CN101031290B

CN101031290B - Modafinil modified release pharmaceutical compositions

Info

Publication number: CN101031290B
Application number: CN200480027001XA
Authority: CN
Inventors: 阿尔帕·帕里克; 匹尤什·R·帕特尔
Original assignee: Cephalon LLC
Current assignee: Cephalon LLC
Priority date: 2003-09-18
Filing date: 2004-09-20
Publication date: 2011-09-21
Anticipated expiration: 2024-09-20
Also published as: ZA200603030B; UA94380C2; CN101031290A

Abstract

Pharmaceutical compositions comprising modafinil. The pharmaceutical compositions can have a release profile which is different than that of traditional pharmaceutical compositions of modafinil.

Description

The modafinil pharmaceutical compositions that improvement discharges

The application requires to be filed in the interests of 18 days U.S. Provisional Application of JIUYUE in 2003 60/504,028.

Invention field

The present invention relates to the acetamide derivative modafinil.Modafinil (C ₁₅H ₁₅NO ₂S) be 2-(benzhydrylsulfinyl) acetamide, be also referred to as the 2-[(diphenyl methyl) sulfenyl] acetamide.

Background of invention

1. modafinil

According to description, modafinil presents that " neuropsychopharmacology spectrum is characterized in that, exists with hyperactive excitement and hypermotility; And do not exist the effect of stereotypy (except high dose time) and apomorphine and amphetamine to strengthen " (United States Patent (USP) 4,177,290; Hereinafter referred to as " ' 290 patent ", the document is incorporated herein by reference).Take separately that motoricity that modafinil can cause mice increases and the nocturnalism of monkey increases people such as (, Eur.J.Pharmacol.180:49 (1990)) Duteil.The neuropsychopharmacology character of modafinil significantly is different from amphetamine (people such as Saletu, Int.J.Clin.Pharm.Res.9:183 (1989)).Modafinil is considered to regulate central process α after touch ₁-adrenoreceptor, and do not participate in dopaminergic system (people such as Duteil, supra).Modafinil is used for human body by successful test, to treat special property hypersomnia and the narcolepsy people such as (, Prog.Neuro-Psych.Biol.Psych.12:695 (1988)) Bastuji sent out.

Modafinil has shown excessive daytime sleepiness, parkinson disease, urinary incontinence, multiple sclerosis fatigue, ADHD, Alzheimer, sleep apnea, obstructive sleep apnea, depression and the ischemia that can treat narcolepsy, drowsiness, excessive sleepiness (for example following the drowsiness of sleep and Arousal disorders) effectively, follow narcolepsy.

Narcolepsy is a kind of chronic disease, it is characterized by: intermittent narcolepsy, lasting over-drastic daytime sleepiness and unusual rapid eye movement (" REM ") sleep indication as the sleep-outbreak REM cycle, damping off, sleep paralysis and hypnagogic hallucination or the two have (Assoc.of SleepDisorders Centers, Sleep 2:1 (1979)).Great majority have the patient's of narcolepsy nighttime sleep also can be destroyed (Montplaisir, people such as in Guilleminault compile, Narcolepsy, Spectrum Pub., New York, pp.43-56).Pathologic is drowsiness, no matter is owing to narcolepsy or other reason, all be disabling property and have a potential danger.Except narcolepsy, the reason that pathologic is drowsiness comprises chronic sleep loss (people such as Carskadon, Sleep, 5:S73 (1982); People such as Carskadon, Psychophysiology, 18:107 (1981)); Sleep apnea (people such as Kryger, Principles and Practice of Sleep Medicine (principle of hypnosphy and put into practice), W.B.Saunders Co., Philadelphia, Pa. (1989)); With other sleep disorder (International Classification of Sleep Disorders:Diagnostic andCoding Manual (International Classification of sleep disorder: diagnosis and coding manual), American SleepDisorder Association, Rochester, Minn. (1990)).No matter be that pathologic is drowsiness all can to produce outbreak, attention reduction and the behavior mistake of unconscious sleep owing to narcolepsy or other reason.Thereby, it relevant with multiple transportation and industrial accident (people such as Mitler, Sleep11:100 (1988)).Can reduce or eliminate the drowsiness therapeutic agent of pathologic will be not only to single patient but also significant to public health and safety.

Other purposes of modafinil is suggested.United States Patent (USP) 5,180,745 disclose and use modafinil to provide neuroprotective as human body, especially for the treatment parkinson disease.The levorotatory form of modafinil, promptly (-) benzhydrylsulfinyl-acetamide may have potential benefit (United States Patent (USP) 4,927,855) to the treatment of depression, hypersomnia and Alzheimer.European publication application 547952 (being published on June 23rd, 1993) discloses the use modafinil as the ischemia resisting medicine.European publication application 594507 (being published on April 27th, 1994) discloses the use modafinil and has treated urinary incontinence.

United States Patent (USP) RE37,516 disclose the pharmaceutical composition with qualification granularity, especially following compositions, the modafinil particle that wherein accounts for the total effective dose 95% of accumulation in the compositions has less than about 200 microns diameter.

Can by precipitation, pelletize and grinding or by extrude/round as a ball (spheronization) form the modafinil particle.

2. replacement dosage form: general

In the time can not using conventional oral or injectable formula, it is very important passing medicine control.The feature of controlled release includes but not limited to:

A. the slow release of water soluble drug;

B. the rapid release of low-solubility drug;

C. be delivered to ad-hoc location;

D. in same prescription, send two or more active matters; With

E. based on the system of the carrier that can dissolve or degrade and be easy to eliminate.

Controlled drug delivery can also provide following advantage:

A. get rid of over administration or underdosage;

B. levels of drugs is kept within the required range;

C. reduce the needs of repeat administration;

D. increase patient compliance; With

E. assist to change or prevent side effect.

The peroral dosage form that can provide zero level or one-level to discharge is known, and wherein time per unit discharges medicine with stable basically rate of release.These dosage forms are gratifying for the pharmaceutical dosage form of using many medicines.These dosage forms make the blood levels of medicine be increased to peak value, begin to fall after rise then when medicine is drained by metabolism or with other form.

But, in some environment, need more stable medicine blood levels or a plurality of peak value.Can provide the dosage form of this effect to be commonly called " prolongation release dosage form ".When being used for this paper, provide the prolongation release dosage form of normally stable medicine blood levels to be called as in time " slow release form ", provide the dosage form at differentiable medicine blood levels peak to be called as " pulse release form " in time.Below these two kinds of forms are carried out general description.

A. slow release form

The slow releasing pharmaceutical prescription can provide the rapid release of medicine, release that can also prolong drug, thus in a period of time, the blood levels of medicine is remained in the narrow relatively scope.

Can according to routine the slow releasing pharmaceutical prescription be made for compressed tablets by for example hydrogel tablet technology.In other alternative method, in pharmaceutical industries, will provide the pharmaceutical formulation of sustained release property to incapsulate routinely.In this case, can prepare the slow releasing capsule dosage form by the following method: medicine is mixed with one or more binding agents, form uniform mixture, water or solvent such as ethanol are with the mixture moistening then, form extrudable plasticity piece, therefrom extrude minor diameter, typically be the medicine/matrix cylinder of 1mm diameter, fragment into suitable length, be converted into spheroid with the circle rolling device of standard.After with the spheroid drying, then can carry out film coating to delay stripping.The amount that needs to obtain required therapeutic effect is put into pharmaceutically useful capsule such as starch or gelatine capsule with film-coated spheroid then.Spheroid with different rate of releasing drug can be combined in the capsule, to obtain required rate of release and blood levels.United States Patent (USP) 4,138,475 disclose the prolongation release of pharmaceutical compositions of being made up of hard gelatin capsule, use the film coating spheroid of being made up of the mixture of propanol and microcrystalline Cellulose to fill this hard gelatin capsule, wherein the thin film dress material is made up of ethyl cellulose and optional hydroxypropyl emthylcellulose and/or plasticizer.

