmaceutically effective plasma concentration between doses.

  The modified release coating and / or modified release matrix material creates a lag time between the release of the active ingredient from the first population of active ingredient-containing particles and the release of the active ingredient from the subsequent population of active ingredient-containing particles. . Where one or more populations of active ingredient-containing particles provide modified release, the modified release coating and / or modified release matrix material causes a lag time between the release of active ingredients from different populations of active ingredient-containing particles. The duration of these lag times can vary by changing the composition and / or the composition and / or amount of the modified release coating and / or changing the composition and / or amount of the modified release matrix material used. Can be changed. That is, the duration of the lag time can be designed to mimic the desired plasma profile.

  The modified release composition of the present invention is particularly commonly used because the plasma profile produced by the modified release composition upon administration is substantially similar to the plasma profile produced by administration of two or more IR dosage forms administered sequentially. It is useful for administration of loxoprofen that is administered three times a day. In one embodiment of the invention, the composition delivers loxoprofen in a trimodal manner. Upon administration, the composition produces a plasma profile that substantially mimics the plasma profile obtained by administering three consecutive doses of loxoprofen IR dose according to a standard treatment regime.

  In another aspect of the invention, the composition is designed to produce a plasma profile that minimizes or eliminates plasma concentration level fluctuations associated with administration of two or more consecutively administered IR dosage forms. Is done. In such embodiments, the composition provides an immediate release component that accelerates the onset of action by minimizing the time from administration to a pharmaceutically effective plasma concentration level and a pharmaceutically effective plasma concentration level between administrations. At least one modified release element for maintenance can be provided.

  As used herein, the term “microparticle” refers to a state of matter identified by the presence of individual particles, pellets, beads, or granules, regardless of their size, shape, or form. As used herein, the term “multiparticulate” refers to a plurality of individual or agglomerated particles, pellets, beads, granules or mixtures thereof, regardless of their size, shape or form.

The term “modified release” as used herein includes non-immediate release and includes controlled release, sustained release, sustained release and delayed release.
As used herein, the term “time delay” refers to the time period between administration of a dosage form containing the composition of the present invention and release of the active ingredient from that particular component.

As used herein, the term “lag time” refers to the time between the release of an active ingredient from one element of the composition and the release of the active ingredient from subsequent elements of the composition. .
As used herein, the term “erodible” refers to a formulation that is worn, attenuated or reduced by the action of a substance in the body.

As used herein, the term “diffusion control” refers to a formulation that can spread as a result of spontaneous movement such as moving from a higher concentration to a lower concentration.
As used herein, the term “osmotic pressure control” refers to a formulation that can spread on both sides of the membrane through a semipermeable membrane that tends to equalize the concentration of the formulation into a highly concentrated solution. Say.

  The active ingredients in each element may be the same or different. For example, the composition may include an element that contains only loxoprofen as an active ingredient. Alternatively, the composition comprises a first element comprising loxoprofen and at least one subsequent element comprising an active ingredient other than loxoprofen suitable for co-administration with loxoprofen, or a first ingredient comprising an active ingredient other than loxoprofen. It may comprise at least one subsequent element comprising the element and loxoprofen. Indeed, if the active ingredients are compatible with each other, two or more active ingredients may be incorporated into the same element. The active ingredient present in one element of the composition may be combined with, for example, an enhancer compound or a sensitizing compound in subsequent elements of the composition to modify biocompatibility or its therapeutic effect. Good.

  The term “enhancer” as used herein refers to a compound that can enhance the absorption and / or biocompatibility of an active ingredient by promoting the total transport of GIT in animals such as humans. Enhancers include medium chain fatty acids; salts, esters, ethers and their derivatives, including glycerides and triglycerides; as may be prepared by reacting ethylene oxide with fatty acids, higher alcohols, alkylphenols or sorbitan or glycerol fatty acid esters. Non-ionic surfactants; cytochrome P450 inhibitors, P glycoprotein inhibitors, etc .; and mixtures of two or more of these reagents, but are not limited to these.

