CN101321526A - Combination of rosiglitazone and donepezil for improvement of cognitive function - Google Patents

Abstract

The invention relates inter alia to a pharmaceutical composition comprising both rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof which is of use in the treatment or prophylaxis of Alzheimer's disease or other dementias and mild cognitive impairment. The invention also relates to oral dosage forms comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof.

Description

Be used to improve the rosiglitazone and the donepezil compositions of cognitive function

The present invention relates to compositions, the purposes of described compositions in treatment and the damage of prevention mild cognitive, Alzheimer (Alzheimer ' s disease) and other dementia, and relate to the method for using described compositions to treat or prevent.Especially, the present invention relates to compositions, described compositions comprises cholinesterase inhibitor, particularly donepezil and PPAR-gamma agonist, particularly rosiglitazone.

Alzheimer (AD) was described by Bavaria psychopathist AloisAlzheimer first in 1907.Alzheimer is progressive, debilitating disease, and for causing dull-witted common cause.General symptom comprises memory impairment, cognitive function disorder, behavior change (comprise bigoted, vain hope, suppress forfeiture) and language function decline.On the pathology, AD is characterised in that the appearance-neural inflammatory speckle (claiming senile plaque sometimes) and the neurofibrillary tangles of two kinds of dissimilar brain injury traditionally.

Neural inflammatory speckle is extracellular amyloid beta-protein (A β) deposit, is generally thread form, about 10 to the 150 μ m of cross section, and relevant with aixs cylinder with the dendron damage.A β is formed through a series of secretase cracking by amyloid precursor protein (APP).A β ₄₀, the peptide of 40 residues is A beta forms of the normal maximum that produces of cell, yet, in neural inflammatory speckle, find to comprise in a large number 42 amino acid whose A β (A β ₄₂).Though A β ₄₀Also be arranged in speckle, but A β ₄₂With A β ₄₀It is obviously bigger to compare hydrophobicity, therefore is easier to assemble.Think that (some months was to several years) development forms neural inflammatory speckle through a period of time.Though the degree of amyloid deposition and the relation between the cognitive impairment still have arguement, the amyloid deposition of known speckle form occurs in before the clinical symptoms appearance.

Neurofibrillary tangles sees in all endochylemas of the neuronic nuclear of AD patient usually.Entanglement is formed by paired fiber, and described fiber damaged forms monocycle.These highly insoluble fibers are made up of the microtubule-associated protein tau of unusual hyperphosphorylation.Formation that evidence suggests entanglement is that neuron is to the progressively accumulative reaction of A β.

Clinically, the common mode heredity that AD can autosomal dominant, yet, think that most of cases (about 90%) are for distributing.Two types of this disease is highly similar on the phenotype, and distributes type AD relatively, and many (like this, it has been generally acknowledged that the type AD of distributing is tardy AD or LOAD) early appear in rarer familial form AD usually.The information (for example APP sudden change and presenilin 1 and 2 genes) of the similarity explanation performance autosomal dominant type mechanism feature of general phenotype is with tardy to distribute type AD relevant.Usually, familial form AD is relevant with the increase that A β produces, however the result of the removal of defects that the type AD of distributing may be conventional A β to be produced.

Determined a large amount of type that distributes AD promoting factors, having comprised: the allelic existence of e4 of age, low cholesterol concentration, high systolic pressure, high glucose concentration, hyperinsulinism concentration, unusual sugared tolerance and apo E people BMJ 1997315:1045-1049 such as () Kuusisto J.

More information about AD is seen substantially: Selkoe D Physiol.Rev.200181 (2): 741-766; People CNS Drugs 200317 (1): 27-45 such as Watson G.

The mild cognitive damage refers to that the patient has the situation of slight cognitive function damage, and described damage can detect from patient's premorbid baseline, but severity is not enough to reach the AD diagnostic criteria.Like this, can think that MCI is usual aging experimenter's normal cognitive function and the transitive state between the unusual cognitive function in the dementia.MCI can classify according to the type of the cognitive defect that detects again.Only there is the defective representative of memory to forget type MCI; Yet the MCI of other type comprises the defective in multiple cognitive zone (comprising memory), or defective independent, non-memory zone.In colony research, measure in the scope of the rate of carrying out of forgeing type MCI to AD (more information is seen people Arch Neurol 200158:1985-1992 such as Petersen) at annual 10-20%.