B. pulse release form

As mentioned above, according to patient's needs, during drug administration, the peroral dosage form that provides zero level or one-level to discharge may be gratifying in some cases, wherein discharges medicine with stable basically rate of release in the time per unit.

But, in some cases, can provide two or more drug doses with the pulse release form, and not need twice or oral administration repeatedly typically with the predetermined amount of time between each dosage or at the gastrointestinal ad-hoc location.But, a spot of this pulse releasing system that can be Orally administered is only arranged, this is because to the used size of dosage form or the potential restriction of material.

Term " pulse release form " (hereinafter being sometimes referred to as " impulse form ") is a synonym with term " regulation and control delivery system ", according to Peppas (N.A.Peppas, Preface in R.Gurny; H.E.Junginger; N.A.Peppas (Eds.) Pulsatile Drug Delivery, CurrentApplications and Future Trends, 1 Ed., page 5-5, Wiss.Verlagsges., Stuttgart 1993), this term is meant the delivery system that can send contained medicament in predetermined space.

Up to the present, the preferred application area of medicine impulse form is following disease, as ischemic heart desease, asthma, arthritis, avoid producing toleration, HIV/AIDS and pain status (H.E.Junginger, OralApplications of Pulsatile Drug Delivery in R.Gurny to nitrate, antibiotic and the contraceptive steroid that has absorption window; H.E.Junginger; N.A.Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and FutureTrends, Ed.1, pages 113-134, Wiss.Verlagsges., Stuttgart 1993).The influence that these diseases or the pain status time that is subjected to changes is treated them best thereby can discharge the medicament forms that adapts to disease incident or pain invasion and attack generation with the interval that can make medicament (pulse).Clearly, in these cases, " time control " pulse delivery system is more favourable.In other cases, " Position Control " delivery system (for example treat colon disease, or use colon as the absorption position based on peptide and proteinic product) is proved to be more effective.

Typical medicine impulse form is sent contained medicament in a step (monopulse system), two steps (bimodal, double-pulse system).Allow and, described in addition may be in several steps the more complicated system and the hybrid system of delivering drugs.

Junginger (H.E.Junginger, Oral Applications of Pulsatile DrugDelivery in R.Gurny; H.E.Junginger; N.A.Peppas (Eds.) Pulsatile DrugDelivery, Current Applications and Future Trends, Ed.1., pages 113-134, Wiss.Verlagsges., Stuttgart 1993) provided the example of medicine impulse form, specifically enumerated: coated tablet, piller or microsphere, osmosis system, special capsule, time control burst release system and special layering tablet.

3. the administration of modafinil

Typically, to suffering from the people that the disease of response is arranged with modafinil to treat, once a day or the modafinil of administered twice 100mg and/or 200mg dosage.Preferably, use the single dosage that contains the effective dose modafinil to the patient who wakes.But, in some cases, be enough to continuously treatment modafinil is had one or more diseases of response for the blood levels with modafinil increases to, behind first dosage about six hours to 12 hours, can use second dosage that also comprises the effective dose modafinil.

For conventional administration, wish that the blood levels of medicine maintains between maximum blood levels and the minima, maximum blood levels is represented toxic level, and medicine is no longer valid when being lower than minima.But, be difficult to keep blood levels.For example, regular dosage form can provide unsettled haemoconcentration curve.After using first dosage, blood levels may increase and surpass maximum desired level, before using second or subsequently dosage, falls back to the level that is lower than minimum effect level then.Take modafinil subsequently, may repeat above-mentioned circulation unfriendly.

Summary of the invention

In one embodiment of the invention, can be in the time period that prolongs, the blood levels curve of medicine maintained be higher than minimum effect level and be lower than maximum desired level.Therefore, in one embodiment, the invention provides the dosage form that comprises modafinil, it can provide in about 6 hours to 12 hours time period and delay effect.

Described a kind of pharmaceutical composition in another embodiment of the invention, said composition includes but not limited to that releasing mechanism is different from Provigil

The modafinil pharmaceutical compositions of (modafinil) releasing mechanism, and provide can effectively change patient Somnolence and other can be with the neurological disease of modafinil to treat such as the compositions of ADHD.

In one embodiment, the present invention includes the pharmaceutical composition of unit dosage forms, thereby when administration, this unit dosage forms discharges the modafinil of two or more effective doses, wherein the release of at least one effective dose modafinil falls behind an interval, does not have medicine to discharge from dosage form in this interval basically.

In another embodiment, the present invention includes the pharmaceutical composition of unit dosage forms, thereby when administration, this unit dosage forms discharges the modafinil of first effective dose, be the interval that does not wherein have medicine from dosage form, to discharge basically then, behind this interval, from pharmaceutical composition, discharge the modafinil of second effective dose.

In another embodiment, the present invention includes the pharmaceutical composition of unit dosage forms, thereby when administration, this unit dosage forms can discharge the modafinil of effective dose immediately, the present invention also provides the modafinil that discharges second slower amount, the release of second amount modafinil wherein takes place in given interval, the blood levels of modafinil remains on normally stable level in this interval, and it typically is in or is higher than effective treatment has response to modafinil disease or the essential minimum level of disease.

In embodiment also, the present invention includes by prolonging the modafinil of effective dose in the release dosage form to administration the present invention, with the Somnolence's that changes mammal such as people method.

In embodiment also, the present invention includes by the present composition, with the Somnolence's that changes mammal such as people method to the administration effective dose.

The accompanying drawing summary

Fig. 1 has shown that the present invention postpones to prolong the modafinil release profiles of an embodiment of release dosage form.

Fig. 2 has shown that the present invention postpones to prolong the prediction modafinil plasma concentration curve of an embodiment of release dosage form.

Fig. 3 has shown the dissolution curve of six illustrative modafinil prescriptions.

Fig. 4 has shown the dissolution curve of three illustrative modafinil prescriptions.

Fig. 5 has shown hoop (banded) tablet that adds prepared in accordance with the present invention.

Fig. 6 has shown that the illustrative modafinil prescription from table 1 adds the dissolution curve that binds round tablet than the modafinil prescription from table 1.

Fig. 7 has shown the dissolution curve of illustrative modafinil slow release prescription in acid medium.

Fig. 8 has shown the dissolution curve of illustrative modafinil slow release prescription in acid medium.

Fig. 9 has shown the dissolution curve of " tablet capsule ", " granule capsule sheet (granulation caplet) ", " layering tablet " and monolayer slow releasing tablet.

Detailed Description Of The Invention

As disclosed herein with as employed in the present composition and the method, modafinil compounds can comprise racemic mixture, can randomly be: sour form, for example the metabolism acid of modafinil or benzhydrylsulfinyl acetic acid; The sulfone form; The hydroxylating form; Conjugate form such as modafinil compounds and protein, polysaccharide, glucosiduronic acid or sulfate conjugation; Or polymorphic forms; It can comprise chemical compound and the polymorphic kind of modafinil or the derivant of analog, enantiomer or congener and prodrug of the substituent such as the row of grade that contains the modafinil phenyl.In preferred embodiments, modafinil compounds is for example Provigil

Contained modafinil compounds in (modafinil).But other form that it should be noted that modafinil also is applicable to the present invention, for example with Provigil

(modafinil) bioequivalent modafinil is stablized polymorphic.Be known in the art, prodrug is the chemical compound that can be converted into activating agent (modafinil) in patient's body.