  In the above embodiments where one or more loxoprofen-containing components are present, the ratio of loxoprofen contained in each element may be the same or different depending on the desired dosing regimen. Loxoprofen present in the first and subsequent elements may be in any amount sufficient to produce a pharmaceutically effective plasma concentration level. Loxoprofen, when applied, may be present in one substantially optically pure stereoisomer or racemic mixture, or in two or more stereoisomer formulations. Loxoprofen is preferably present in the composition in an amount of about 0.1 to about 500 mg, preferably in an amount of about 1 to about 100 mg. Loxoprofen is preferably present in the first element in an amount of about 0.5 to about 60 mg; more preferably, loxoprofen is present in the first element in an amount of about 2.5 to about 30 mg. . Loxoprofen is present in the subsequent element in an amount within the same range as described for the first element.

  The time release characteristics for loxoprofen delivery from each element can be varied by modifying the composition in each element, including modifying any excipients and / or coatings that may be present. You can also. In particular, when such a coating is present, the release of loxoprofen can also be controlled by changing the amount of modified release coating on the composition and / or particles. If more than one modified release element is present, the modified release coating of each of these elements may be the same or different. Similarly, if modified release is facilitated by containing a modified release substrate material, the release of the active ingredient can be controlled by the choice and amount of modified release substrate material used. The modified release coating can also be present in each element in an amount sufficient to provide the desired lag time for each particular element. The modified release coating may be present in each element in an amount sufficient to provide the desired time difference between the elements.

  The delay time and / or time delay for the release of loxoprofen from each element also varies by modifying the composition of each element, including modifying any excipients and coatings that may be present. Can be made. For example, the first element may be an immediate release element such that loxoprofen is released immediately after administration. Alternatively, the first element may be, for example, a time-delayed immediate release element in which loxoprofen is released substantially immediately after a time delay. The second and subsequent elements may be, for example, the time-delayed immediate release element described above, or alternatively a time-delayed sustained or sustained release element in which loxoprofen is released in a controlled manner over time. It may be.

  One skilled in the art will appreciate that the actual nature of the plasma concentration curve will be affected by combining all the factors described above. In particular, the delay time between delivery of loxoprofen in each element (and thus onset of action) and delivery can be controlled by varying the composition of each element and the coating (if present). . That is, a number of release and plasma profiles can be obtained by varying the composition of each element (including the amount and nature of one or more active ingredients) and by varying the lag time. Depending on the duration of the lag time between the release of loxoprofen from each element and the nature of the release of loxoprofen from each element (ie, immediate release, sustained release, etc.), the plasma profile is sustained (ie, A single peak), or a peak in the plasma profile that is well separated, may be well defined (eg, if the delay time is long) or some overlap (eg, if the delay time is short) Also good.

  The plasma profile that results upon administration of a single dosage unit comprising the composition of the invention is advantageous when preferred to deliver two or more pulses of the active ingredient that do not require administration of two or more dosage units. is there. Moreover, such a multimodal plasma profile is particularly useful when treating pain and / or inflammation. For example, a standard loxoprofen treatment regimen consists of administering 2 or 3 immediate release dosage forms every 4 hours. This type of dosing regime has been found to be pharmaceutically effective and is widely used.