Similar other dementia that causes cognitive defect comprises vascular dementia, Lewy corpusculum dementia, the relevant dementia with parkinson of volume temporal lobe dementia.

Apolipoprotein is a glycoprotein, and it takes place with brain development, synapse and be relevant to the reaction of nerve injury.Apo E (ApoE) is a protein component of plasma lipoprotein.The main isoform of ApoE has three kinds (that is, ApoE2, ApoE3 and ApoE4), is three allelic products on single locus.Therefore, individuality can be homozygote (APOE2/2, APOE3/3 or APOE4/4) or heterozygote (APOE2/3, APOE2/4 or APOE3/4).Modal allele is APOE3, about 0.78 (the people Mol.Interventions 20022:363-375 such as Bales KR) of its gene frequency in white people (Caucasian population), and modal genotype is APOE3/3.

The aminoacid sequence of three kinds of isoforms only shows slight variation, sums up and sees the following form 1.

Aminoacid sequence in the table 1-apolipoprotein isoform changes

The allelic dependency that carries and develop into the risk of AD of APOE4 has been known a period of time, and record (people PNAS 199390:1977-1981 such as Strittmatter WJ in the literature; RosesAD Ann Rev Med 199647:387-400).Yet, because e4 is allelic exists for easy predisposing factor and not diseases induced, so only the genotype of APOE is not enough to diagnostic detection AD people New Engl.J.Med.1998338:506-511 such as () MayeuxR.

In two allelic individualities of APOE4 are arranged, it is that more than three times of an APOE4 allele individuality are only arranged that age causes the risk of the AD of (age-adjusted), and the risk that the AD that the age causes in the allelic individuality of APOE4 is only arranged is almost three times (people Science 1993261 (5123): 921-3 such as Corder that do not have APOE4 allele individuality; People BMJ 1994309:636-638 such as Kuusisto J).With respect to other AD patient, age of onset, amyloid burden that the homozygous patient of APOE4 shows early increase and levels of acetylcholine decline.The APOE4 gene frequency changes in ethnic group, found in white people about 0.15, but in AD patient up to 0.4 (people Neurology 199343 (8) such as Saunders: 1467-72).

APOE2, be the rarest in three kinds of common alleles, find that it has the allelic protective effect with respect to modal APOE3, the allelic individuality of APOE2 is arranged and do not have the allelic individuality of APOE2 to compare to be usually expressed as later (people Nature Genetics19947 (2): the 180-4 such as Corder of seizure of disease; People Mol Interventions 20022:363-375 such as Bales KR).Found that the APOE2 gene frequency is about 0.07 in white race colony.Nearest data show that in case possible AD symptom occurs, it is irrelevant that APOE4 state and disease are carried out speed.

Carbohydrate metabolism is very important in central nervous system's cell function.Verified in AD patient the special brain carbohydrate metabolism in zone reduce (people New Eng J Med 1996334:752-758 such as Reiman EM; Alexander, people Am J Psychiatry 2002159:738-745 such as GE), in LOAD and familial form AD (people such as Small GW, PNAS 200097:6037-6042).

Because in carrying the allelic individuality of one or two APOE4, many years before the prediction age that clinical symptoms takes place, just can detect the glycometabolic reduction of brain of regional special pattern, (the people New Eng J Med 1996334:752-758 such as Reiman EM that therefore has patient's the glycometabolic reduction of brain of AD risk relevant with the APOE situation; People such as Rossor M, Annals NY Acad Sci 1996772:49-56; People such as Small GW, PNAS 200097:6037-6042).

Insulin is also very important in periphery and maincenter energy metabolism.The excretory plasma insulin of beta Cell of islet on the feed with fasting during, regulate the glucose level in the blood, the glucose uptake rate in the glucose transporter control insulin sensitivity tissue of insulin sensitivity.The increase of blood glucose causes the release of insulin, and the decline of blood glucose simultaneously causes increasing the release that liver is exported the feedback regulation hormone of glucose.The insulin ability reduces, and to stimulate Sugar intake and feasible inhibition glycogen output (claiming insulin resistant again) and to serve as the insufficient insulin secretion reaction of compensation insulin resistant, causes type ii diabetes.

