KR101199654B1 - Stable extended release oral dosage composition - Google Patents

Abstract

It contains in the core a pseudoephedrine or a salt thereof (e.g., pseudoephedrine sulfate), which is an effective nasal decongestant that is effective to bring the geometric maximum plasma concentration of pseudoephedrine from about 7.60 hours to about 8.40 hours to about 345 ng / ml to about 365 ng / ml. ; There are two or three film coatings on this core, wherein the second coating material has a geometric maximum plasma concentration of desloratadine from about 2.15 ng / ml to about 2.45 ng / ml at about 4.0 to about 4.5 hours. Described is a film-coated sustained release solid oral composition containing desloratadine, a non-sedative antihistamine, in an amount effective to the extent that the composition is compatible with allergic and / or inflammatory diseases of the skin and airways. It is used to treat patients exhibiting associated signs and symptoms.

Desloratadine, pseudoephedrine, film coating, allergic, inflammatory

Description

Stable sustained release oral composition {STABLE EXTENDED RELEASE ORAL DOSAGE COMPOSITION}

The present invention relates to a film-coated sustained release solid oral composition containing a film envelope coating containing a nasal decongestant pseudoephedrine and a non-sedative antihistamine desloratadine in a controlled release core. It is about.

Such compositions for solid oral administration of the present invention may be used for allergic and / or inflammatory diseases, such as allergic and / or inflammatory diseases of the skin or upper and lower respiratory tracts, as well as patients exhibiting symptoms and symptoms associated with colds. For example, it is useful for treating patients exhibiting symptoms and symptoms associated with allergic rhinitis, seasonal allergic rhinitis and nasal congestion, upper respiratory disease, allergic rhinitis and nasal congestion.

Desloratadine, also called descavetoxyloratadine, is described in US Pat. No. 4,659,716 as a non-sedative anti-histamine agent useful as an anti-allergic agent. U.S. Patent No. 6,100,274 describes a composition containing desloratadine. US Pat. No. 5,595,997 describes a method of treating depressive symptoms of seasonal allergic rhinitis using desloratadine and compositions therefor. Desloratadine is hydroxylated at position 3 upon oral absorption, resulting in the metabolite 3-hydroxydesloratadine.

U.S. Patent Nos. 4,990,535 and 5,100,675 describe coated tablets that are continuously released twice daily, wherein the tablet coating includes descavetoxyloratadine, a hydrophilic polymer and polyethylene glycol, and the tablet core is acetaminophen. , Pseudoephedrine or salts thereof, swellable hydrophilic polymers and pharmaceutically acceptable excipients.

U.S. Patent No. 5,314,697 describes a sustained release tablet containing a matrix core comprising pseudoephedrine sulfate and a coating material comprising loratadine.

The prior art does not describe any compositions for film-coated solid oral administration, which are released once daily, according to the present invention.

Although it has been desirable to successfully develop a desloratadine- pseudoephedrine once-a-day formulation, an effective daily dose of desloratadine is delivered in excess of 12 hours (preferably 16 hours) of the pseudoephedrine component while continuing to deliver. It may be desired to achieve a release rate profile that releases over an extended period of time.

Treatment of symptoms and symptoms associated with colds, as well as allergic and / or inflammatory diseases of the skin or upper and lower respiratory tracts, eg, seasonal allergic rhinitis and nasal congestion, on a once-daily basis It would be desirable to increase patient compliance to have effective and safe sustained release desloratadine- pseudoephedrine products when used for care, and / or alleviation.

We provide desloratadine- pseudoephedrine 1 day with a release rate profile that consistently delivers an effective daily one-time dose of desloratadine while releasing pseudoephedrine over a long period of time greater than 12 hours, preferably at least 16 hours. The product was found once.

Accordingly, the present invention provides a film coating comprising (a) a core comprising an effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof, and (b) uniformly covering such core and comprising an effective amount of desloratadine. Wherein the amount of pseudoephedrine or a pharmaceutically acceptable salt thereof is a geometric maximum of about 7.60 hours to about 8.40 hours after administration of a single dose of the composition. It is effective to have a plasma maximum plasma concentration of about 345 ng / ml to about 365 ng / ml, wherein the amount of desloratadine is about 4.0 to about 4.5 hours after administration of a single dose of the composition. Film-coated sustained release solids effective to bring about a geometric maximum plasma concentration of from about 2.10 ng / ml to about 2.45 ng / ml Administration provides for compositions.

The compositions of the present invention are intended for use in patients in need of treatment of allergic and / or inflammatory diseases (eg, urticaria) of the upper and lower respiratory tract and skin, including nasal symptoms and nasal symptoms of seasonal allergic rhinitis including nasal congestion. It is useful for treating diseases. The exact dosage and administration regimen may be determined by the attending physician in view of the teachings herein, depending on the patient's requirements, such as the age, sex and severity of the allergic and / or inflammatory disease being treated. Determination of the appropriate dosage and method of administration for a particular patient will be within the skill of the attending physician.

The present invention includes (a) a core comprising an effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof, and (b) a film coating that uniformly coats the core and includes an effective amount of desloratadine. Wherein the amount of pseudoephedrine or a pharmaceutically acceptable salt thereof is a geometric maximum plasma concentration of pseudoephedrine about 7.60 hours to about 8.40 hours after administration of a single dose of the composition. Is effective to bring about 345 ng / ml to about 365 ng / ml, wherein the amount of desloratadine has a geometric maximum plasma concentration of desloratadine of about 2.10 about 4.0 to about 4.5 hours after administration of a single dose of the composition. Provided are film-coated sustained release solid oral administration compositions effective to be from ng / ml to about 2.45 ng / ml.

Furthermore, a preferred embodiment of the film-coated sustained release solid oral composition of the present invention is that the geometric maximum plasma of 3-hydroxydesloratadine after about 5.50 hours to about 6.25 hours of administration of a single dose of the composition. The concentration is about 0.75 ng / ml to about 1.15 ng / ml.

More preferred embodiments of the film-coated sustained release solid oral composition of the present invention have a geometric maximum plasma concentration of desloratadine of about 2.10 ng after about 4.0 to about 4.5 hours of administration of a single dose of the composition. / ml to about 2.45 ng / ml and the geometric maximum plasma concentration of 3-hydroxydesloratadine is from about 0.75 ng / ml to about 1.15 ng after about 5.50 hours to about 6.25 hours of administration of a single dose of the composition. to be / ml.

Thus, in one preferred embodiment, the present invention maintains the desired pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine, and pseudoephedrine, listed above, and at 25 ° C and about 60% Therapeutic in the core contains less than about 2%, preferably less than about 1.4% to about 1.6% of desloratadine degradation products, such as N-formyl desloratadine, even when stored for a period of at least about 24 months at relative humidity. A pharmaceutical composition is provided comprising an effective amount of pseudoephedrine sulfate and an effective amount of desloratadine in a film coating.

In addition, the inventors have previously placed the first coating material between the film-coating material comprising desloratadine and the core containing the nasal decongestant (e.g., pseudoephedrine salt, preferably pseudoephedrine sulfate), The desired pharmacokinetic parameters of desloratadine, 3-hydroxy desloratadine and pseudoephedrine are maintained over a period of more than 12 hours, while maintaining desloratadine less than 2% degradation with N-formyldesloratadine. It was found that desloratadine can be released from the second film-applicant and sustained release of pseudoephedrine sulfate, a nasal decongestant from the core (preferably matrix core).