  Any coating material that modifies the release of loxoprofen in the desired manner can be used. In particular, coating materials suitable for use in the practice of the present invention are marketed as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, trademarks Eudragit® RS and RL. Polymeric coating materials such as ammonio methacrylate copolymers, polyacrylic acid and polyacrylates and methacrylate copolymers sold under the trademarks Eudragit® S and L, polyvinylacetodiethylaminoacetate, hydroxypropylmethylcellulose acetate succinate, shellac Carboxyvinyl polymer, sodium alginate, carmellose sodium, carmelo Hydrogels and gel molding materials such as calcium, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch and low cross-linking cellulose-based cross-linking polymers that promote moisture absorption and polymer matrix expansion, hydroxy Propylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gum arabic, Sodium carboxymethylcellulose, (swellable hydrophilic polymer) poly (hydroxyalkyl methacrylate) (molecular weight ~ 5k-5,000k), Livinylpyrrolidone (molecular weight 10k-360k), anionic and cationic hydrogels, low-residue polyvinyl alcohol, agar and swellable mixture of carboxymethylcellulose, styrene, ethylene, propylene or isobutylene and maleic anhydride Copolymer, pectin (molecular weight ˜30k-300k); polysaccharides such as agar, acacia, karaya, tragacanth, algin and guar, polyacrylamide, Polyox® polyethylene oxide (molecular weight ˜100k-5,000k), AquaKeep (registered) Acrylate polymer, diester of polyglucan, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate (eg, Explot) b (registered trademark); Edward Mandell C. Ltd.); polysaccharide, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, nitrocellulose, carboxymethylcellulose, ethercellulose, polyethylene oxide (for example, Polyox (registered trademark), Union Carbide), ethyl cellulose methyl, ethyl hydroxyethyl cellulose, cellulose acetate, butyrate cellulose, propionate cellulose, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol Fatty acid ester, polyacrylamide, polyacryl Acid, methacrylic acid or copolymers of methacrylic acid (eg Eudragit®, Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural gum, lecithin, pectin, alginate, ammonia alginate, sodium, calcium, potassium alginate , Propylene glycol alginate, agar, and hydrophilic polymers such as gums such as Arabia, Karaya, locust bean, tragacanth, carrageen, guar, xanthan, scleoglucan and mixtures and blends thereof. It is not limited. One skilled in the art will appreciate that excipients such as plasticizers, lubricants, solvents, etc. may be added to the coating. Suitable plasticizers include, for example, acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; dipropine; dibutyl phthalate; acetyl monoglyceride; polyethylene glycol; castor oil; triethyl citrate; polyhydric alcohol, glycerol, acetate ester, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, Diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate, tri Sooctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-andyl phthalate, di-n-tridecyl phthalate, tri-2 -Ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

  Where the modified release component comprises a modified release matrix material, any suitable modified release matrix material or suitable combination of modified release matrix materials can be used. Such materials are known to those skilled in the art. The term “modified release matrix material” as used herein includes hydrophilic polymers, hydrophobic polymers and mixtures thereof that can modify the release of loxoprofen dispersed in vitro or in vivo. Modified release matrix materials suitable for the practice of the present invention include microcrystalline cellulose, sodium carboxymethylcellulose; hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and hydroxypropylcellulose; polyethylene oxide; alkylcelluloses such as methylcellulose and ethylcellulose; polyethylene glycol, polyvinylpyrrolidone , Cellulose acetate (acteate), cellulose acetate butyrate, cellulose acetate (acteate) phthalate, cellulose acetate (acteate) trimellitate, polyvinyl acetate phthalate, polyalkyl methacrylate, polyvinyl acetate and mixtures thereof, but are not limited thereto.

  The modified release composition of the present invention may be incorporated into any suitable dosage form that facilitates release of the active ingredient in a pulsatile manner. In one aspect, the dosage form comprises a blend of different populations of active ingredient-containing particles that make up the immediate release and modified release elements, the blend being filled into a suitable capsule, such as a hard or soft gelatin capsule. . Alternatively, different individual populations of active ingredient-containing particles may be compressed (possibly with other excipients) into small tablets that may then be filled into capsules in an appropriate ratio. Another suitable dosage form is a multi-layer tablet. In this case, the first element of the modified release composition may be compressed into one layer with a second component subsequently added as the second layer of the multi-layer tablet. The population of loxoprofen-containing particles that make up the composition of the present invention may further be included in a rapidly dissolving dosage form as an effervescent dosage form or an immediate dissolution dosage form.

  In one embodiment, the composition comprises at least two loxoprofen elements: a first loxoprofen component and one or more other loxoprofen components. In such embodiments, the first loxoprofen element of the composition may exhibit a variety of release profiles, including that substantially all loxoprofen contained in the first element is rapidly absorbed upon administration of the dosage form. Examples include release profiles that are released, released rapidly after a time delay (delayed release), or released slowly over time. In one such aspect, loxoprofen contained in the first element is rapidly released upon administration to a patient. As used herein, “rapid release” includes a release profile in which at least about 80% of the active ingredient of the element is released within 1 hour after administration, and the term “delayed release” Refers to a release profile such that the active ingredient of the element is released (rapidly or slowly) after a time delay, and the terms “controlled release” and “sustained release” refer to at least one of the active ingredients contained in the element A release profile where 80% is released slowly.