According to the present invention, can in improvement release dosage form such as pulsed release dosage form and/or slow release formulation, provide modafinil, as in the lower part in greater detail.

The pulsed release dosage form of modafinil

In one embodiment, modafinil pulse release form of the present invention can comprise the modafinil activity core that has one or more dress materials above it, is referred to herein as " the coating core of modafinil ".The coating core of modafinil also can be with the modafinil of a certain amount of suitable rapid release, include but not limited to Provigil

(modafinil) is used in combination, and be as described below.

In another embodiment, the present invention can comprise a certain amount of modafinil of rapid release and the modafinil of at least the second amount of being suitable for, prepare modafinil that they make second amount and have delay before taking place discharging, and the release of second portion modafinil can be prolonged in time.This embodiment is referred to herein as " delay of modafinil prolongs release ".Various pulsed release dosage forms are described below.

A. the coating core of modafinil

In one embodiment, the activity core of dosage form of the present invention can comprise inert particle such as the sugared ball of commercially available superfine product (non-pareil).Modafinil amount in the core depends on the dosage of hope.Usually, by the gross weight of core, core can comprise about 5wt% to 90wt%, more typically be the medicine of 5wt% to 60wt%.Those skilled in the art can select the modafinil of appropriate amount to be used for coating or be included in the core, to obtain required dosage form.Typically, the coating core can comprise about 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg or about 400mg modafinil.

Can use aqueous medium or acceptable solvent medium to prepare core particle.The inert binder type that is used for water soluble drug is bonded to inert particle is not crucial, but typically uses water solublity or pure soluble adhesive.By concentration binding agent is dispersed in the water, can uses binding agent such as polyvinylpyrrolidone (PVP), carboxyl alkyl cellulose, polyethylene glycol oxide, polysaccharide such as glucosan, corn starch, hydroxypropyl emthylcellulose (in old monograph nomenclature, to be called " HPMC " with about 0.5wt% to 5wt%; New monograph name is called " hypromellose (hypromellose) "), hydroxypropyl cellulose.Modafinil can be present in or is suspended in this dress material prescription with the solution form.Drug level can be between about 10wt% to 30wt%, and this depends on the viscosity of dress material prescription.

In one embodiment, can be by pelletize or by extruding and the round as a ball activity core for preparing.Can be at high shear granulator such as Fielder In comminutor or fluidized bed pelletizer such as the GlattGPCG comminutor; modafinil, binding agent such as PVP, optional dissolution rate controlling polymers such as high viscosity HPMC (or " hypromellose ") and optional other pharmaceutically acceptable excipient (as described below) is blended together; by interpolation/sprinkling pelletize fluid such as water or alcohol and pelletize; to form agglomerate, drying.Can use the extruder piece that will wet to extrude and round as a ball, with preparation spherical particle (pearl).In these embodiments, by extruding or the gross weight of pelletize core, the medicine carrying capacity can be as high as 90wt%.

The rete of coating on the pastille particle can comprise plastifying enteric polymer, and another layer can comprise the mixture of insoluble polymer and water of plasticity dispersibility/enteric polymer, wherein the weight ratio of insoluble polymer of Cun Zaiing and aqueous dispersion polymers can for 10: 1 to 1: 1, typically be about 4: 1 to 1: 1, gross weight by the multiparticulates dosage form, the gross weight of dress material is about 15wt% to 80wt%, is more typically about 20wt% to 60wt%.

Optional centre contains sorrel and can comprise organic acid such as fumaric acid, citric acid, succinic acid, tartaric acid, malic acid and maleic acid; With binding agent such as PVP.It should be noted that common use water solublity or alcohol soluble polymer.By the gross weight of coating pearl, the weight of this acidity dress material is about 5wt% to 20wt%.Acid in this film can postpone the dissolving of enteric polymer in the internal layer, thereby increases lag time, and reduces the rate of release of active component from the coating pearl.Can also optimize the single weight of composition and theca interna, middle rete and the theca externa of polymer film outer layer, thereby realize the pulse release curve of modafinil based on the external/interior dependency of prediction.Therefore, can optimize pulsed release dosage form of the present invention, thereby section back and/or the specific position in patient's digestive tract of form of administration discharge a certain amount of modafinil, the modafinil of preferred effective dose at the fixed time.

The representative example that is used for enteric polymer of the present invention comprises cellulosic ester and derivant (Cellacefate, Hydroxypropyl Methylcellulose Phathalate, HPMC-AS), Opaseal, pH-responsive type methacrylic acid-methylmethacrylate copolymer and lac.These polymer can be used as dried powder or aqueous dispersion.More operable commercially available material are: the methacrylic acid copolymer of being made by Rhom Pharma of selling with trade name Eudragit (L100, S100, L30D), from the Cellacefate (Cellacefate) of EastmanChemical Co., from the Aquateric (Cellacefate aqueous dispersion) of FMC Corp. with from the Aqoat (HPMC-AS aqueous dispersion) of Shin Etsu K.K..

The representative example that is used for insoluble polymer of the present invention comprises cellulose derivative (for example ethyl cellulose), polyvinyl acetate (from the Kollicoat SR30D of BASF), the neutral copolymer based on ethyl acrylate and methyl methacrylate, the acrylate with quaternary ammonium group and methacrylate copolymer such as Eudragit NE, RS or RS30D, RL or RL30D etc.

Usually will be used to form the enteric solubility and the insoluble polymer both plasticising of film.Can be used for the representative example of the plastifying plasticizer of film is comprised: glycerol triacetate, tributyl citrate, triethyl citrate, the positive butyl ester of citric acid acetyl three, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglyceride etc. or its mixture.By polymer, the amount of plasticizer can be more typically about 10wt% to 25wt% for about 3wt% to 30wt%.The type and the content thereof of plasticizer depend on polymer, and/or the character of coating system (for example based on water or solvent, based on solution or dispersion and all solids).

Usually, wish by using hydroxypropyl emthylcellulose (HPMC or hypromellose) (Opadry Clear

) film, with before apply pulse release film dress material with particle surface bottoming (prime), or separate different retes.Though typically use HPMC (or hypromellose), also can use other to be coated with substrate such as hydroxypropyl cellulose (HPC).

Can use that normally used any packaging technique is applied to the film dress material on the core in the pharmaceuticals industry, but fluidized bed coating is useful especially.

The present invention also provides the method for preparing the commutator pulse release dosage form, and this method may further comprise the steps:

1) with medicine and polymer adhesive with inert particle such as superfine product seed (sugared ball) coating, perhaps by pelletize or/and extrude/round as a ball preparation pastille particle, to form the active medicine particle;

2) with plastifying enteric coat with described active medicine particle coating, thereby form plastifying enteric coated drug particle; With

3) use the mixture of insoluble polymer and enteric polymer with described plastifying enteric coated drug particle coating.

In the present invention, second operation and the 3rd operation can be exchanged, and when adjusting the release profiles of drug particle, this feature provides extra adaptability.Another extra adaptability of the present invention is, randomly uses to contain the film of organic acid (for example fumaric acid or succinic acid) between second operation and the 3rd coating operation, thereby further adjusts the lag time and the release profiles of drug particle.The dosage form of the present invention that comprises the pastille particle of multiple coatings can adopt various ways.

In one embodiment, prescription can use single particulate form, thereby provides the time control pulse of medicine to discharge in several hours in oral back, and perhaps targeting is to the specific absorption position.In another embodiment, can in compound dosage form, (for example in gelatine capsule) will comprise the dosage form of the present invention and a certain amount of modafinil combination that is suitable for rapid release of multiple coatings pastille particle, thereby the compound dosage form with modafinil immediate release section and time control pulse release portion will be provided.