Therefore, in one preferred aspect, the present invention

(a) 1. a sustained release amount of a pharmaceutically acceptable decongestant,

    2. polymer matrix,

    3. Water insoluble basic calcium salt, magnesium salt or aluminum salt,

    4. binder,

    5. lubricants, and

    6. Optionally, a matrix core comprising glidant;

(b) 1. water-swellable film-forming neutral or cationic copolymer esters,

    2. grease,

    3. film-modifiers, and

    4. A first film applicator which uniformly covers said matrix core, optionally comprising an anti-foamer; And

(c) 1. Desloratadine in an amount released immediately,

   2. water-swellable film-forming neutral or cationic copolymer esters,

    3. grease,

    4. water-soluble film-modifiers, and

    5. Provided is a film-coated sustained release solid composition for oral administration, optionally comprising a second film coating material uniformly covering the first coating material, including an antifoaming agent.

In a preferred embodiment of this film-coated sustained release solid oral composition of the present invention, in a USP paddle method at 100 rpm, at least about 80% of desloratadine is released within about 45 minutes into a 0.1N HCl solution at 37 ° C. And release about 64% of pseudoephedrine sulfate within 6 hours, release 88% of pseudoephedrine sulfate within 12 hours, and contain less than about 2% of desloratadine degradation products, such as N-formyl desloratadine.

In another preferred embodiment, the present invention

(a) A matrix core comprising the following components:

ingredient mg / core

    Pseudoephedrine sulfate approximately 240

    Hydroxypropyl methylcellulose 2208

    100,000 cps. About 160-480

    Ethylcellulose about 40-120

    Dibasic calcium phosphate dihydrate about 56-162

    Povidone about 20-60

    Silicon dioxide about 6-12

    Magnesium stearate about 2-6

Approximate Matrix Core Weight Ranges: About 518-1082mg

   ; And

(b) (1) a neutral copolymer of ethyl acrylate and methyl acrylate,

    (2) a lubricant selected from the group consisting of talc, silicon dioxide and magnesium stearate,

    (3) polyethylene glycol selected from polyethylene glycol 200 to polyethylene glycol 8000, and

    (4) a first film coating material uniformly covering said matrix core, optionally comprising a pharmaceutically acceptable mixture of a homogeneous liquid methyl siloxane polymer and silica gel; And

(c) (1) an amount of death effective to ensure that the geometric maximum plasma concentration of desloratadine is from about 2.10 ng / ml to about 2.45 ng / ml after administration of a single dose of the composition from about 4.0 hours to about 4.5 hours. Loratadine,

    (2) a neutral copolymer of ethyl acrylate and methyl acrylate,

    (3) a lubricant selected from the group consisting of talc, silicon dioxide and magnesium stearate,

    (4) polyethylene glycol selected from polyethylene glycol 200 to polyethylene glycol 8000, and

    (5) film-coated, optionally comprising a second film coating material that uniformly covers the first film coating material, comprising a pharmaceutically acceptable mixture of homogeneous liquid methyl siloxane polymer and silica gel Provided is a composition for sustained release solid oral administration.

The above-mentioned preferred film-coated sustained release solid composition for oral administration may further comprise a third film coating material uniformly covering the second film coating material, comprising:

(1) a neutral copolymer of ethyl acrylate and methyl acrylate,

(2) a lubricant selected from the group consisting of talc, silicon dioxide and magnesium stearate,

(3) at least one water-soluble film-modifier selected from polyethylene glycol selected from the group consisting of low viscosity hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, sodium carboxymethyl cellulose, and polyethylene glycol 200 to polyethylene glycol 8000, or mixtures thereof,

(4) pharmaceutically acceptable dyes, and

(5) Optionally, a pharmaceutically acceptable mixture of homogeneous liquid methyl siloxane polymer and silica gel.

In a more preferred aspect, the invention

(a) A matrix core comprising the following components:

ingredient mg / core

    Pseudoephedrine sulfate approximately 240

    Hydroxypropyl methylcellulose 2208

    100,000 cps. About 160-480

    Ethylcellulose about 40-120

    Dibasic Calcium Phosphate Dihydrate About 54-162

    Povidone about 20-60

    Silicon dioxide about 6-12

    Magnesium stearate about 2-6

Approximate (Matrix Core) Weight Range: About 518-1082mg

    ; And

(b) about 1.36 to about 4.08 mg of a neutral copolymer of ethyl acrylate and methyl acrylate having an average molecular weight of 800,000 based on the total amount of the first film coating material,

    (2) about 1.36 to about 4.08 mg of a lubricant selected from the group consisting of talc, silicon dioxide and magnesium stearate,

    (3) about 0.136 to about 0.408 mg of polyethylene glycol selected from polyethylene glycol 6000 to polyethylene glycol 8000, and

    (4) optionally from about 2.96 to 8.89 mg of a first film coating material uniformly covering the matrix core, comprising from about 0.11 to about 0.33 mg of a pharmaceutically acceptable mixture of homogeneous liquid methyl siloxane polymer and silica gel; And

(c) (1) about 5.0 to about 6.0 mg of desloratadine in a 24-hour amount,

    (2) about 3.04 to about 9.12 mg of a neutral copolymer of ethyl acrylate and methyl acrylate having an average molecular weight of 800,000,

    (3) about 3.5 to about 10.5 mg of a lubricant selected from the group consisting of talc, silicon dioxide and magnesium stearate,

    (4) about 0.915 to about 2.75 mg of polyethylene glycol selected from polyethylene glycol 6000 to polyethylene glycol 8000, and

    (5) from about 12.60 to a second film coating material uniformly covering said first film coating material, optionally comprising from about 0.14 to about 0.42 mg of a pharmaceutically acceptable mixture of homogeneous liquid methyl siloxane polymer and silica gel. Provided is a film-coated sustained release solid composition for oral administration comprising about 38.79 mg.

In one preferred embodiment, the present invention

(a) A matrix core comprising the following components:

ingredient mg / core

    Pseudoephedrine sulfate approximately 240

    Hydroxypropyl methylcellulose 2208

    100,000 cps. About 160-480

    Ethylcellulose about 40-120

    Dibasic calcium phosphate dihydrate about 56-162

    Povidone about 20-60

    Silicon dioxide about 6-12

    Magnesium stearate about 2-6

Approximate Matrix Core Weight Ranges: About 518-1082mg

    ; And

(b) a neutral copolymer of ethyl acrylate and methyl acrylate having a molecular weight of 800,000, based on the total amount of the first film coating material,

    (2) a lubricant selected from the group consisting of talc, silicon dioxide and magnesium stearate,

    (3) polyethylene glycol selected from polyethylene glycol 200 to polyethylene glycol 8000, and

    (4) a first film coating material uniformly covering said matrix core, optionally comprising a pharmaceutically acceptable mixture of a homogeneous liquid methyl siloxane polymer and silica gel; And

(c) Based on the total amount of second film coating material, (1) the geometric maximum plasma concentration of desloratadine is from about 2.10 ng / ml to about 2.45 after from about 4.0 hours to about 4.5 hours after administration of a single dose of the composition. desloratadine in an amount effective to be ng / ml,

    (2) a neutral copolymer of ethyl acrylate and methyl acrylate having an average molecular weight of 800,000,

    (3) a lubricant selected from the group consisting of talc, silicon dioxide and magnesium stearate,

    (4) polyethylene glycol selected from polyethylene glycol 200 to polyethylene glycol 8000, and

    (5) a film-coated book, optionally comprising a second film coating material that uniformly covers the first film coating material, comprising a pharmaceutically acceptable mixture of a homogeneous liquid methyl siloxane polymer and silica gel. Release compositions for oral administration are provided.