Insulin passes through blood/brain barrier through the transport process transhipment of Insulin receptor INSR mediation.The periphery level of insulin is relevant with level among the central nervous system (CNS), that is, the increase of periphery insulin causes the increase of CNS insulin.Evidence suggests that insulin is relevant with the normal memory function, and periphery insulin metabolism disease, for example insulin resistant and hyperinsulinemia can have a negative impact to memory.The increase of the glucose utilization that insulin promotes can cause S-acetyl-coenzyme-A glycolysis product, and S-acetyl-coenzyme-A is the important substance during neurotransmitter acetylcholine is synthesized.The decline of levels of acetylcholine is the key character of AD.

Peroxisome proliferation activated receptor γ (PPAR-γ) is the isolated member of the steroid/thyroid/retinoid receptor superfamily of part activating transcription factor.PPAR-γ is one of PPARs subfamily member who is closely related of separate gene coding (people Cell 199268:879-887 such as Dreyer C; People Mol.Endocrinol.19926:1634-1641 such as Schmidt A; People J.Biol.Chem.1993268:26817-26820 such as Zhu; People Proc.Nat.Acad.Sci.USA 199491:7355-7359 such as Kliewer SA).Separate three kinds of mammiferous PPARs, be called PPAR-α, PPAR-γ, PPAR-δ (also claiming NUC-1).Three kinds of PPARs regulate the expression of genes of interest by in conjunction with DNA sequence element (being called PPAR response element (PPRE)).So far, confirmed that PPREs is the enhancer of the lipometabolic gene coded protein of many adjustings, shown PPARs in lipogenesis signal cascade and fat stable state, play a significant role (people Trends Endocrin.Met.19934:291-296 such as Keller H).

European patent 306228 is described the PPAR-gamma agonist of thiazolidine diketone derivative class, and it is used for the treatment of type ii diabetes as insulin sensitizer.These chemical compounds have the hyperglycemia activity.Wherein a kind of preferred compound chemistry of Miao Shuing is called 5-[4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl] benzyl] thiazolidine-2,4-diketone, and general rosiglitazone by name.The salt of this chemical compound comprises maleate, describes in WO94/05659.European patent application, publication number: 0008203,0139421,0032128,0428312,0489663,0155845,0257781,0208420,0177353,0319189,0332331,0332332,0528734,0508740; International patent application, publication number 92/18501,93/02079,93/22445 and U.S. Patent number 5104888 and 5478852, some thiazolidinedione PPAR-gamma agonists are also disclosed.The particular compound of mentioning comprises 5-[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] benzyl] thiazolidine-2,4-diketone (also claiming pioglitazone), 5-[4-[(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (also claiming ciglitazone), 5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (also claiming troglitazone) and 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-and the 5-ylmethyl) thiazolidine-2,4-diketone (also claiming englitazone).

United States Patent (USP) 6,294,580 (disclosure of this patent is incorporated herein by reference) have been described the PPAR gamma agonist chemical compound of a series of non-thiazolidinedioneses, but the tyrosine derivative that O-and N-replace is still effective in the treatment of type ii diabetes as insulin sensitizer.Wherein a kind of chemical name of such chemical compound is N-(2-benzoyl phenyl)-O-[2-(5-methyl-2-phenyl-4-oxazolyl) ethyl]-L-tyrosine (also claiming 2 (S)-(2-benzoyl-phenyl amino)-3-{4-[2-5-methyl-2-phenyl-oxazole-4-yl)-ethyoxyl]-phenyl }-propanoic acid or common name farglitazar).

A large amount of clinical evidences show that (people New Eng J Med 1996334:752-758 such as Reiman EM is appearring and occurring in the APOE4-carrier in the glycometabolic damage of brain during the AD before the AD clinical symptoms takes place; People such as Rossor M, Annals NY Acad Sci 1996772:49-56; People such as Small GW, PNAS 200097:6037-6042).

Merge clinical and epidemiology evidence, show also that insulin resistant can interfere with the development and be the danger of AD.Yet definite constitutive relations is complicated between insulin resistant and the AD, and still imperfectly understands now.

Shown that hyperinsulinemia is the risk factor of AD.In a research, author's conclusion is that AD does not rely on APOE genotype (people BMJ 1997315:1045-1049 such as Kuusisto J), this research in the hyperinsulinemia experimenter, not having the old experimenter's of hyperinsulinemia of APOE4 allele (APOE4-) AD prevalence is 7.5%, and the AD prevalence is 1.4% in normal blood insulin experimenter by comparison; In the hyperinsulinemia experimenter, it is 7.0% that the APOE4 old experimenter's of allelic hyperinsulinemia (APOE4+) AD prevalence is arranged simultaneously, and the AD prevalence is 7.1% in normal blood insulin experimenter by comparison.Other studies show that between APOE genotype and insulin resistant and to have contact (people CNS Drugs 200317 (1) such as Watson G: 27-45).