Because the optional immediate release section and the coating core of modafinil can comprise about 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg or about 400mg modafinil separately, so coating core dosage form of the present invention can comprise about 10mg to 800mg modafinil.

B. the delay of modafinil prolongs releasing pattern

In going back an embodiment, provide the modafinil dosage forms that the bimodal blood curve of modafinil (for example curve shown in Fig. 2) can be provided at least.Especially, the present invention can comprise following dosage form, and wherein this dosage form comprises the modafinil that at least a portion is suitable for the modafinil of rapid release and is suitable for postponing prolonging second amount of release.

In this embodiment, as shown in Figure 1, first's modafinil is discharged immediately, shown in the vertical bar that 1 hour locates among Fig. 1.Particularly, using the back in first hour, can from dosage form of the present invention, discharge a part of modafinil (100mg for example, as shown in Figure 1).And as shown in Figure 1, there is a time period, wherein do not have modafinil 1 basically) be released and/or 2) can enter patient's blood flow and/or 3) carry out biological utilisation from the second portion modafinil of being used, as locating in 2 hours and 3 hours among Fig. 1 shown in the lacking of dissolution bar.But after about 0 to 3 hour, more preferably after about 4 hours, extra modafinil can discharge from dosage form of the present invention, and the release of second portion can continue after initial application about 3 hours to 12 hours or the longer time.

Shown in 4 hours to 10 hours vertical bar among Fig. 1, the release of second portion modafinil took place in the time period that prolongs, and typically take place behind the lag time that does not have modafinil to discharge.Therefore, in this article, this dosage form that can have delay before beginning to discharge a certain amount of modafinil, preferred effective dose modafinil is called as " postpone to prolong and discharge " dosage form or compositions.This dosage form can use separately or with other dosage form combined administration.

Can the influence to blood levels of this dosage form of the present invention or compositions be described with reference to Fig. 1 and 2.For modafinil, wish that typically the blood levels of modafinil rises at least about 2 μ g/ml.But this haemoconcentration is corresponding to using back modafinil amount of biological utilisation behind the modafinil rapid release in first hour, as shown in Figure 1 with top described.But after about 2 hours to 4 hours, the blood levels of modafinil may reduce, and reduces in some cases to be lower than desired level, as shown in Figure 2.The present invention is designed to, typically after the immediate release section that discharges modafinil, in some preferred embodiments, after the modafinil blood levels begins to reduce, the second portion modafinil can enter blood flow, therefore wishing does not need to use second modafinil dosage, just blood levels can be increased to and/or remain on or greater than about 2 μ g/ml.

Therefore, in one embodiment of the invention, first's modafinil can have and commercially available modafinil form, especially Provigil

The initial pharmacokinetic curve that the curve of (modafinil) is consistent basically.Therefore, the present invention can comprise that about 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg or about 400mg have the modafinil of rapid release curve.

The modafinil that immediate release section comprises typically accounts for about 60wt% to 90wt% of immediate release section.Filler and other excipient constitute final weight percent.Be used for the particularly preferred embodiment that the present invention postpones to prolong releasing pattern, immediate release section comprises about 79.9wt% modafinil, 9.9wt% lactose monohydrate, 5wt% polyvinylpyrrolidone 90,5wt%Ac-Di-Sol (cross-linking sodium carboxymethyl cellulose) and 0.5wt% magnesium stearate.

In some embodiments, the modafinil of rapid release can be the modafinil described in the United States Patent (USP) RE 37,516, and its content is incorporated herein by reference in view of the above.The modafinil combination of rapid release prescription and a certain amount of delay prolongation release formulation as following further description, can be combined in then in dosage form such as gelatine capsule, the preferred hard gelatin capsule, thereby form compound dosage form.

Describe below at the modafinil that is suitable in the dosage form that the patient uses, using and postpone to prolong release composition.

B1. be suitable for postponing to prolong the prescription of release

Some modafinil prescription that can postpone to prolong release is described in the table 1.

As shown in table 1, can be with modafinil and polyhydric alcohol such as mannitol, coagulating agent such as Polyox

Coagulating agent and lubricant such as stearic acid make up, and postpone to prolong the granule that discharges composition of modafinil to obtain to provide.In certain embodiments of the invention, the delay of dosage form of the present invention prolongation release portion can comprise about 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg or about 400mg modafinil.In some specific embodiment, as described in following table 1, can use the 100mg modafinil, reach about 150mg thereby make total delay prolong release formulation weight.

Table 1: postpone to prolong prescription

Use above-mentioned prescription, utilize standard method, include but not limited to encapsulated method, can make capsule sheet, tablet or other dosage forms that whether delay fills a prescription.But it should be noted that these dosage forms typically have " slow release " blood curve if more do not talk about, promptly dosage form typically discharges modafinil immediately after absorption, and discharges modafinil in time continuously, shown in Fig. 3 and 4.Also these compositionss can be mixed with dosage form, these compositionss also can have the prolongation release profiles, in back 3 hours to 12 hours of absorption, typically be in 4 hours to 12 hours, more typically for discharging modafinil in 6-12 hour.

The dosage form that forms with the described compositions of table 1 randomly can be carried out end coating, the tablet sealing is used for processing subsequently.Suitable sealant includes but not limited to: HPMC (or hypromellose), HPC, PEG and combination thereof.

Therefore, if not more words, the dosage form that produces from the compositions by the described preparation of top table 1 typically has " slow release " curve, also can be used to prepare other modafinil improvement release dosage form, include but not limited to " tablet capsule ", " granule capsule sheet " and " layering tablet " slow release formulation, below they are described further.But, for the purposes of the present invention, preferably have the composition of modafinil that postpones to prolong release according to above-mentioned and table 1 preparation.

Relatively by the dissolution (in 0.1N HCl, testing dissolution) of the compositions of the described preparation of table 1, wherein compositions dissolution is in time listed in Fig. 3 and 4, along with the weight percent increase of polyhydric alcohol and coagulating agent, the time delay before modafinil discharges initial the generation also increases.And as shown in Figure 4,, when the amount of the amount of modafinil and/or cellulose (being Avicel PH200) increases, be minimum to the influence of modafinil release with respect to shown in the table 1 and described prescription F1.

Therefore, in order further to slow down the release of modafinil, and in some embodiments, for in a period of time, typically be to use and prevent in back 0.5 hour to 4 hours that modafinil from discharging, preferably the dosage form that will have a listed composition of table 1 with one or more bands of one or more polymeric materials adds hoop, as described in greater detail.

B2. polymeric material strip

Modafinil dosage forms added hoop, preferably adding in the embodiment of the present invention of hoop around circumference, the polymeric material strip can be made up of any polymeric material, preferred insoluble polymer material, the more preferably material that does not corrode or do not degrade during making up a prescription relatively.Typical insoluble polymer comprises the insoluble polymer that this paper is above-mentioned.

In these embodiments, the quantity of band, position and thickness can be controlled the rate of release of modafinil.In the present invention, if used a plurality of bands, can between band, there be the distance of 0.5mm, 1.0mm, 1.5mm, 2.0mm, 2.5mm or 3.0mm.The width of each band can be 0.5mm, 1.0mm, 1.5mm or 2.0mm, and thickness is about 0.1 μ m to 100 μ m, more typically is 0.1 μ m to 50 μ m, is 0.1 μ m to 20 μ m in some preferred embodiments.

As shown in Figure 5, in one embodiment of the invention, have two annular polymeric bands at the capsule sheet that from above-mentioned F1 prescription, forms.Width with 20 and 30 is respectively about 1mm, and the distance 40 between them is about 2mm.