More preferred compositions of the present invention are as follows:

1. Matrix core

ingredient mg / core

    Pseudoephedrine Sulfate USP 240

    Hydroxypropyl methylcellulose 2208

    USP 100,000 cps. 320

    Ethylcellulose NF Type 7 80

    Dibasic Calcium Phosphate Dihydrate

    USP 108

    Povidone USP 40

    Silicon Dioxide NF 8

    Magnesium Stearate NF 4

Approximate Matrix Core Weights: 800 mg

2. Matrix core coating material

 (1) first film coating material

ingredient mg / tablet

    Simethicone 0.22

    Polyethylene Glycol 8000 0.27

    Talc NF 2.72

    Ethyl acrylate / methyl methacrylate

    Neutral Copolymer (30% dispersion in water) 2.72

First coating material weight: 5.93mg

(2) 2nd film (immediate release type) coating material

ingredient mg / tablet

   Desloratadine 6.0

   Simethicone 0.28

   Polyethylene Glycol 8000 1.83

   Talc NF 5.88

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 6.09

Second coating material weight: 20.08mg

(3) third film coating material

ingredient mg / tablet

   Hydroxypropyl methylcellulose 2910

   USP 6cps 2.09

   Talc NF 5.79

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 4.18

   Polyethylene Glycol 8000 NF 0.42

   Simethicone 0.11

   Spectra Spray Med Blue Dye 3.65

3rd coating material weight: 16.24 mg

Approximate total weight of the three coatings: 42.37 mg

Approximate tablets (matrix core and three coatings) Weight: 842.97 mg

Another more preferred composition of the present invention is as follows:

1. Matrix core

ingredient mg / core

    Pseudoephedrine Sulfate USP 240

    Hydroxypropyl methylcellulose 2208

    USP 100,000 cps. 320

    Ethylcellulose NF Type 7 80

    Dibasic Calcium Phosphate Dihydrate

    USP 108

    Povidone USP 40

    Silicon Dioxide NF 8

    Magnesium Stearate NF 4

Approximate Matrix Core Weights: 800 mg

2. Matrix core coating material

 (1) first film coating material

ingredient mg / tablet

    Simethicone 0.22

    Polyethylene Glycol 8000 0.27

    Talc NF 2.72

    Ethyl acrylate / methyl methacrylate

    Neutral Copolymer (30% dispersion in water) 2.72

First coating material weight: 5.93mg

(2) 2nd film (immediate release type) coating material

ingredient mg / tablet

   Desloratadine 5.0

   Simethicone 0.28

   Polyethylene Glycol 8000 0.61

   Talc NF 5.17

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 6.09

   Hydroxypropyl methylcellulose 2910

   USP 6cps 3.05

2nd coating material weight : 20.20mg

(3) third film coating material

ingredient mg / tablet

   Hydroxypropyl methylcellulose 2910

   USP 6cps 2.09

   Talc NF 5.79

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 4.18

   Polyethylene Glycol 8000 NF 0.42

   Simethicone 0.11

   Spectra Spray Med Blue Pigment 3.65

Third coating material weight: 16.24 mg

Approximate total weight of three coatings: 42.37mg

Approximate tablets (Matrix Core + 3 coatings) Weight : 842.97mg

Similar results would be expected if a decongestive effective amount of another pharmaceutically acceptable pseudoephedrine salt (eg, pseudoephedrine hydrogen chloride) was used in place of pseudoephedrine sulfate.

Compositions of the present invention may include allergic and / or inflammatory diseases of the upper and lower respiratory tract, including nasal and nasal symptoms of seasonal allergic rhinitis including nasal congestion, and allergic and / or inflammatory diseases of the skin (eg, Urticaria) is useful for patients in need of treatment.

During the course of developing the compositions of the invention, it has been found that desloratadine decolorizes and becomes unstable when stored with various excipients as described in US Pat. No. 5,314,697 as part of a matrix core containing pseudoephedrine sulfate. Excipients that decolor and destabilize desloratadine include, but are not limited to, acidic excipients having a pH of less than 7 in water, such as organic acids (eg, carbonyl-containing substances such as stearic acid, povidone, crospovidone, and lactose), ethyl Cellulose and hydroxypropyl methylcellulose. Polymers such as hydroxypropyl methylcellulose and binders such as povidone are useful as polymer matrices for slow release of pseudoephedrine sulfate from an internal polymer matrix core.

The inventors have found that an inner core matrix containing a nasal decongestant (e.g., pseudoephedrine sulfate), hydroxypropyl methylcellulose, ethyl cellulose and povidone, is a water-swellable film-forming neutral or cationic copolymer ester, film By uniformly covering with a first coating material containing a modifier and a lubricant, desloratadine can be safely applied onto the first coating material. Desloratadine has a profile (80% release in 0.1N HCl in less than 45 minutes) that releases immediately to an acceptable level from the second coating, and at 25 ° C. and about 60% relative humidity (“RH”) It has been found to contain less than about 2%, preferably about 1.4% to about 1.6% N-formyldesloratadine even after storage for at least months (preferably up to 36 months).

Desloratadine from such a second coating material when a third film coating material comprising water-swellable film-forming neutral or cationic copolymer ester and polyethylene glycol as the film modifier is placed on the second coating material. The rate of dissolution and the rate of dissolution of pseudoephedrine from the core is lowered to an unacceptably low level.

Surprisingly, when low viscosity hydroxypropyl methylcellulose is added as a film modifier to this third coating material, the dissolution rate of the two active ingredients (pseudoephedrine sulfate and desloratadine) makes the core matrix uniform to the two film coating materials. Recovery was at almost the same level as obtained when applied.

"Allergic and inflammatory diseases of skin and airways" means allergic and inflammatory diseases and symptoms found in the upper and lower airways from the nose to the lungs and on the skin. Typical allergic and inflammatory diseases of the skin and upper and lower airways include asthma, sinusitis, colds (NSAIDs, including seasonal and perennial allergic rhinitis, non-allergic rhinitis, allergic and non-allergic asthma) For example, aspirin, ibuprofen or acetaminophen and / or decongestants such as pseudoephedrine), dermatitis, especially allergic and atopic dermatitis, and urticaria and symptomatic dermographism as well as retinopathy, And small vascular diseases associated with diabetes.

The amount of desloratadine effective to treat or prevent allergic and inflammatory diseases of the skin and upper and lower respiratory tract will depend on the age, sex, weight of the patient and the severity of the patient's allergic and inflammatory diseases. Typically, the amount of desloratadine effective for treating or preventing allergic and inflammatory diseases is, from a single dose, from about 2.5 mg / day to about 60 mg / day, preferably from about 2.5 mg / day to about 20 mg / day, About 4.0 mg / day to about 15 mg / day, or about 5.0 mg / day to about 10 mg / day, more preferably about 5.0 mg / day to about 10.0 mg / day, most preferably about 5.0 mg / day to about 6.0 mg / day.