For example, the homozygous patient's insulin metabolism of non-APOE4 allele unusual (particularly plasma insulin level increase), the possible factor that develops into AD among these patients is described, and the homozygous patient of APOE4 allele shows normal insulin periphery level.Compare the minimizing (people Neurology 199850:164-168 such as Craft S) that all shows the cerebrospinal fluid insulin level with non-AD experimenter for two groups.In addition, there is not the allelic patient of APOE4 with respect to the glucose clearance of APOE4+ patient's insulin-mediated descend people Neuroendocrinology 199970:146-152 such as () Craft S.

Generally acknowledge that normal cholinergic signal conduction is that the normal function for example remembered of spiritual process is necessary.A large amount of evidences show AD patient's cholinergic signal conduction abnormalities, and intensity of anomaly is relevant with the cognitive impairment level.The many-side research of AD disease is carried out and observed cholinergic function obstacle between relation still imperfectly understand.Although a large amount of cholinesterase inhibitor shows the effectiveness that is used for the treatment of AD, and follow the untoward reaction of acceptable degree, these inhibitor comprise tacrine (Cognex ^TM), galantamine (Reminyl/Radazyne ^TM), the bright (Exelon of Li Fansi ^TM) and donepezil (Aricept ^TM), but do not prove that so far the use of muscarine or nAChR agonist has clinical value.More information sees, for example, and people J.Pharmacol.Exp.Ther.2003306 (3): 821-827 such as Terry AV.

In a research of delivering recently, studied the purposes of donepezil in the individuality of mild cognitive damage (transitive state between usual aging and early stage AD), donepezil shows the ratio that the patient develops into AD during preceding 12 months after the administration reduces, though 3 years the time two groups as broad as long.In addition, behind 12 months the beneficial effect of pro-, in the quicker deterioration that occurred disease in 24 months subsequently.Though after 3 years, treatment colony compares there was no significant difference with placebo group, compares the danger that develops into AD descend people New Engl.J.Med.2005352:2379-2387 such as () Petersen R with placebo group but carry one or two copy APOE4 allelic patient.

The purposes of insulin sensitizer in treatment AD proposed in the past.International Patent Application WO 98/39967 discloses the method for treatment or prevention AD, and described method is by reducing the medicine of serum insulin levels, for example thiazolidinedione.International Patent Application WO 99/25346 discloses the method for the disease of treatment or the mediation of prevention apoptosis, described disease is neurodegenerative diseases for example, comprises AD and parkinson, and described method is by giving apoptosis inhibitor, insulin sensitizer for example is as rosiglitazone.International Patent Application WO 00/32190 discloses the method for treatment or prevention AD, and described method is by giving PPAR-gamma agonist, for example thiazolidinediones pioglitazone and rosiglitazone.International Patent Application WO 00/35437 discloses the method for improving patient's mental act that mental act descends, and described method is by giving insulin sensitizer, for example thiazolidinediones pioglitazone and rosiglitazone.

In the parkinson disease model; evidence suggests that thiazolidinediones (comprising rosiglitazone and pioglitazone) can protect dopaminergic cell to prevent multiple toxic damages; comprise acetaldehyde (people (2006) Biochem Biophys Res Comm 340 such as Jun; 221-227), MPTP (people (2004) JNeurochem 88 such as Dehmer; 494-501) and 8-OHDA (people (2004) FASEB 18 such as Chen, 1162-1164).

Although the PPAR-gamma agonist for example rosiglitazone and cholinesterase inhibitor for example donepezil all can be used for treating mild cognitive damage and AD, prior art does not show to merge uses these two kinds of medicines.

Therefore, a first aspect of the present invention provides compositions, and described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, and pharmacy can be accepted diluent or carrier.

Infer pharmacy and can accept the mixture that diluent or carrier can be material, promptly one or more pharmacy can be accepted the merging of diluent or carrier.