Add the stripping of hoop capsule sheet with mode same as described above (promptly in 0.1N HCl).The hoop capsule sheet that adds of prescription F1 is shown among Fig. 6 with respect to the dissolution of the prescription F1 capsule sheet of no polymer belt.As shown in Figure 6, add hoop prescription and further slowed down the release of modafinil, but prolonged the time period that modafinil discharges and/or enter blood flow and/or biological utilisation.In some embodiments, band can postpone the generation that modafinil discharges, thereby has the lag time (being also referred to as " delay " or " postponing to discharge ") that does not discharge modafinil.Typically, it can more typically be 0 to 3 hour for using the back 0 to 4 hour that the generation of modafinil postpones, and more typically is 0.5 hour to 4 hours, is 1 hour to 2 hours in some embodiments.

In order further to postpone the generation of modafinil from add the hoop dosage form, can randomly will add the hoop dosage form coatings with suitable enteric coat.Those skilled in the art can easily obtain suitable enteric coat, and it includes but not limited to Eudragit L30D-55 and PEG, suitable dress material and following table 2 listed one or more polymer relevant with above-mentioned modafinil coating core.Enteric coat also can comprise other excipient such as Talcum.Can be with about 2 μ g/cm ²To 10 μ g/cm ², typically with about 7 μ g/cm ²Level will add the hoop dosage form coatings.In preferred embodiments, enteric coat can postpone the generation of modafinil, thereby has the time that does not wherein discharge modafinil behind form of administration.Typically, after with suitable enteric coat coating, modafinil is 0.5 hour to 4 hours from the generation delay that adds the hoop dosage form (for example adding of enteric coating bound round the capsule sheet) of coating, more typically is 1 hour to 2 hours.

After this, in some embodiments of the present invention, can the modafinil of above-mentioned rapid release dosage and the hoop capsule sheet that adds of enteric coating be combined to (for example in single gelatine capsule) in the single compound dosage form with conventional method.About 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg or about 400mg modafinil can be comprised separately because immediate release section and delay prolong release portion, about 10mg to 800mg modafinil can be comprised so delay of the present invention prolongs the compound dosage form of release.This dosage form can obtain and the top similar modafinil blood curve of curve shown in Figure 2.

The slow release formulation of modafinil

Comprise that except above-mentioned the delay of slow release formulation types prolongs the release formulation, also described other suitable embodiment of modafinil slow release prescription below.Every kind of complex composition described below comprises rapid release prescription and slow release prescription (describing below) at least.Therefore, the dosage form embodiment that in the present invention, is called " slow release " can typically not have the delay that modafinil takes place after using, and this class dosage form can not have the following significant time period yet, but does not wherein have the medicine biological utilisation from dosage form.

In one embodiment, " tablet capsule " of indication of the present invention can comprise capsule, this capsule comprise by preparation be used for rapid release tablet form first's modafinil and be used for the modafinil of second portion at least of tablet form of slow release by preparation.

In another embodiment, " the granule capsule sheet " of indication of the present invention can comprise capsule or capsule sheet, and described capsule or capsule sheet comprise and be used for first's modafinil particles of rapid release by preparation and what be used for slow release can be the modafinil of second portion at least of tablet form by preparation.

In going back an embodiment, " the layering tablet " of indication of the present invention can comprise having two-layer or more multi-layered tablet.In this embodiment, tablet can comprise the modafinil that is used for rapid release by preparation.This embodiment can also comprise the second layer modafinil that is used for slow release by preparation.

In C1 to the C3 part above-mentioned each embodiment will be described in more detail below.In addition, above-mentioned each embodiment can comprise about altogether 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg or 400mg or more modafinils in first (immediate release section), comprises the modafinil of 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg or 400mg or more additional quantity at second portion.Therefore, composite slow release dosage form of the present invention can comprise that about 10mg is to about 800mg or more modafinil.

C1. tablet capsule

In " tablet capsule " of the present invention embodiment, tablet capsule comprises a certain amount of modafinil of second portion at least that is suitable for the modafinil of rapid release and continues to discharge a certain amount of modafinil at most in 6-12 hour when taking in after tablet capsule is taken in.

In this embodiment of the present invention, the 50-95% modafinil is the rapid release prescription of tablet form at least, can be Provigil

(modafinil).Preferably comprise the composition of modafinil that is suitable for rapid release at least about 80% tablet capsule.Though with reference to " pulse release " prescription, the residue of tablet capsule embodiment can comprise the modafinil slow release prescription that top table 1 describes in detail by weight, the preferred tablet capsule comprises the modafinil slow release prescription part of describing in the following C4 part.

Can will comprise the tablet of modafinil rapid release prescription and the tablet of slow release prescription and be combined in single dosage form such as the gelatine capsule in a usual manner.

C2. granule capsule sheet

One embodiment of the invention comprise granule capsule sheet, and wherein the 50-95% modafinil is the rapid release prescription at least, can be Provigil

The granule of (modafinil) (with the tablet difference).Preferably comprise the composition of modafinil of the particle form that is suitable for rapid release at least about 80% granule capsule sheet, said composition typically is included in the isolating capsule sheet.Though with reference to " pulse release " prescription, the residue of granule capsule sheet embodiment can comprise the modafinil slow release prescription that top table 1 describes in detail by weight, preferred particulates capsule sheet comprises the modafinil slow release prescription part of describing in the following C4 part.

Can be in a usual manner, will comprise the capsule sheet of modafinil rapid release prescription and slow release formula combination in single dosage form such as gelatine capsule.

C3. layering tablet

In the present invention's " layering tablet " embodiment, the layering tablet comprises a certain amount of modafinil of second portion at least that is suitable for the modafinil of rapid release and a certain amount of modafinil is provided in 6-12 hour at most immediately when taking in after taking in tablet capsule.

In this embodiment of the present invention, the 50-95% modafinil is the rapid release prescription at least, can be Provigil

(modafinil).Preferably comprise the composition of modafinil that is suitable for discharging immediately at least about 80% layering tablet.Though with reference to " pulse release " prescription, the residue of layering tablet embodiment can comprise the modafinil slow release prescription that top table 1 describes in detail by weight, preferred layering tablet comprises the modafinil slow release prescription part of describing in the following C4 part.

Can in a usual manner as make up this two kinds of prescriptions in tablet machine, thereby after processing, final lamellar dosage form has two-layer or more multi-layered, ground floor comprises the rapid release prescription of modafinil at least, and the second layer comprises the slow release prescription.

C4. slow release prescription

As mentioned above, every kind of slow releasing composition comprises a certain amount of modafinil, it is prepared as follows, with at 4 hours in 12 hours, more typically in 12 hours, discharged modafinil at 6 hours.Prolong release formulation, the especially prescription described in the table 1 though can replace above-mentioned delay with reference to the described prescription of slow release, vice versa, preferably uses the described formulation of this paper lower part slow release formulation of the present invention.

As mentioned above, the slow release prescription of the present invention modafinil amount that can comprise typically is about 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg or 400mg.Typically, slow release prescription of the present invention also comprises at least a suitable polymers, and this polymer includes but not limited to one or more polymer described in the following table 2, and the wherein wt percentage rate also is described in the rightest hurdle of table 2.