Desloratadine is a non-sedative, long-acting histamine antagonist with potent selective peripheral H1-receptor antagonist activity. After oral administration, loratadine is rapidly metabolized to the pharmaceutically active metabolite desloratadine or descarboethoxyloratadine. In vitro and in vivo animal pharmacological studies were performed to evaluate various pharmacodynamic effects of desloratadine and loratadine. In assessing anti-histamine activity in mice (comparison of ED ₅₀ values), desloratadine does not relatively cause changes in behavioral changes in behavioral, neurological or autonomic function. The possibility of desloratadine or loratadine occupying the brain's H1-receptor was evaluated in guinea pigs after intraperitoneal administration, and the results indicate that access to the central histamine receptor for desloratadine or loratadine is not easy. Present it.

In addition to anti-histamine activity, desloratadine has been demonstrated to have anti-allergic and anti-inflammatory activity from numerous in vitro and in vivo tests. These in vitro tests (primarily performed on cells of human origin) indicate that desloratadine can inhibit many events in the cascade of allergic inflammation. These anti-inflammatory effects on desloratadine are independent of the H1-antagonist effect of desloratadine, including the release of inflammatory mediators histamine, trotase, leukotriene and prostaglandin D2 from mast cells; Release of inflammatory cytokines, including IL-4, IL-6, IL-8 and IL-13; Release of inflammatory chemokines such as regulated upon activation, normal T cell expressed and presumably secreted (RANTES); Superoxide anion production of polymorphonuclear neutrophils; Expression of cellular adhesion molecules such as intracellular adhesion molecules (ICAM-1) and P-selectin in endothelial cells; And eosinophil migration and coalescence.

In vivo studies also suggest that the inhibitory effect of desloratadine on allergic bronchial spasms and coughs may be expected.

The clinical efficacy and safety of desloratadine have been recorded in 3,200 seasonal allergic rhinitis patients in four double-blind randomized clinical trials. These chemical findings have demonstrated the efficacy of desloratadine in treating adult and adolescent patients with seasonal rhinitis.

Nasal decongestants useful in the present invention include phenylpropanolamine, phenylephrine and pseudoephedrine. Pseudoephedrine, as well as its pharmaceutically acceptable acid addition salts, such as HCl or H ₂ SO _4, are sympathetic stimulants known to those skilled in the art as safe as effective therapeutic agents for treating nasal congestion, It is common to administer orally simultaneously with anti-histamines to treat associated nasal congestion. In the present invention, it is preferable to use pseudoephedrine as a nasal decongestant, and more preferably, pseudoephedrine sulfate.

In the process of developing the composition for oral administration of the present invention, selecting the polymer to be used in the polymer matrix core is a desired period of 12 hours or more, preferably 12 to 16 hours, more preferably 16 hours or more of pseudoephedrine sulfate. It has been found to be important for slow release. For example, using 4,000 cps or 15,000 cps of hydroxypropyl methylcellulose as the polymer in the matrix core did not allow a single dose of pseudoephedrine sulphate to be released over a more desirable period of 16 hours or more. We have found that only choosing to incorporate three specific polymers of a certain weight ratio into the matrix core can achieve the desired pseudoephedrine release profile. (1) 4 parts by weight of hydroxypropyl methyl cellulose 2208 USP 100,000 cps (2) 1 part by weight of ethyl cellulose and (3) 1/2 part by weight of povidone as secondary binder, only adding pseudoephedrine sulfate from the matrix core Sustained release can be achieved for a more preferred period of time or more. The matrix core also contains a certain amount of silicon dioxide as a glidant and magnesium stearate as a lubricant. The hardness 22 ± 6 Strong-Cove Unit (SCU) of tablets is not significantly affected by higher levels of lubricant (6 mg / tablet), but the lubricant level for 1 part by weight of povidone as secondary binder is 1/10 of the lubricant. It is preferable to keep by weight part.

As used herein, the term “lubricant” refers to a substance that has been added so that it can be compressed into a dosage form (eg, a tablet) after being released from a mold or die.

Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like. Preferably magnesium stearate or talc is used.

The term "glidant" as used herein refers to a material such as an anti-caking agent that enhances the flowability of the powder mixture.

Suitable glidants include silicon dioxide and talc. Preferably, silicon dioxide is used.

As used herein, the term "binding agent" means all substances added to help hold the pharmaceutical composition together and to release the medicament therefrom.

Suitable binders are selected from the group consisting of crosslinked polymers of croscarmellose sodium, carboxymethylcellulose sodium, povidone, crospovidone, starch, cellulose, alginate and gums (USP XXII, p. 1858 (1990)). . Preferably, povidone is used.

Typical suitable antifoams include a mixture of homogeneous liquid methyl siloxane and silica gel (commercially available under the trade name Simethecone).

The term "water-swellable film-forming neutral or cationic copolymer ester" as used herein refers to neutral and cationic copolymers of substituted and unsubstituted methyl or ethyl methacrylate esters with ethyl acrylate. it means.

상표명, EUDRAGIT NE30D로 시판중인 것과 바스프(BASF, Mt Olive, New Jersey 소재)로부터 시판 중인 콜리코트(Kollicoat)와 같은 에틸 아크릴레이트와 메틸 메타크릴레이트의 중성 공중합체가 있다. 에틸 아크릴레이트와 메틸 메타크릴레이트를 기준으로 하여 중성 공중합체(평균 분자량 약 800,000)를 30중량% 함유하는 수성 분산액이 바람직하다.Typical suitable water-swellable film-forming neutral copolymer esters are EUDRAGIT from Pharma Polymers, a Huls group company.

Neutral copolymers of ethyl acrylate and methyl methacrylate, such as Kollicoat, sold under the trade name EUDRAGIT NE30D and commercially available from BASF, Mt Olive, New Jersey. Preference is given to aqueous dispersions containing 30% by weight of a neutral copolymer (average molecular weight about 800,000) based on ethyl acrylate and methyl methacrylate.

Typical suitable water-swellable film-forming cationic copolymer esters include the commercially available EUDRAGIT E copolymers and "Amono" as 12.5% solution (EUDRAGIT E 12.5) or solids (EUDRAGIT E 100) sold by Parma Polymers. Based on dimethylaminoethylmethacrylate and neutral methacrylic esters, such as quaternary ammonium copolymers described in USP / NF as "Amononic" methacrylate copolymers, type "A" and type "B" Cationic copolymers. Such copolymers are commercially available as aqueous dispersions of copolymers of acrylic esters and methacrylic esters with low (substituted) content of quaternary ammonium groups present as salts (eg quaternary ammonium chloride). Type A and Type B are commercially available as 30% aqueous dispersions under the trade names EUDRAGIT RL 30D and EUDRAGIT RS 30D, respectively. Preference is given to using water-swellable film-forming neutral copolymer esters based on ethyl acrylate and methacrylate.

As used herein, the term “water soluble film modifier” means a film-forming agent that modifies the water-swellable characteristics of the film-forming neutral or cationic copolymer esters useful in the compositions of the present invention. Typically suitable water soluble film-modifiers include low viscosity (≦ 20 cps) cellulose such as low viscosity hydroxypropyl methylcellulose rose, low viscosity hydroxyethyl methylcellulose; Low viscosity sodium carboxymethylcellulose; Or polyethylene glycol selected from polyethylene glycol 200 to polyethylene glycol 8000.