  The second loxoprofen element of the embodiment may also exhibit a variety of release profiles including an immediate release profile, a delayed release profile or a controlled release profile. In one such embodiment, the second loxoprofen element exhibits a delayed release profile such that the elemental loxoprofen is released after a time delay. In other such embodiments, the second loxoprofen element exhibits a controlled release profile such that the elemental loxoprofen is released over a period of about 12-24 hours after administration.

  In embodiments where the first loxoprofen element exhibits an immediate release profile and the second loxoprofen element exhibits a modified release profile, the loxoprofen in the first and second elements is released over different time periods. In one such embodiment, loxoprofen in the first element is released rapidly and loxoprofen in the second element is released within about 12 hours of administration. In other such embodiments, loxoprofen in the first element is released rapidly and loxoprofen in the second element is released within about 24 hours of administration. In yet other such embodiments, the loxoprofen in the first element is released rapidly and the loxoprofen in the second element is released over about 12 hours from administration. Further, in other such embodiments, loxoprofen in the first element is released rapidly and loxoprofen in the second element is released over about 24 hours from administration. Further, in other such embodiments, loxoprofen in the first element is released rapidly and loxoprofen in the second element is released over at least about 12 hours from administration. Further, in other such embodiments, loxoprofen in the first element is released rapidly and loxoprofen in the second element is released over at least about 24 hours from administration.

  The plasma profile resulting from administration of a dosage form of the invention comprising an immediate release loxoprofen element and at least one modified release loxoprofen element is the plasma profile or IR and modified release resulting from administration of two or more IR dosage forms administered sequentially. The plasma profile that results from the separate administration of the dosage forms can be substantially similar. That is, the dosage form of the present invention may be particularly useful for administration of loxoprofen when it is desired to maintain pharmacokinetic parameters, but there are problems with it.

  In one aspect, the composition and the solid oral dosage form containing the composition are such that substantially all loxoprofen contained in the first element is released prior to the release of loxoprofen from at least one second component. Releases loxoprofen. Where the first element comprises an IR element, it is preferred that the release of the loxoprofen from at least one second element is delayed, eg, until substantially all of the loxoprofen in the IR element is released. Release of loxoprofen from the at least one second component can be delayed as described in detail above using a modified release coating and / or modified release matrix material.

  If it is desired to minimize patient tolerance by providing a dosing regimen that facilitates the elimination of the first dose of loxoprofen from the patient tissue, the release of loxoprofen from subsequent elements will result in the first It may be delayed until substantially all of the loxoprofen contained in the element has been released, and further may be delayed until the release of at least partial loxoprofen from the first element has disappeared from the patient's tissue. In one aspect, the release of loxoprofen from subsequent elements of the composition is delayed at least about 2 hours after administration of the composition, if not substantially. In other embodiments, the release of loxoprofen from subsequent elements of the composition is delayed by at least about 4 hours after administration of the composition, but if not substantially, preferably about 4 hours.

  As described herein, the present invention also includes various types of modified release systems in which loxoprofen may be delivered in a pulsed or sustained manner. The system comprises a film comprising loxoprofen in a polymer matrix (monolithic device); loxoprofen contained in a polymer (storage device); polymer colloidal particles or microcapsules (microparticles, microspheres or nanoparticles) in the form of storage and substrate devices A loxoprofen contained in a polymer containing hydrophilic and / or leachable additives, for example to provide a porous device, a device in which loxoprofen release is controlled osmotically (both storage and substrate devices) A second polymer, a surfactant or a plasticizer, etc .; an enteric coating (ionized and dissolved at an appropriate pH); a polymer with pendent drug molecules (covalently) bound (soluble); and, for example, osmotic Examples include devices with dynamically controlled discharge rates such as pressure pumps. It is not.

  The delivery mechanism of the present invention can control the release rate of loxoprofen. If one mechanism releases loxoprofen at a constant rate, the other mechanism varies as a function of time depending on factors such as changing concentration gradients or other additive leaching that results in porosity.

  Ideally, the polymers used in the sustained release coating are necessarily biocompatible and biodegradable. Natural polymers such as Aquacoat (R) (FMC Corporation, Food & Pharmaceutical Products Division, Philadelphia, USA) (ethylcellulose mechanically spheroidized to a pseudolatex dispersion on an aqueous basis, set to submicron size or less), And synthetic polymers such as Eudragit® (Rohm Pharma, Weiterstadt.) In the range of poly (acrylate, methacrylate) copolymers are both known in the art.