Table 2:

Polymer	Kind	Level (%)
			Eudragit RSPO RLPO NE30D-suspension ^*	Acrylate-methacrylate polymers is insoluble, and high osmosis is insoluble, and hypotonicity is insoluble, and is permeable	10 10、15、30 20
Carbopol 971P 934P 974P	Cross-linked polyacrylic acid polymer is lightly crosslinked, and slowly release altitude is crosslinked in SGF, and it is crosslinked to discharge rigidity in whole GIT, discharges medicine in SIF rapidly	10、15 10 10、20
			Methocel K4M ^*	Water miscible HPMC, viscosity: 4000 the milli handkerchief-second	15、18、30

Methocel：Avicel K4M K100M K15M K4M ^*	Water miscible: insoluble MCC K4M viscosity: 4000 milli handkerchiefs-second K100M viscosity: 100000 milli handkerchiefs-second K15M viscosity: 15000 handkerchief-seconds in the least	10、14、14.5、15、 16.5、18、30 5 10 7、10、12?
			Polyox coagulating agent WSRN301 WSRN60K	Water miscible, poly-(ethylene oxide) polymer MW: 5,000,000 MW:4,000,000 MW:2,000,000	5、8、9、9.5、10、 20 10、12.5、15、20 20、30、40
Keltone HVCR	The alginate high viscosity	10
			Ethyl cellulose Ethocel 100FP	40 microns of water-insoluble ethyl cellulose granularities	5-15
Kolidon?SR?	80% polyvinyl acetate and 19%Povidone, the part water soluble	20?

It should be noted that and to add the polymer that indicates " * " by wet granulation.

Filler includes but not limited to lactose and dicalcium phosphate, and lubricant includes but not limited to magnesium stearate.

In some embodiments, modafinil can account for 20wt% to 30wt%, 30wt% to 60wt% at least or the 70wt% of slow releasing composition.The residuals weight of compositions can be filler, lubricant and above-mentioned polymer.In preferred embodiments, polymer can account for the 5wt% to 20wt% of slow releasing composition, more preferably 7wt% to 10wt% or 10wt% to 16.5wt%.In highly preferred embodiment, polymer is cellulosic polymer such as Methocel K4M, and content is about 10wt%.Can prepare the slow release prescription by direct compression or wet granulation.

Fig. 7 and 8 has shown various slow releasing tablets dissolution curve separately.Prepare slow releasing tablet from the slow release prescription, the modafinil gross weight is 100mg, and total sheet heavily is 250mg.Fig. 7 has shown the dissolution by the tablet of direct compression preparation, and Fig. 8 has shown the dissolution by the tablet of wet granulation preparation.Instruction according to this paper prepares this two kinds of prescriptions.

The dissolution curve of tablet capsule, granule tablet, layering tablet and used separately slow release prescription is shown among Fig. 9.Dosage form comprises immediate release section and slow-released part.Slow-released part comprises MethocelK4M as polymer, and it accounts for the 7wt% to 16.5wt% of slow-released part.As shown in Figure 9, the tablet capsule embodiment shown in dissolve sooner in the time period, and independent slow release prescription dissolves the most slowly.

Excipient and other composition

Though described compositions disclosed herein and method according to some embodiment, should be appreciated that, can use for example inert diluent or the Orally administered modafinil dosage forms as herein described of assimilable edible carrier.In duricrust or the soft shell gelatin capsules of also compositions can being packed into, be pressed in the tablet, or directly be included in the food of diet.These compositionss and preparation should comprise at least 0.1% reactive compound.Certainly, the percentage rate of compositions and preparation can change, and about 2wt% that can account for Unit Weight easily is to about 60wt%.

Tablet, piller, capsule etc. also can comprise following any material: binding agent such as gum tragacanth, arabic gum, corn starch or gelatin; Excipient such as dicalcium phosphate; Disintegrating agent such as corn starch, potato starch, alginic acid etc.; Lubricant such as magnesium stearate; Can add sweeting agent such as sucrose, lactose or glucide, or aromatic such as Herba Menthae, wintergreen oil or cherry flavor.When dosage form is capsule, except the above-mentioned material type, can also comprise liquid-carrier.Various other materials can be used as dress material and exist, or otherwise change the physical form of dosage form.For example, can use lac, sugar or the two is with tablet, piller or capsule coating.Syrup or elixir can comprise: as the reactive compound sucrose of sweeting agent, as the methyl hydroxybenzoate of antiseptic and propyl hydroxybenzoate, dyestuff and spice for example Fructus Pruni pseudocerasi or orange essence.Certainly, any materials that is used to prepare any dosage form all should be that pharmacy is pure, is nontoxic basically under used amount.In addition, reactive compound can be included in slow releasing preparation and the prescription.

In some embodiments, disintegrating agent is added in the prescription helping all or a part of dosage form taking the back disintegrate, thereby discharge at least a portion active component.Some common disintegrating agents comprise several modified cellulose derivants such as cross-linking sodium carboxymethyl cellulose and other modified starch derivative such as primojel.Those of ordinary skill in the art be also to be understood that other composition, binding agent and lubricant can further influence the dissolution curve of dosage form.

In addition, also can comprise surfactant such as ion-type, nonionic and/or bile salts surfactant in the present invention.Anion surfactant includes but not limited to: alkyl sodium sulfate (Sodium Lauryl Sulphate

) and 2-Sulfosuccinic acid salt derivative such as docusate sodium.Nonionic surfactant includes but not limited to: polyoxyethylene sorbitan fatty acid ester (Polysorbate) is as Tween 20

, Tween 80

, Tween 40

, Span 20 The fatty acid ester of Polyethylene Glycol such as Gelucire 44/14

, Gelucire 50/13

, saturated polyglycolyzed glyceride (comprising monoglyceride, diglyceride or triglyceride); (Imwitor 308 as Monooctamoin for medium-chain monoglyceride (from 6 to 10 carbon atoms are long)

), glycerol list alkyl caproate (CapmulMCM C-8

), glycerol caprylate/decanoin (Capmul MCM

); Polyoxyethylene glycerol caprylate and polyoxyethylene caproin (Labrasol

); (Miglyol 612 for medium-chain fatty acid ester such as decanoin and tricaprylin

); The block copolymer of ethylene oxide and propylene oxide, the block copolymer of polyoxyethylene-polyoxypropylene such as Poloxamer 188 (Pluronic F-68

), Poloxamer 237 (Pluronic F-87

), Poloxamer 338 (Pluronic F-108

), Poloxamer 407 (Pluronic F-127

), Poloxamer 124 (Pluronic L-44 ); (Myrj 52 for KIKKOL MYS-40-polyethoxylated (40) stearic acid

), ethoxylated castor oil-polyethoxylated (60) castor oil hydrogenated (Cremophor EL ), ethoxylation hydrogenation stearic acid (hydrostearic acid) Polyethylene Glycol 660 hydroxy stearic acid ester (Solutol HS 15), polyoxyethylene alkyl ether (from 12 to 18 carbon atoms long) polyoxyethylene (20) cetyl-octadecyl ether (Atlas G-3713 for example

), (Brij 96 for the oily ether of polyoxyethylene (10)

, Brij 97

, Oleth 10

), polyglycol ether (Triton X-100

, Triton X-114

, Triton X-405

, Triton N-101

) and lecithin such as phospholipid (two myristoyl DL-α-phosphatidylcholine).The bile salts surfactant comprises but is not limited to: deoxycholic acid, NaTDC, cholic acid, sodium taurocholate.

The compositions and methods of the invention also can make up with the other medicines composition of effective dose, include but not limited to can be used for treating the ingredient of neurological disorder.Suitable ingredient comprises antidepressants.Useful antidepressants include but not limited to: tricyclic antidepressant (" TCA "), selective serotonin reuptake inhibitor (" SSRI "), 5-hydroxy tryptamine and norepinephrine reuptake depressant (" SNRI "), dopamine reuptake depressant (" DRI "), norepinephrine reuptake depressant (" NRU "), dopamine, 5-hydroxy tryptamine and norepinephrine reuptake depressant (" DSNRI "), oxidase inhibitor (" MAOI ") comprise the reversible inhibitor (RIMA) of A MAO-B B.