It is preferable to use polyethylene glycol 6000 to polyethylene glycol 8000 as the film modifier for the first and second coating materials, and more preferably to use polyethylene glycol 8000 for each coating material.

Preference is given to using polyethylene glycol in the third coating with low viscosity hydroxypropyl methylcellulose. More preferably, a mixture of polyethylene glycol 8000 and hydroxypropyl methylcellulose 2910 cps is used for the third film outermost film coating material.

As used herein, the term “water-insoluble basic calcium salt, magnesium salt and aluminum salt” means pharmaceutically acceptable carbonates, phosphates, silicates and sulfates of calcium, magnesium and aluminum, or mixtures thereof. Typically suitable pharmaceutically acceptable basic salts include calcium sulfate anhydride, calcium sulfate hydrate (e.g. calcium sulfate dihydrate), magnesium sulfate anhydride, magnesium sulfate hydrate, dibasic calcium phosphate, dibasic calcium silicate, magnesium tri Silicates, magnesium phosphates, aluminum silicates; More preferred are hydrates of magnesium phosphate, aluminum phosphate and calcium phosphate. Most preferred is the use of dibasic calcium phosphate dihydrate.

Hydroxypropyl methylcellulose 2910 acts as a film-forming agent in the film coating and polyethylene glycol acts as a film modifier. Other suitable film-forming polymers that may be used are low viscosity (720 cps) hydroxypropyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose.

The composition for oral administration of the present invention has a shelf life of at least 24 months (e.g. 36 months and 48 months) when the tablet is stored in a standard package at 2-30 ° C. under ambient conditions maintaining 60% relative humidity. provide a shelf life.

In preparing tablet cores, povidone is dissolved in a mixture of alcohol and water. Pseudoephedrine sulfate, hydroxypropyl methylcellulose 2208 USP 100,000 cps, ethylcellulose and dibasic calcium phosphate are mixed and granulated with an aqueous alcoholic solution containing povidone. This granulate is pulverized and dried at a loss rate of 0.5 to 2.0% at drying.

The dried granulate is pulverized and mixed with the required amount of silicon dioxide and magnesium stearate. The final mixture is compressed to produce an internal polymer matrix core composition.

Typically, the coating material is applied to the inner polymer matrix core in the following manner.

The core is filled into a suitable applicator pan. Water-dispersion of talc, simethicone, polyethylene glycol 8000 and EUDRAGIT NE 30D is applied to the matrix core as the first coating material. Subsequently, a dispersion of desloratadine, simethicone, EUDRAGIT NE30D, polyethylene glycol 8000NF and talc is applied to the matrix core thus applied. Next, a third coating material containing a dispersion of FD & C Blue No. 2 aluminum lake, talc, simethicone, EUDRAGIT NE30D, hydroxypropyl methylcellulose 2910cps., And polyethylene glycol 8000NF containing EDTA as chelating agent was applied. do. The tablets thus applied are then stamped (using black ink) and packaged in storage plastic bottles and blisters at a temperature of 2 to 30 ° C. under ambient conditions.

During the course of developing the formulations of the present invention, we found that in vitro dissolution studies resulted in desloratadine release rates and increased pH (especially pH values> 7.0) compared to that for 5 mg tablets of desloratadine. It was found that all of the desloratadine concentrations were lowered. In vivo studies have shown that Tmax is greater than 4 hours and much of the process of desloratadine absorption occurs in the small intestine with an alkaline pH (pH value> 7.0).

The inventors have found that death by increasing the level of hydroxypropyl methylcellulose in the second film coating material containing desloratadine, lowering the level of plasticizers (e.g. polyethylene glycol 8000) and of lubricants (e.g. talc) It has been found that it can increase the release of loratadine (see Example 4).

In another preferred embodiment, the effective amount of desloratadine in the second film coating material is increased to 6.0 mg and the amount of talc reduced (about 1.12 mg) to obtain an acceptable pharmacokinetic profile (Example 3 and Table 3). Reference).

For solid oral dosage forms of the invention, the geometric mean maximum plasma concentration of pseudoephedrine (PES) is about 345 ng / ml at a time (Tmax) of about 7.60 to about 8.40 hours after administration of a single dose of the composition to a healthy subject. To about 365 ng / ml; The geometric mean maximum plasma concentration of desloratadine (DL) is preferably from about 2.10 ng / ml to about 2.45 ng / ml (Tmax) at about 4.0 to about 4.5 hours after administering a single dose of the composition to a healthy subject. Is between about 2.15 ng / ml and about 2.35 ng / ml); The geometric mean maximum plasma concentration of 3-hydroxydesloratadine (3-OH-DL) may range from about 0.75 ng / ml at a time (Tmax) about 5.50 to about 6.25 hours after administration of a single dose of the composition to a healthy subject. About 1.15 ng / ml, preferably about 0.85 ng / ml to about 1.05 ng / ml, more preferably 0.88 ng / ml to about 1.02 ng / ml.

First Pharmacokinetic Study

The purpose of this pharmacokinetic study was to compare the formulation of Example 2 of the present application (DL 5 mg / dl) with the 5 mg of Example 11 of US Pat. No. 6,100,274 (USP '274) and the sustained release pseudoephedrine core as a reference. PES 240 mg) to determine the bioavailability and bioequivalence of desloratadine (DL), 3-OH DL and pseudoephedrine (PES). This study is a randomized three-way crossover of an open-level single dose of Phase I, performed with a seven day washout period between treatments. For 36 healthy male and female subjects, the following treatments were performed in the order of randomly assigned codes.

Treatment A: One 5 mg DL / 240 mg PES tablet of Example 2.

Treatment B: One DL 5 mg tablet of Example 11 of USP '274.

) D-24 코트로 도포된 클라리틴

D-24로부터의 타원형의 서방출형 슈도에페드린 코어] 1개.Treatment C: 240 mg pseudoephedrine sulfate [placebo claritin

) Claritin Coated with D-24 Coat

One elliptical sustained release pseudoephedrine core from D-24.

The tablets were administered with 180 ml (6 fluid ounces) of non-carbonated room temperature water. The tablets were swallowed as is without chewing or crushing. After dosing, the oral cavity was examined to determine whether the subject swallowed the tablet. The subject is fasted until the four-hour course of study is complete. Two hours after taking it, I was allowed to drink water. For 4 hours after taking it, you could stay awake or sit on a chair. All subjects were kept within the study site until 120 hours blood samples, vital signs, and laboratory test results were obtained.

A series of blood samples (10 ml) were collected in tubes containing heparin as anti-coagulant at the following time points: 0 (before dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, After 8, 10, 12, 16, 20, 24, 36, 48, 72, 96 and 120 hours. No food was allowed for 4 hours after dosing. Drinking water is not allowed from 1 hour before to 1 hour after ingestion, but 120 ml administered with the treatment is allowed. Plasma concentrations of pseudoephedrine were determined using certified liquid chromatography using serial mass spectroscopy (LC / MS / MS) with a lower limit of quantitation (LOQ) of 10.0 ng / ml and a linear range of 10.0 to 400 ng / ml. It was. Average pharmacokinetic parameters associated with them are provided in Table 1.