Storage Device The standard approach for modified release is to encapsulate or include the drug completely (eg as a core) within a polymer film or coating (ie spray / pan coated with microcapsules or core). That is.

  Various factors that can affect the dispersion process can be easily applied to storage devices (eg, effects of additives, polymer function (ie, sink solution pH), porosity, film molding conditions, etc.) Therefore, the choice of polymer must be considered important in the development of storage devices. Modeling the release characteristics of storage devices (and monolithic devices) where drug transport is a solution-diffusion mechanism, ie, Fick's second law (unsteady flow conditions; concentration-dependent flow rates) for the associated critical conditions A standard solution is included. If the device contains a dissolved active agent, it decreases exponentially over time as the release rate attenuates within the device as the concentration (activity) of the agent (ie, the driving force for release) (ie, Primary release). However, when the active agent is in saturated suspension, the driving force for release in that case remains constant until the device is saturated. Alternatively, release rate kinetics are controlled desorption and are a function of the square root of time.

  The transport properties of the coated tablet can increase the osmotic pressure that would work to penetrate out of the tablet internally, and because of the coated nature of the tablet core (permeable) It can also be promoted compared to a film.

  The effect of deionized water on salt-containing tablets coated with poly (ethylene glycol) (PEG) containing silicone elastomer and the effect of water without film was investigated. It has been found that the release of salt from the tablet is a combination of diffusion through the pore-filled moisture and osmotic pump function formed by hydration of the coating. The transport of potassium chloride through a film containing only 10% PEG was insignificant, although it was observed that the expansion without the similar film was widened, and was due to the release of potassium chloride caused by transpore diffusion. Indicated that porosity was required. The salt-molded and coated salt tablets were found to expand in deionized water and changed to a flattened form as a result of strengthening the internal hydraulic press: produced by the change in form A means of measuring force was provided. As expected, osmotic power decreased with increasing PEG content level. If the PEG level is low, moisture is absorbed through the hydrated polymer, but if the PEG content (20-40%) is high, the porosity of the potassium chloride is due to the porosity due to the coating being dissolved. Pressure due to flow rate decreased.

  Osmotic pumps that contribute to the release of salts from tablets by developing (separately and independently) the release of two different salts (eg, potassium chloride and sodium chloride) as methods and equations develop The relative magnitude of transpore diffusion can now be calculated. At low PEG levels, i.e. about 20% loading, the release of both mechanisms was almost equivalent, producing only low pore number density, and osmotic flow increased to a level higher than transpore diffusion. However, increasing the hydraulic press decreased the osmotic pressure inflow and osmotic pump. With increased PEG loading, the hydrated film became more porous and less resistant to salt spills. That is, even though the osmotic pump increased (compared to the low filling), the release mechanism of transpore diffusion was dominant. The osmotic release mechanism has also been reported as a water-soluble core-containing microcapsule.

Monolithic equipment (substrate equipment)
Monolithic (substrate) devices are commonly used to control drug release. This is probably because it can be prepared relatively easily compared to a storage device and there is no risk of unexpectedly high dosages, which can result from rupture of the storage device membrane. . In such devices, the active agents are present as dispersions within the polymer matrix, which are typically made by compression of the polymer / drug mixture or by dissolution or melting. The dose release characteristics of the monolithic device may depend on the solubility of the drug in the polymer matrix or, in the case of a porous matrix, the solubility in the sink solution in the pore network of the particles and the (permeability of the film). (Higher) network bending depends on whether the drug is diffused into or dissolved in the polymer. If the drug loading is low (0-5% W / V), the drug will be released by the solution diffusion mechanism (if there are no pores). With high drug loading (5-10% W / V), the release mechanism will be complicated by the loss of drug due to the presence of cavities formed near the surface of the device. That is, such cavities expand with environmentally derived solutions that increase the rate of drug release.