In certain embodiments, suitable antidepressants can include but not limited to one or more in the following antidepressants: adatanserin hydrochloride; Adinazolam; Adinazolam Mesylate; Alaproclate; Aletamine hydrochloride; Amedalin hydrochloride; Amitriptyline hydrochloride; Amoxapine; Aptazapine maleate; Azaloxan fumarate; Nitrogen

Indole; Azipramine Hydrochloride; Bipenamol hydrochloride; BUPROPIONE HCl; Butacetin; AY-62014; Caroxazone; Cartazolate; Ciclazindol; The hydrochloric acid cidoxepine; The methanesulfonic acid cilobamine; Citalopram (citalipram); Clodazone hydrochloride; Clomipramine Hydrochloride; The fumaric acid cotinine; Ciclindole; Cypenamine hydrochloride; Cyprolidol hydrochloride; Ciproximide; Daledalin tosylate; Dapoxetine hydrochloride; The maleic acid dazadrol; Hydrochloric acid nitrogen

Neil; Desipramine hydrochloride; Dexamisole; Deximafen; Neodalit (Hssle); Rydar (Cutter).; Altapin (Marion); Doxepin hydrochloride; Salt acidity Luo Xiding; He is bright according to chlorine for maleic acid; Encyprate; AF-1191; Fantridone hydrochloride; Fenmetozole hydrochloride (fehmetozole); Fenmetramide; Fezolamine fumarate; Fluotracen hydrochloride; Fluoxetine; Fluoxetine Hydrochloride; The hydrochloric acid fluparoxan; Gamfexine; The sulphuric acid guanoxyfen; The hydrochloric acid imafen; Hydrochloric acid imiloxan (imiloxan); Impamin; Indeloxazine hydrochloride; Intriptyline hydrochloride; Iprindole; Isocarboxazid; Ketipramine fumarate; Lofepramine hydrochloride; Lortalamine; Maprotiline; Aueural; U-24973A; Milacemide hydrochloride; Minaprine Hydro-chloride; Rice chlorine is flat; Moclobemide; Modaline sulfate; Napactadine hydrochloride; Napamezole hydrochloride; Nefazodone hydrochloride; Nisoxetine; Hydrochloric acid nitrafudam (nitrafudam); Nomifensine maleate; Psychostyl; Octriptyline phosphate; Opipramol hydrochloride; Oxaprotiline hydrochloride; Oxypertine; Paroxetine; W-1544a; Pirandamine hydrochloride; Pizotifen; The hydrochloric acid pridefine; Prolintane hydrochloride; Protriptyline hydrochloride; Quipazine maleate; Rolicypram; Seproxetine hydrochloride; Sertraline hydrochloride; Sibutramine hydrochloride; Sulpiride; Suritozole; The hydrochloric acid tametraline; The fumaric acid tampramine; Tandamine hydorchloride; Thiazesim hydrochloride; Thozalinone; Tomoxetine hydrochloride; Trazodone hydrochloride; Trebenzomine hydrochloride; Trimeprimine; Trimipramine maleate; VENLAFAXINE HCL; Viloxazine hydropchloride; Zimelidine hydrochloride; The chlorobenzene pyrrole

In certain embodiments, antidepressants comprise: citalopram, fluoxetine, fluoxetine Hydrochloride, paroxetine, paroxetine hydrochloride and/or Clomipramine Hydrochloride, wherein preferred citalopram, paroxetine, fluoxetine, fluoxetine Hydrochloride, most preferably citalopram.

The other medicines such as the tiagabine that can be used for treating depression also can be used in combination with the present invention.

Prescription and administration

The suitable dose of modafinil at about 10mg between about 1000mg modafinil, more typically between about 15mg to 800mg modafinil.Useful especially dosage includes but not limited to 100mg and 200mg modafinil.Preferably, modafinil has the granularity of qualification, and wherein 95% particle is less than or equal to about 200 microns.

Most preferably with the Orally administered pharmaceutical composition as herein described of the form of carrier such as tablet, capsule, powder, piller, liquid/suspensoid or Emulsion.The administration carrier can comprise pharmaceutical carrier.Carrier can include the reagent of the dissolubility, absorption, taste, color or the quality that help carrier or its content.

Because many factors, for example carrier prepares the expectation shelf-life of toleration and modafinil, and carrier of the present invention can comprise ± 10-15% modafinil particle.For example, can be labeled as the carrier that contains the 50mg modafinil beginning to prepare, estimate that modafinil live vol wherein reduces after storing one month to 2 years with 55mg for example or 58mg modafinil.In order to compensate the drug degradation of expection, the carrier for preparing with this adjustment falls within the scope of the present invention.

In dosage form of the present invention, the modafinil total amount can for about 15mg to about 600mg, in other embodiments, the total amount of modafinil can be at least about extremely about 600mg of 50mg in the dosage form.In preferred embodiments, dosage form comprises 100mg or 200mg modafinil.

In one embodiment, prescription can comprise two or more drug particles with different release characteristics, one or more improvement that for example will have obvious different lag time and a rate of release discharge pearls with or not with the combination of rapid release pearl, discharge delivery system to form commutator pulse.Perhaps, can be with slow release formulation and pulsed release dosage form combination.

Also can be with the multiple coatings microgranule combination of two or more medicines, to obtain synergy and enhanced patient compliance.

Therapeutic Method

Though relating to, the specific embodiment that this paper proposes has the modafinil that limits granularity, but this area has proposed other purposes (for example treating parkinson disease, urinary incontinence, Alzheimer, ADHD etc.) of modafinil, and those are united with invention disclosed herein with being coated with suitably.

Therefore, the present invention also comprises by use the method that the modafinil of effective dose in the present composition changes the mammal Somnolence to mammal such as people.

In addition, the present invention includes by using the method that the modafinil of effective dose in the present composition strengthens Vigilance or strengthens sleep rhythm regularity.

The present invention also comprises a kind of method in its scope, this method is by using a certain amount of modafinil as one or more oral dosage, wherein unit dose comprises the modafinil in the present composition of effective dose, thereby treatment suffers from the mammal of modafinil-responsive diseases or symptom after diagnosing, and described disease or symptom include but not limited to: narcolepsy, drowsiness, excessive sleepiness (for example following the drowsiness of sleep and Arousal disorders), follow the excessive daytime sleepiness of narcolepsy, parkinson disease, urinary incontinence, multiple sclerosis fatigue, ADHD, Alzheimer, sleep apnea, obstructive sleep apnea, depression and ischemia.

The dissolution test

As referred herein, use Vankel USP Type III device, with 20 soak/minute (dipper minute) carry out the dissolution test to the tablet from each prescription, and keep sink conditions (sink condition).With 0.5 hour interval sampling, analyze with the UV spectrophotometer.Fig. 7 and 8 shows the modafinil cumulative percentage rate that discharges in time from each prescription.

Embodiment 1:

Use the low ethanol comminution granulation of shearing, criticize with the hand-made 100g that is equipped with listed each prescription of table 1.By the manual sieves of 16 orders (hand screen), tray drying is spent the night at ambient temperature then with the granule wet grinding.Dried granule dry grinding by the manual sieve of 16 orders, is done with hands and stearic acid then and mixed.With the manual tablet machine of Globe Pharma, the final blend of 150mg that will be equivalent to the 100mg modafinil with 1000lb pressure manually is pressed into the cryptomere tablet of 4 * 12mm.All tablets are carried out end coating with tablet sealing, for subsequently the hoop that adds provides suitable surface.Use VectorLDCS 20/30 coating device, tablet is carried out end coating with HPMC/PEG 8000 (50: 50 by weight).