The mean DL Cmax after administration of the DL tablet of Example 2 of the present invention or the 5 mg desloratadine tablet of Example 11 of USP 6,100,274 was 1.79 and 2.23 ng / ml, respectively, and reached an average Tmax value of 6.78 and 5.10 hours, respectively. It was.

Mean (% CV ^a ) pharmacokinetic parameters of DL, and 3-OH DL from healthy subjects after oral administration of a single dose of DL D-24 and DL DL Example 2-5 mg / 240 mg (treatment A) Examples 11-5 mg of USP '274 (Process B) Parameter (unit) Average % CV Average % CV Cmax (ng / ml) 1.79 35.8 2.23 34.8 Tmax (hr) 6.78 57.3 5.10 52.5 3-OH DL Example 2-D-24 5 mg / 240 mg (treatment A) Examples 11-5 mg of USP '274 (Process B) Average % CV Average % CV Cmax (ng / ml) 0.695 59.4 0.832 55.2 Tmax (hr) 6.09 ^b 32.7 4.96 ^b 31.4 a:% CV is the coefficient of change (%), which is a relative measure of variability [Steele and Torrie,
"Principles and Procedures of Statistics", (1980) 2 nd Edition, McGraw-Hill, NY,
p.27].
b: n = 35

The mean 3-OH DL Cmax after administration of the 5 mg DL / 240 mg PES tablet of Example 2 herein and the 5 mg desloratadine tablet of Example 11 of USP 6,100,274 was 0.695 and 0.832 ng / ml, respectively, and 6.09 and 4.96 hours, respectively. The average Tmax value of was reached. The peak plasma concentration of 3-OH DL was slowly reduced to a half-life of 29.6 hours after administration of the 5 mg DL / 240 mg PES tablet of Example 2 herein, and 29.5 hours after administration of the 5 mg DL tablet of Example 11 of USP 6,100,274. It gradually decreased with half life of.

For DL and 3-OH DL plasma concentrations, Cmax and AUC (tf) were statistically compared after administering the tablets of Example 2 herein and the 5 mg desloratadine tablets of USP 6,100,274.

The results showed that the 90% confidence intervals for DL and 3-OH DL did not meet 80-125% bioequivalence criteria for both Cmax and AUC (tf). In subjects who could determine AUC (I), the confidence interval of DL for AUC (I) did not meet the 80-125 biological equivalence criteria. However, the confidence interval of 3-OH DL for AUC (I) met 80 to 125 bioequivalence criteria.

Average pharmacokinetic parameters of pseudoephedrine are provided in Table 2.

In healthy subjects after oral administration of a single dose of DL D-24 and 240 mg pseudoephedrine sulfate (oval sustained release pseudoephedrine core from Claritin D-24 coated with placebo Claritin D-24 coat) Mean (% CV ^a ) Pharmacokinetic Parameters of Pseudoephedrine (n = 36) Pseudoephedrine Example 2 herein
5mg / 240mg Pseudoephedrine sulfate
Oval from Claritin D-24
Sustained release pseudoephedrine core) Average % CV Average % CV Cmax (ng / ml) 386 25 349 18.1 Tmax (hr) 8.42 34 7.36 36.3 AUC (tf) (ng-hr / ml) 6438 42 6225 38.5 tf (hr) 44.0 37 40.0 25.8 AUC (I) (ng-hr / ml) 6780 40 6452 37.3 t1 / 2 (hr) 10.3 148 7.25 21.6 a:% CV is the coefficient of change (%), which is a relative measure of variability [Steele and Torrie,
Principles and Procedures of Statistics ", (1980) 2nd Edition, McGraw-Hill, NY,
p.27].

The average pseudoephedrine Cmax after administration of the 5 mg DL / 240 mg PES tablet of Example 2 or the 240 mg pseudoephedrine sulfate sustained release core is 328 and 349 ng / ml, respectively. The Cmax and AUC (tf) values for DL D-24 (5 mg / 240 mg) vs. 240 mg pseudoephedrine sulfate (sustained release core) were statistically compared. The ability to detect a 20% difference in treatment mean at two-tailed of 0.05 for log-converted Cmax and AUC (tf) is 100% and 93%, respectively.

The 90% confidence interval for pseudoephedrine met the 80-125% bioequivalence criterion for both Cmax and AUC (tf). In addition, for subjects capable of determining AUC (I), the confidence interval of DL for AUC (I) met 80-125 biological equivalence criteria.

Second pharmacokinetic study

Subjects were placed in the study site at least 12 hours (-1 day) prior to performing each treatment. On the morning of Day 1, after starving overnight for 10 hours, each subject was subjected to one of the following treatments based on the number of subject genders and the study period:

Treatment A: One tablet of Example 2 herein (5 mg DL / 240 mg PES),

Treatment B: One tablet of Example 3 herein (6 mg DL / 240 mg PES),

Treatment C: One 5 mg DL tablet of Example 11 of USP '274 plus one 120 mg PES tablet (oval sustained release pseudoephedrine core).

The study procedure, blood collection time and analysis method outlined in the first study described above were used.

Average pharmacokinetic parameters are shown in Table 3. The ability to detect a 20% difference in the treatment mean of DL at two-tailed of 0.05 for log-transformed AUC (tf), AUC (I) and Cmax values was 89%, 90% and 88%.

Healthy adult volunteers after oral administration of a single dose of the DL tablets of Example 2 (5DL / 240PES mg), the DL tablets of Example 3 (6DL / 240PES mg) or 5 mg DL tablets of USP '274 plus one 240 mg PES tablet Mean (% CV ¹ ) pharmacokinetic parameters of DL, 3-OH DL and pseudoephedrine at (n = 42) DL process Cmax (ng / ml) / CV Tmax (hr) / CV A ² 1.91 44 4.69 52 B ³ 2.35 43 4.33 50 C ⁴ 2.28 40 3.87 67 3-OH DL process Cmax (ng / ml) / CV Tmax (hr) / CV A ² 0.77 28 6.67 52 B ³ 1.00 39 6.12 48 C ⁴ 0.93 31 5.68 58 Pseudoephedrine process Cmax (ng / ml) / CV Tmax (hr) / CV A ² 353 30 7.71 45 B ³ 362 28 8.14 46 C ⁴ 349 22 8.31 47 1:% CV is the coefficient of change (%), which is a relative measure of variability [Steele and Torrie,
Principles and Procedures of Statistics ", (1980) 2nd Edition, McGraw-Hill, NY,
p.27].
2: Treatment A = 1 tablet of Example 2 (5 mg / 240 mg).
3: Treatment B = 1 tablet of Example 3 (6 mg / 240 mg).
4: Treatment C = USP 6,100,274 One 5 mg DL tablet of Example 11 + 240 mg pseudoephedrine
1 tablet

As a result, based on the plasma 3-OH DL concentration, the 5 mg / 240 mg tablet of Example 2 was not equivalent to the 5 mg DL tablet of Example 11 of USP '274, and the 6 mg DL / 240 mg PES of Example 3 It is shown to be a biological equivalent to the 5 mg DL tablet of Example 11 of USP '274.

These results show that the bioequivalence of pseudoephedrine from the formulations of Examples 2 and 3 was established relative to the reference product.