WO03/061648 relates to the use of acetylcholinesteraseinhibitors inhibitors (for example donepezil), is used to reduce insulin resistant and is used for the treatment of type ii diabetes.Have according to the document that other medicine that uses can make up with acetylcholinesteraseinhibitors inhibitors in treating diabetes, and these other medicines comprise insulin and insulin analog; The type ii diabetes medicine is sulfonylurea, biguanides, alpha-glucosidase inhibitor, thiazolidinediones for example, and meglitinides; Phosphodiesterase inhibitor; Cholinergic agonist; Nitric oxide donors; Antioxidant; With the chemical compound that increases glutathion.Although rosiglitazone is one of medicine clear and definite in the long list, merge to use acetylcholinesteraseinhibitors inhibitors and rosiglitazone to use tabulation to go up a kind of more favourable suggestion in many other medicines than merging.There is not acetylcholinesterase to suppress to merge the example that uses with other medicines.

WO2005/074917 relates to the method for using cholinesterase inhibitor (phenserine) treatment diabetes or diabetes associated conditions (for example cognitive impairment), and described cholinesterase inhibitor is donepezil, galantamine or tacrine for example.Have according to the document that the cholinesterase inhibitor similar compound can for example sulfonylureas, meglitinide, biguanide, thiazolidinedione or alpha-glucosaccharase enzyme inhibitor merge and use with blood sugar lowering.Once more, do not have cholinesterase inhibitor similar compound and other medicines to merge the example that uses, and do not have rosiglitazone more to illustrate than other antidiabetic drug purposes.

Opposite with prior art, compositions of the present invention is intended to improve the cognitive function of suffering from or easily suffering from mild cognitive damage, Alzheimer or other dull-witted experimenter, rather than the treatment diabetes.

Therefore, the present invention also provides compositions, it comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, and pharmacy can accept diluent or carrier, and described compositions is used to improve the cognitive function of suffering from or easily suffering from mild cognitive damage, Alzheimer or other dull-witted experimenter.

In addition, the invention provides to improve and suffer from or easily suffer from the method for mild cognitive damage, Alzheimer or other dull-witted experimenter's cognitive function, described method comprises the compositions to experimenter's administration safety and effective dose, and described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.

On the other hand, the present invention also provides compositions to be used for improving the purposes of suffering from or easily suffering from the medicine of mild cognitive damage, Alzheimer or other dull-witted experimenter's cognitive function in preparation, and described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.

On the other hand, the invention provides the combination of rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, the two simultaneously, separate or use in order, be used to improve the cognitive function of suffering from or easily suffering from mild cognitive damage, Alzheimer or other dull-witted experimenter.Related fields provide to improve suffers from or easily suffers from the method for mild cognitive damage, Alzheimer or other dull-witted experimenter's cognitive function, and described method comprises the combination to described experimenter's while, separation or order administration rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.Related fields provide rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt to be used for improving the purposes of medicine of suffering from or easily suffering from mild cognitive damage, Alzheimer or other dull-witted experimenter's cognitive function in preparation, described two kinds of medicines simultaneously, separate or order merges and uses.

There has been controversial report in influence in using the damage of cholinesterase inhibitors for treating mild cognitive, Alzheimer or other dementia about APOE4 allele.People such as Poirier (Proc.Natl.Acad.Sci.U.S.A. (1995), 92,12260-12264) point out when AD patient uses the tacrine treatment, the improvement that 83% non-APOE4 carrier shows cognitive function, however 60% APOE4 carrier does not change after 30 weeks or worsens.

Yet, people such as Greenberg (Arch.Neurol., (2000), 57,94-99) state that they can not determine APOE4 allele and donepezil treatment is lacked dependency between the reaction, and people such as Winblad (Neurology (2001), 57,489-495) point out that the APOE genotype does not influence the useful reaction to the donepezil treatment.

Before the priority the earliest of this patent application, do not have tangible proof to show to use the PPAR-gamma agonist for example rosiglitazone suffer from improvement or easily suffer from MCI, AD or other dull-witted experimenter's cognitive function, only useful to the homozygous experimenter of non-APOE4 allele, and to the benefit maximum of the non-carrier of APOE4 allele.

Yet the inventor has shown that now PPAR-gamma agonist rosiglitazone is significantly more effective for the treatment that is not APOE4 allele homozygote patient, and is the most effective to the treatment of not carrying APOE4 allele patient.

Therefore, compositions of the present invention is to being that the homozygous patient of APOE4 allele provides maximum benefit, and preferably to pre-determine the experimenter in some aspects of the invention described above be not APOE4 allele homozygote.The experimenter can, for example pre-determine and be APOE4-.