  As a means of increasing permeability, a plasticizer (eg, poly (ethylene glycol)), a surfactant or an adjuvant (ie, a component that enhances the effect) is added to the substrate device (and storage device) (in contrast, plasticity). The agent is volatile and functions to easily assist in film formation, i.e., although it is usually a more desirable property for polymer paint coatings to function to control permeability) Is common. By increasing the porosity, PEG leaching, as a function of PEG filling, linearly increases the permeability of the (ethylcellulose) film, but the film retains its coating properties and electrolyte transport does not occur It was worth noting. It was estimated that the enhanced permeability occurred because the thickness due to PEG leaching was effectively reduced. This is a plot of cumulative permeate flow rate per unit area as a function of time, as the plot shows a linear relationship between permeation rate and mutual film thickness, as predicted for a transport mechanism in a uniform Fickian solution. And film mutual thickness when PEG-filled at 50% W / W. Extrapolation of the linear region of the graph to the time axis resulted in a positive intercept on the time axis when the film thickness was reduced to zero. Changing these delay times results in two diffusion flow rates (drug flow rate and PEG flow rate) early in the experiment, and more normal delay times while the permeation density in the film is enhanced. It was. When caffeine was used as the permeate, a negative lag time occurred. Although this phenomenon cannot be explained, it was noted that caffeine was shown to have a low partition coefficient in the system, which was also the nature of aniline permeation through polyethylene films exhibiting similar negative time differences. Deserves.

  The effect of surfactant added on the (hydrophobic) substrate device was studied. Surfactants are released in three possible mechanisms: (i) enhanced solubilization: (ii) improved “wetting” to the dissolution medium and (iii) pore formation resulting from surfactant leaching: It was thought that the speed could be increased. For the systems tested (Eudragit® RL100 and RS100 plasticized with sorbitol, a range of flurbiprofen and surfactants as drugs) so that the dissolution medium can be accessed within the substrate Due to the disintegration within the matrix, the most significant effect on release depends on surfactants that are more water soluble, but the effect was better for Eudragit® RS than Eudragit® RL. Nevertheless, it was concluded that improving tablet wetting only partially improved drug release, suggesting that release was controlled by diffusion rather than dissolution. This is clearly associated with latex film studies because polymer latexes suitable for pharmaceutical coatings can be readily prepared in the presence of surfactants, as opposed to the absence of surfactants. The two polymers differed in that only Eudragit® RS exhibited an anionic / cationic surfactant and drug interaction. This was considered a difference in the level of quaternary ammonium ions on the polymer.

  There are also composite devices consisting of a polymer / drug substrate coated in a drug-free polymer. The device was constructed from an aqueous Eudragit® grid and was found to provide sustained release by diffusion of the drug from the core through the shell. Similarly, a drug-containing polymer core was made and coated with a shell that was eroded by gastric juice. The release rate of the drug is found to be relatively linear (a function of the rate limiting the diffusion process through the shell), although only the release from the core is found to decrease with time, and to the thickness of the shell. It was found to be inversely proportional.

Fine Particles A method for producing hollow fine particles has been reported. Hollow microparticles were formed by preparing an ethanol / dichloromethane solution containing drug and polymer. The polymer / drug / solvent diffused by a droplet forming system process such that when poured into water, ethanol rapidly diffuses the precipitated polymer at the surface of the droplet, resulting in hard shell particles that contain the drug dissolved in dichloromethane. An emulsion was formed to contain the particles. A gas layer of dichloromethane was formed in the particles observed to foam on the surface of the aqueous layer after diffusion through the shell. The hollow spheres are filled with moisture that can be removed during drying when decompressed. No drug was found in the water. Highly porous matrix-based particulates have also been reported. Substrate-based fine particles were prepared by dissolving drugs and polymers in ethanol. When added to water, ethanol diffuses from the emulsion droplets, releasing highly porous particles. The microparticles are suggested for use as floating drug delivery devices for use in the stomach.

Suspension devices Means have been developed to attach to a range of drugs, such as analgesics and antidepressants, using esters combined with poly (acrylate) ester latex particles prepared by aqueous emulsion polymerization. These lattices can autocatalyze drug release by hydrolysis of ester bonds as they pass through the ion exchange resin so that the polymer end functional group is converted to its strong acid form.