Third Pharmacokinetic Study

Forty healthy volunteers participated in a study that randomly crossovered open-label single doses in three ways. After starving overnight for 10 hours, subjects were randomly applied as follows:

Treatment A: 5 mg DL / 240 mg PES of Example 4 herein

Treatment B: DL 5 mg + pseudoephedrine sulfate 240 mg of USP '274 Example 11.

The procedure listed above was carried out to carry out the process of the first study.

Average pharmacokinetic parameters for DL, 3-OH DL and pseudoephedrine are provided in Table 4.

DL in healthy adult volunteers (n = 40) after oral administration of a single dose of “1 5 mg D-24 tablet of Example 4” or “1 5 mg DL tablet of USP '274 + 1 240 mg pseudoephedrine tablet” Mean (% CV ¹ ) pharmacokinetic parameters of 3-OH DL and pseudoephedrine DL process Cmax (ng / ml) / CV Tmax (hr) / CV A ² 2.15 41 4.13 66 B ³ 2.30 44 4.83 62 3-OH DL process Cmax (ng / ml) Tmax (hr) A ² 0.89 48 5.60 42 B ³ 1.07 36 6.10 37 Pseudoephedrine process Cmax (ng / ml) Tmax (hr) A ² 382 34 7.83 29 B ³ 399 32 8.43 36 1:% CV is the coefficient of change (%), which is a relative measure of variability [Steele and Torrie,
Principles and Procedures of Statistics ", (1980) 2nd Edition, McGraw-Hill, NY,
p.27].
2: Treatment A = 1 tablet of Example 4 herein (5 mg DL / 240 mg PES).
3: Treatment B = USP 6,100,274 One 5 mg DL tablet of Example 11 + 240 mg pseudoephedrine
1 tablet

Example 1

This example illustrates the preparation of a preferred oral composition of the present invention. The components and their specific amounts are listed below.

1. Matrix core

  A. Manufacturing Method

   1.Povidone is dissolved in a mixture of 3 parts by weight of alcohol and 1 part by weight of purified water.

   2. Pseudoephedrine sulfate, hydroxypropyl methylcellulose 2208, ethylcellulose and dibasic calcium phosphate dihydrate are combined in a suitable mixing vessel and mixed under a nitrogen overlay.

   3. Granulate the mixture of step 2 into the solution of step 1. This wet granulated material is passed into a suitable grinding equipment to break up a large mass.

  4. The wet granulated material is dried at about 70 ° C. in a suitable fluid bed processor so that the loss on drying, measured by moisture balance or equivalent, is between 0.5 and 2.0%.

   5. Pass the dried granules into suitable grinding equipment.

   6. To these dried and ground granules, the necessary amounts of silicon dioxide and magnesium stearate are added and mixed.

   7. Compress this blend on a suitable tablet compressor.

The matrix core is applied in the following manner:

A. Preparation of Dispersions and Solutions for Coating

 1. First film coating solution

  (1) Simethicone and polyethylene glycol 8000 are dispersed in a portion of purified water and stirred until completely dissolved.

  (2) To the product of step 1, the remaining purified water and talc are added and the resulting suspension is stirred until homogeneous at room temperature.

  (3) The homogeneous suspension of step 2 thus formed is slowly added to the stirred EUDRAGIT NE30D dispersion and the resulting mixture is continuously mixed until a uniform dispersion is formed. Pass this dispersion into the screen.

  (4) Spray the dispersion onto a matrix core maintained at 40 ° C. ± 5 ° C. on a rotating pan.

  (5) The matrix cores thus applied are dried on a rotating pan.

 2. Dispersion solution for applying the second film

  (1) Simethicone and polyethylene glycol 8000 are dispersed in a portion of purified water. Additional water is added and it is stirred at room temperature until the dispersion is completely dissolved.

  (2) Desloratadine is slowly added to the dispersion of Step 1 and mixed until a uniform dispersion is formed. The homogeneous dispersion thus formed is combined with talc and shaken continuously until a homogeneous suspension is formed.

  (3) The dispersion of Step 2 is added to the EUDRAGIT NE 30D dispersion and mixed until a uniform dispersion is formed. Pass this dispersion into the screen.

  (4) Spray the required amount of dispersion from step 3 onto the matrix core with the first coating material in a rotating pan at 25-27 ° C.

  (5) The matrix cores thus applied are dried on a rotating pan.

 3. Solution for Coating Third Film

  (1) Hydroxypropyl methylcellulose 2910 is added to hot purified water (75 ° C.) and stirred until a solution is formed. The solution thus formed is cooled to room temperature.

  (2) In a separate container, add simethicone and polyethylene glycol 8000 to purified water and continue mixing until a solution is formed.

  (3) Talc is added to the solution of step 2 and mixing is continued until a uniform dispersion is formed.

  (4) The solution of step 1 is added to the dispersion of step 3 and mixed continuously.

  (5) FD & C Blue No. containing EDTA as a chelating agent. 2 Aluminum Lake is added to purified water in a third vessel.

  (6) The Blue Lake solution of step 5 is added to the dispersion of step 4 and mixed until a homogeneous mixture is formed.

  (7) Slowly add the mixture of step 6 to the dispersion of EUDRAGIT NE 30D and continue mixing until a uniform dispersion is formed.

  (8) Pass the dispersion of step 6 into the 60 mesh screen.

  (9) Spray the required amount of the dispersion of step 8 onto the twice-coated matrix cores in a rotating pan at 35 to 45 ° C. The three-coated matrix cores are dried in tablet form in a rotating pan.

  (10) The tablets thus formed are taken out of the pan and further dried at 40 ° C. for 16 hours.

Example 2

The following more preferred composition of the present invention is prepared according to the procedure of Example 1 above.

1. Matrix core

ingredient mg / core

    Pseudoephedrine Sulfate USP 240

    Hydroxypropyl methylcellulose 2208

    USP 100,000 cps. 320

    Ethylcellulose NF Type 7 80

    Dibasic Calcium Phosphate Dihydrate

    USP 108

    Povidone USP 40

    Silicon Dioxide NF 8

    Magnesium Stearate NF 4

Approximate Matrix Core Weights: 800 mg

3. Matrix core coating material

 (1) First film coating material:

ingredient mg / tablet

    Simethicone 0.22

    Polyethylene Glycol 8000 0.27

    Talc NF 2.72

    Ethyl acrylate / methyl methacrylate

    Neutral Copolymer (30% dispersion in water) 2.72

First coating material weight: 5.93mg

(2) 2nd film (immediate release type) coating material

ingredient mg / tablet

   Desloratadine 5.0

   Simethicone 0.28

   Polyethylene Glycol 8000 1.83

   Talc NF 7.00

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 6.09

Second coating material weight: 20.20mg

(3) third film coating material

ingredient mg / tablet

   Hydroxypropyl methylcellulose 2910

   USP 6cps 2.09

   Talc NF 5.79

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 4.18

   Polyethylene Glycol 8000 NF 0.42

   Simethicone 0.11

   Spectra Spray Med Blue Dye 3.65

3rd coating material weight : 16.24mg

Approximate total weight of the three coating materials : 42.37 mg

Approximate tablets (matrix core and three coatings) Weight : 842.97 mg

In vitro dissolution profiles of the tablets of Example 1 were measured in 0.1N HCl solution stirred at 37 ° C. for the first 1 hour, followed by stirred phosphate buffer with a pH of 7.5 at 37 ° C. 80% of desloratadine in the coating material dissolved in the first 45 minutes, and the total amount of pseudoephedrine sulfate in the matrix core was slowly released through erosion and dissolution mechanism over 16 hours.