Embodiment 2:

Band is applied on the core tablet surface of embodiment 1 around circumference.Use contains the Eudragit of 8wt% glycerol triacetate as plasticizer NE30D solution is with two wide 1mm, at interval the band of 2mm is applied on single station tablet hooping machine (single station tablet banding machine).Add hoop solution and also comprise a small amount of FD﹠amp; C Red 40 is to allow the visual examination band.Band is applied on the surface of each core matrix tablet, at ambient temperature dried overnight.

After the drying, will add the hoop tablet and carry out the top coating, with the viscosity of sealing surfaces and minimizing band.With HPMC/PEG 8000 (50: 50 by weight) tablet is carried out the top coating.

Embodiment 3:

To add the hoop tablet coating with enteric polymer, with the generation (about two hours) of suitable delay release.Use Vector LDCS 20/30 coating device, use Eudragit

L30-55/PEG 8000/ Talcum (84: 8: 8 by weight) will add the hoop tablet coating.

Embodiment 4:

Can be from Cephalon, Inc is with trade name Provigil

(modafinil) obtains the prescription of modafinil immediate release section.In order to be used to add the hoop tablet, use the Hobart planetary-type mixer, prepare immediate release section by the low aqueous comminution granulation of shearing.In 50 ℃ pressure air-oven, the tray drying granule, to water capacity less than 2%.Use the Erweka oscillating mill that dried granule is ground by 40 mesh sieves, use Patterson-Kelly V-arrangement blender then itself and dry blended with magnesium stearate.

Embodiment 5:

The enteric coating of a certain amount of embodiment 4 rapid release prescriptions and embodiment 3 is added the hoop tablet to be combined in the gelatine capsule of #1 size, so that the compound dosage form with the bimodal release profiles of modafinil to be provided, wherein immediate release section discharges from dosage form and by biological utilisation, and being does not then wherein have other modafinil to be released time period with biological utilisation basically.After about 2 hours, discharge and the other modafinil of biological utilisation.

Embodiment 6:

Slow release prescription for by the direct compression preparation adds modafinil, polymer and filler in the Turbula mixer to, mixes 10 minutes to 20 minutes.Add lubricant, remix 5 minutes.On Manesty Beta tablet machine, carrying out rounding processing (round tooling) compressed mixture at the 9.5mm place then, is the tablet of 250mg to form gross weight, and 100mg was a modafinil during wherein total sheet was heavy.

Embodiment 7:

For slow release formulation by the wet granulation preparation, modafinil, polymer, filler are added in the Erweka mixer, mixed 5 minutes to 20 minutes.In mixer, add pelletize fluid, remix 5 minutes then.Then in Blue M electric oven with 40 ℃ of drying composites, be less than or equal to 1.5% up to water capacity.Make dry mixture by the Erweka mixer of 16 mesh sieves is housed then.In the Turbula mixer, merge dry mixture and magnesium stearate then, mixed 5 minutes.Compressed mixture on Manesty Beta tablet machine carries out rounding processing at the 9.5mm place then, and forming gross weight is the tablet of 250mg, and 100mg was a modafinil during wherein total sheet was heavy.

Definition

" particle " used herein is meant the gathering physical location of acetamide compound, i.e. one or an acetamide.

" pact " used herein is meant and adds or deduct 10 of institute's indicating value, thereby " about 20mg " is meant 18 to 22mg.

Used herein " substantially by ... form " be meant and get rid of other active component that but the active component that comprises excipient and additional amount is to solve degraded or other problem.

" effective dose " used herein is meant a certain amount of modafinil, and it can effectively treat drowsiness or doze state, can reduce or eliminate the modafinil amount of doze state symptom.The pharmaceutical composition of the present invention of effective dose can be used for strengthening Vigilance or increases sleep rhythm regularity, and treats other disease as herein described.

" pharmaceutical composition " used herein is meant and is used for the treatment of mammiferous medicament, and it comprises to be fit to the modafinil that mode that mammal takes prepares.Pharmaceutical composition of the present invention is also passable, but is not necessary, comprises nontoxic pharmaceutically suitable carrier.Pharmaceutical composition can also comprise the in bulk active modafinil that is used to prepare dosage form.

" controlled drug delivery " is meant the predetermined release of bulk material.

" one-level release " is meant that drug release changes with speed constant and concentration, and promptly what of dosage form Chinese medicine are the medication amount that is discharged in the section in preset time depend on.

" zero level release " be meant with constant rate of speed and carry out drug release, and is depleted up to the amount of dosage form Chinese medicine, promptly no matter has how many medicines, and the medicine of same amount all can consume at the time of specified rate internal diabetes.

Although disclose the present invention with reference to specific embodiments, it is evident that under the situation that does not deviate from true spirit of the present invention and scope, those skilled in the art can design other embodiment and variant.Appended claims should be interpreted as comprising all these embodiments and the variant that is equal to.In addition, the content of all lists of references of quoting of this paper all is incorporated herein by reference in view of the above.

Claims

1. the pharmaceutical composition of a unit dosage forms, wherein after patient's administration, said composition discharges the modafinil compounds of two or more amounts, and this pharmaceutical composition comprises:

A) contain the modafinil compounds of effective dose and the core particle of polymer adhesive;

B) the first kind of film of using with at least 2 endless belt forms that contains insoluble polymer, described insoluble polymer is selected from: ethyl cellulose; Polyvinyl acetate; Neutral copolymer based on ethyl acrylate and methyl methacrylate; With acrylate with quaternary ammonium group and methacrylate copolymer;

C) contain second kind of film of enteric polymer, described enteric polymer is selected from: cellulosic ester, Opaseal, pH-responsive type methacrylic acid-methylmethacrylate copolymer and lac,

Wherein use first kind of film and second kind of film with any order with the core particle coating, to form the active medicine particle; And

D) the rapid release prescription of modafinil compounds, wherein the amount of modafinil compounds in the rapid release prescription accounts for the 60wt% to 90wt% of rapid release prescription.

2. pharmaceutical composition as claimed in claim 1 is wherein by precipitation, pelletize and grinding or extrude/the round as a ball core particle for preparing.

3. pharmaceutical composition as claimed in claim 1, wherein at least a film also comprises plasticizer.

4. pharmaceutical composition as claimed in claim 3, wherein plasticizer is selected from: glycerol triacetate, tributyl citrate, triethyl citrate, the positive butyl ester of citric acid acetyl three, diethyl phthalate, Oleum Ricini, dibutyl sebacate, acetylated monoglyceride and composition thereof.

5. pharmaceutical composition as claimed in claim 1, wherein second kind of film prevents a large amount of releases of modafinil compounds in oral back three hours to six hours of patient.

6. pharmaceutical composition as claimed in claim 1, wherein unit dosage forms is a capsule.

7. pharmaceutical composition as claimed in claim 6, wherein pharmaceutical composition is a hard gelatin capsule.

8. pharmaceutical composition as claimed in claim 1, wherein the rapid release prescription comprises: about 79.9wt% raceme modafinil, about 9.9wt% lactose monohydrate, about 5wt% polyvinylpyrrolidone 90, about 5wt% cross-linking sodium carboxymethyl cellulose and about 0.5wt% magnesium stearate.

9. pharmaceutical composition as claimed in claim 1 also comprises antidepressants.

10. pharmaceutical composition as claimed in claim 1, wherein modafinil compounds is the raceme modafinil.

11. pharmaceutical composition as claimed in claim 1, wherein modafinil compounds is the levorotatory form of modafinil.