  The drug was adhered to the polymer, and the monomer was also synthesized with the pendant drug. The dosage form is prepared so that the drug is conjugated to the biocompatible polymer with a labile chemical bond, for example a second polymer (Eudragit) that releases the drug upon hydrolysis in gastric juice. (RL) prepared from the substituted anhydride used to form the substrate (which is itself prepared by reacting sodium chloride with methacrylolyl chloride and the sodium salt of methoxybenzene acid) Polyanhydride. The use of polymeric Schiff bases suitable for use as pharmaceutical amine carriers has also been reported.

Enteric film The enteric coating consists of a pH sensitive polymer. Typically, the polymer is carboxylated and when the pH is high, the polymer ionizes and causes the polymer to swell or dissolve, but at low pH it does not interact with water at all. The coating may be designed to remain inactive in the acidic environment stomach, but dissolve in the more alkaline intestinal tract, ie, to protect the drug from the acidic environment or to protect the stomach from the drug. it can.

Osmotic pressure regulators Osmotic pumps are similar to storage devices, but contain osmotic agents (eg, active agents in the form of salts) that act to absorb moisture from the surrounding medium through the semipermeable membrane. The device was reported as a basic osmotic pump. Although the pressure is generated within the device and prevents the increase of hydraulic press head, which can have the effect of reducing the osmotic pressure and changing the volume of the device, the device is designed to minimize solute diffusion. The active agent is pushed out of the device through a sized opening. Although the internal dose of the device is constant, there is an excess of solid or saturated solution in the device, and the release rate continues to deliver an amount equivalent to the intake of solvent.

Electrically stimulated release devices Monolithic devices have been prepared using, for example, polyelectrolyte gels that swell so that the pH changes upon application of external electrical stimulation. Release is regulated by changes in applied current and can also produce a constant or pulsed release profile.

Hydrogels In addition to use in drug matrices, hydrogels have been found to be used in many biomedical applications such as, for example, soft contact lenses and various soft implants.

Methods of using modified release loxoprofen compositions In another aspect of the invention, suffering from pain and / or inflammation comprising administering a pharmaceutically effective amount of a loxoprofen composition of the invention in solid oral dosage form. A method of treating a patient is provided. The advantages of the method of the present invention include the frequency of administration required by conventional multiple IR dosing regimes while maintaining the benefit from pulsed plasma profiles or eliminating or minimizing fluctuations in plasma concentration levels. Can be reduced. Reducing the dosing frequency is advantageous for patient compliance, and the method of the present invention can reduce the time spent by medical personnel involved in drug administration by reducing the frequency of patient administration, thereby reducing the cost of medical care. Will adjust.

  In the following examples, all ratios are by weight unless otherwise specified. The term “purified water” as used throughout the examples refers to water purified by passing through a water filtration device. The examples are for illustrative purposes only and are not to be construed as limiting the spirit and scope as defined by the following claims.

Loxoprofen-containing multiparticulate modified release composition A multiparticulate modified release composition of the present invention comprising an immediate release element containing loxoprofen and a modified release component was prepared as follows.

(A) Immediate release element A loxoprofen solution was prepared in the formulations shown in Table 1. The loxoprofen solution is then immediately coated on non-pareil seeds at a level of about 16.9% solids weight gain using, for example, the fluid bed coating equipment GlattGPCG3 (Glatt, Protech Ltd., Leicester, UK). Form IR particles of the emitting element.

(B) Modified Release Component Loxoprofen-containing delayed release particles are prepared by coating the immediate release particles prepared in Example 1 (a) above with the modified release coating solution described in detail in Table 2. Immediate release particles are coated, for example, using a fluidized bed at varying levels up to about 30% weight gain.

(C) Encapsulation of immediate and delayed release particles The immediate and delayed release particles prepared in Examples 1 (a) and (b) above, for example, into a size 2 hard gelatin capsule using a BoschGKF4000S encapsulation device. Encapsulated to a total 20 mg dose strength. This total dose strength of 20 mg loxoprofen was composed of 10 mg immediate release element and 10 mg modified release component.

Loxoprofen-containing multiparticulate modified release composition A multiparticulate modified release loxoprofen composition of the present invention having a modified release component with an immediate release element and a modified release matrix material was prepared in the formulations shown in Tables 5 (a) and (b). .