Example 3

The following more preferred composition of the present invention is prepared according to the procedure of Example 1 above.

1. Matrix core

ingredient mg / core

    Pseudoephedrine Sulfate USP 240

    Hydroxypropyl methylcellulose 2208

    USP 100,000 cps. 320

    Ethylcellulose NF Type 7 80

    Dibasic Calcium Phosphate Dihydrate

    USP 108

    Povidone USP 40

    Silicon Dioxide NF 8

    Magnesium Stearate NF 4

Approximate Matrix Core Weights: 800 mg

4. Matrix core coating material

 (1) First film coating material:

ingredient mg / tablet

    Simethicone 0.22

    Polyethylene Glycol 8000 0.27

    Talc NF 2.72

    Ethyl acrylate / methyl methacrylate

    Neutral Copolymer (30% dispersion in water) 2.72

First coating material weight : 5.93mg

(2) Second film (immediate release) coating material:

ingredient mg / ml

   Desloratadine 6.0

   Simethicone 0.28

   Polyethylene Glycol 8000 1.83

   Talc NF 5.88

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 6.09

2nd coating material weight : 20.08mg

3. Third film coating material

ingredient mg / tablet

   Hydroxypropyl methylcellulose 2910

   USP 6cps 2.09

   Talc NF 5.79

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 4.18

   Polyethylene Glycol 8000 NF 0.42

   Simethicone 0.11

   Spectra Spray Med Blue Pigment 3.65

3rd coating material weight : 16.24mg

Approximate total weight of the three coating materials : 42.37 mg

Approximate tablets (matrix core and three coatings) Weight : 842.97 mg

Example 4

The following more preferred composition of the present invention is prepared according to the procedure of Example 1 above.

1. Matrix core

ingredient mg / core

    Pseudoephedrine Sulfate USP 240

    Hydroxypropyl methylcellulose 2208

    USP 100,000 cps. 320

    Ethylcellulose NF Type 7 80

    Dibasic Calcium Phosphate Dihydrate

    USP 108

    Povidone USP 40

    Silicon Dioxide NF 8

    Magnesium Stearate NF 4

Approximate Matrix Core Weights: 800 mg

5. Matrix core coating material

 (1) First film coating material:

ingredient mg / tablet

    Simethicone 0.22

    Polyethylene Glycol 8000 0.27

    Talc NF 2.72

    Ethyl acrylate / methyl methacrylate

    Neutral Copolymer (30% dispersion in water) 2.72

First coating material weight : 5.93mg

(2) Second film (immediate release) coating material:

ingredient mg / tablet

   Desloratadine 5.0

   Simethicone 0.28

   Polyethylene Glycol 8000 0.61

   Talc NF 5.17

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 6.09

   Hydroxypropyl methylcellulose 2910

   USP 6cps 3.05

2nd coating material weight : 20.20mg

(3) third film coating material:

ingredient mg / tablet

   Hydroxypropyl methylcellulose 2910

   USP 6cps 2.09

   Talc NF 5.79

   Ethyl acrylate / methyl methacrylate

   Neutral Copolymer 4.18

   Polyethylene Glycol 8000 NF 0.42

   Simethicone 0.11

   Spectra Spray Med Blue Pigment 3.65

3rd coating material weight : 16.24mg

Approximate total weight of the three coating materials : 42.37 mg

Approximate tablets (matrix core and three coatings) Weight : 842.97 mg

Similar results would be expected if a decongestive effective amount of another pharmaceutically acceptable pseudoephedrine salt (eg, pseudoephedrine hydrogen chloride) was used in place of pseudoephedrine sulfate.

While numerous preferred embodiments of the invention have been presented above by way of the foregoing examples, it is obvious that the scope of the invention is defined by the appended claims.

Claims (19)

delete delete delete (a) a sustained release core comprising 240 mg of pseudoephedrine or a pharmaceutically acceptable salt thereof; (b) a first film coating material for applying the core without destabilizing amounts of stearic acid, povidone, crospovidone, lactose, ethyl cellulose and hydroxypropylmethyl cellulose 2208; And (c) a second film applicator comprising 5 mg of desloratadine and applying the first film applicator, wherein the pharmaceutical tablet contains actual or simulated storage for at least 24 months at 25 ° C. and 60% relative humidity. Pharmaceutical tablets formulated to produce no more than 2.0% by weight total desloratadine degradation products in the tablets. The pharmaceutical tablet of claim 4 formulated for once-daily administration. The pharmaceutical tablet of claim 4, further comprising a third film applicator comprising hydroxypropylmethyl cellulose 2910. The pharmaceutical tablet of claim 4, further comprising polyethylene glycol. The pharmaceutical tablet of claim 4, further comprising simethicone. The pharmaceutical tablet of claim 4, further comprising talc. The pharmaceutical tablet of claim 4, wherein at least 80% of desloratadine in the tablet dissolves into the stirred 0.1N HCl solution at 37 ° C. in less than 45 minutes. The method of claim 4, wherein at least 80% of the pseudoephedrine or a pharmaceutically acceptable salt thereof in the tablet is dissolved into a stirred 0.1N HCl solution for 1 hour at 37 ° C., followed by a pH of 7.5 at less than 16 hours at 37 ° C. 6. Pharmaceutical tablets dissolved in stirred phosphate buffer. The method according to claim 4, wherein the total desloratadine degradation product N-formyldesloratadine in the tablet is produced from 1.4% to 1.6% by weight after actual or simulated storage for at least 24 months at 25 ° C and 60% relative humidity. Pharmaceutical tablets formulated to be. The pharmaceutical tablet of claim 4, wherein after a single dose of the tablet is administered to a human, an average time to reach peak plasma concentration (Tmax) of desloratadine is achieved 6-7 hours after administration. The pharmaceutical tablet of claim 4, wherein when a single dose of tablet is administered to a human, a peak plasma concentration (Cmax) of desloratadine is produced at 1.79 ng / mL. The pharmaceutical tablet of claim 4, wherein, after a single dose of tablet is administered to a human, an average time to reach peak plasma concentration (Tmax) of pseudoephedrine is achieved 8 to 9 hours after administration. The pharmaceutical tablet of claim 4, wherein when a single dose of tablet is administered to a human, a peak plasma concentration (Cmax) of pseudoephedrine is produced at 328 ng / mL. The agent according to claim 4, wherein the daily steady state area under the concentration time curve (AUC (0 to 24 hours)) of pseudoephedrine is 6438 ng / hr / mL when the tablet is administered daily to a human. Tablets. A pharmaceutical tablet comprising a sustained release core comprising 240 mg of pseudoephedrine or a pharmaceutically acceptable salt thereof, and an immediate release coating comprising 5 mg of desloratadine, Formulated for once-daily administration; A neutral or cationic copolymer ester that forms a water-swellable film in the coating between the core and the immediate release coating; Pharmaceutical tablets formulated to produce up to 2.0% by weight of total desloratadine degradation products in tablets after actual or simulated storage at 25 ° C. and 60% relative humidity for at least 24 months. The pharmaceutical tablet of claim 4 comprising polyethylene glycol, talc and simethicone.