  Simulations show that modified release (CR) formulations using a pulsed release approach can improve patient convenience, promote efficacy, and improve safety. FIG. 1 is a graphical representation of plasma concentration simulations obtained with various ratios of modified release (CR) and immediate release (IR) loxoprofen at the following doses. In the 100% CR formulation, after a gradual increase, the plasma concentration is stable at about 0.75 μg / ml, whereas in the 50% CR / 50% IR formulation, the peak is 2.5 μg / ml at 0 and 12 hours. That's it.

  The pulse system can minimize the fluctuations in plasma concentration levels exhibited by administration of an immediate release dosage form, with constant blood levels and improved efficacy. Pulsed release formulations also minimize GI irritation by ensuring that the concentration of NSAID does not increase locally. Loxoprofen is currently administered three times daily. Modified release formulations can be administered twice a day, thus improving patient compliance.

  It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present invention without departing from the spirit or scope of the invention. That is, the present invention is intended to cover improvements and modifications of the present invention which are included in the claims and their equivalents.

FIG. 1 shows a simulation of plasma concentrations obtained after administration of various ratios of CR (modified release) and IR (immediate release) loxoprofen.

Claims (24)

  A pharmaceutical composition comprising a first element of active ingredient-containing particles and at least one subsequent element of active ingredient-containing particles, wherein at least one said element comprises loxoprofen, wherein at least one said element is further modified release The composition, comprising a coating, a modified release matrix material or both, wherein when the composition is administered to a patient, the composition delivers the active ingredient-containing particles to the patient in a pulsatile manner.   A pharmaceutical composition comprising a first element of active ingredient-containing particles and at least one subsequent element of active ingredient-containing particles, wherein at least one said element comprises loxoprofen, wherein at least one said element is further modified release The composition, comprising a coating, a modified release matrix material, or both, wherein when the composition is administered to a patient, the composition delivers the active ingredient-containing particles to the patient in a sustained manner.   The composition of claim 1 or 2, wherein each element comprises loxoprofen-containing particles.   4. The composition of claim 3, wherein the composition comprises a first element of loxoprofen-containing particles and a second element of one loxoprofen-containing particle.   The composition of claim 4, wherein the first element comprises an immediate release element and the second element comprises a modified release element.   The composition according to claim 1, wherein the active ingredient-containing particles are erodible.   6. A composition according to claims 1-5, wherein the active ingredient-containing particles have a modified release coating.   6. A composition according to claims 1-5, wherein the active ingredient-containing particles comprise a modified release matrix material.   9. A composition according to claims 1-5, 7 or 8, wherein the modified release material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers and mixtures thereof.   10. A composition according to claim 9, wherein loxoprofen is released to the surrounding environment by erosion.   The composition of claim 10, wherein the composition further comprises an enhancer.   11. The composition of claim 10, wherein the amount of loxoprofen contained in the composition is from about 0.1 mg to about 1 g.   A dosage form comprising the composition of claims 1-12.   14. A dosage form according to claim 13 comprising a blend of active ingredient-containing particles contained within a hard capsule or soft gelatin.   15. A dosage form according to claim 14, wherein the active ingredient-containing particles are in the form of minitablets and the capsule contains a mixture of the minitablets.   16. A dosage form according to claim 15, which is in the form of a tablet.   17. The dosage form of claim 16, wherein the loxoprofen-containing particles are provided in a dosage form that dissolves rapidly.   The dosage form of claim 16, wherein the tablet is a fast dissolving tablet.   A method of treating inflammation comprising the step of administering a therapeutically effective amount of the composition of claim 1.   21. The method of claim 19, wherein the inflammation is associated with a symptom selected from the group consisting of myopathy, bone disorder, joint disorder, surgery, chronic arthritis, rheumatism, back pain and traumatic injury.   The composition of claim 1, wherein the modified release coating is a pH dependent polymer for releasing a pulse of the active ingredient to the patient after a time delay of about 6-12 hours after administration of the composition to the patient. object.   24. The composition of claim 21, wherein the polymer coating is a methacrylic acid polymer.   23. The composition of claim 21, wherein the polymer coating comprises a mixture of methacrylic acid copolymer and ammonio methacrylic acid copolymer in a ratio sufficient to achieve a pulse of active ingredient after a time delay of at least about 6 hours.   24. The composition of claim 23, wherein the ratio of ammonio methacrylic acid copolymer to methacrylic acid copolymer is about 1: 1.

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