Another aspect of the present invention provides to improve suffers from or easily suffers from the method for MCI, Alzheimer or other dull-witted experimenter's cognitive function, and described experimenter is not an APOE4 allele homozygote, and described method comprises the following steps:

I) examination experimenter determines that the experimenter is not an APOE4 allele homozygote; Afterwards

Ii) to the compositions of described experimenter's administration safety and effective dose, described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.

Screening method (i) can comprise determines whether the experimenter has APOE2 or APOE3 allele.

In one embodiment of the invention, examination step (i) comprises determines that the experimenter carries the APOE4 allele of single copy.For example can determine that the experimenter is APOE3/APOE4.

In preferred embodiment of the present invention, examination step (i) comprises determines that the experimenter is APOE4-(that is, not carrying APOE4 allele).For example can determine that the experimenter is APOE3/APOE3 or APOE2/APOE3.

For example the experimenter can suffer from or easily suffer from (for example suffering from) MCI or AD.In one embodiment of the invention, the experimenter suffers from MCI (particularly forgetful type MCI).In another embodiment of the invention, the experimenter suffers from Alzheimer.In another embodiment of the invention, the experimenter easily suffers from MCI (particularly forgetful type MCI).In another embodiment of the invention, the experimenter easily suffers from Alzheimer.In another embodiment, the experimenter suffers from or easily suffers from other dementia, and for example vascular dementia, Lewy corpusculum dementia, volume temporal lobe dementia are relevant with parkinson dull-witted.

The present invention also provides examination to suffer from or easily suffer from the method for MCI, Alzheimer or other dementia patients, described method aid forecasting experimenter is to giving the reaction of compositions, described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, and described method comprises examination and carries 0 or 1 APOE4 allele copy to determine whether the experimenter.

Especially, this method comprises that examination is to determine whether the experimenter is APOE4-.

The present invention also provides test kit, comprise (i) compositions, described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt and (ii) instructs description to the homozygous experimenter of non-APOE4 allele (for example pre-determining the experimenter is not APOE4 allele homozygote) administration PPAR-gamma agonist.For example this instructions direct is used compositions to the homozygous experimenter of non-APOE4 allele who suffers from or easily suffer from MCI, Alzheimer or other dementia.According to special aspects of the present invention, the experimenter is APOE4-(for example pre-determining the APOE4 allele of experimenter without any copy).

Randomly, test kit can comprise that one or more are used for determining that the experimenter has 0,1 still 2 allelic reagent of APOE4.This reagent can be selected from probe, primer, antibody or its combination usually.

In the above-mentioned aspect perhaps of the present invention, experimenter's portability, maybe can be defined as or pre-determine to carrying the APOE4 allele of single copy.For example the experimenter can be maybe can be defined as or pre-determine and is APOE3/APOE4.

Shown in following embodiment, the unexpected PPAR-gamma agonist rosiglitazone of finding of inventor is compared with placebo group, suffers from slightly and to produce clinical relevant cognitive function to the patient of moderate AD and improve not carrying APOE4 allele.The allelic patient of APOE4 that presentation of results carries a copy has experienced stable (that is, both do not had remarkable improvement and also do not had remarkable decline) of cognitive function in the rosiglitazone treatment.The homozygous patient of presentation of results APOE4 allele can experience clinical decline in the rosiglitazone treatment, disease it be unclear that naturally although this decline is that treatment causes.

The inventor attempts with theoretical this invention of explanation, and unrestricted.According to a kind of theory, the aminoacid sequence difference between the isoform causes the difference of protein folding.Particularly ApoE2 and ApoE3 are characterised in that be Arg at 112 for Cys and at 61.ApoE4 is characterised in that be Arg at 112 for Arg and at 61.61 and 112 residue interactions and electronegative because of Arg positively charged and Cys in folded protein, ApoE2 and ApoE3 are tightr than the protein folding of ApoE4 at this regional protein folding.Although all ApoE isoforms have experienced degraded in the cell, think because the structure picture difference between the isoform causes ApoE4 to experience degraded faster.The fragment that produces in degraded has lipid and receptor binding site, and they cause mitochondrial toxicity together.The segmental lipid binding site of ApoE4 is than ApoE2 or the more active lipid conjugates of ApoE3 fragment.Therefore, the ApoE4 fragment in conjunction with and to destroy mitochondrial degree bigger than ApoE2 and ApoE3 fragment; This destruction has also influenced mitochondrion and has been transported to synapse from cell space.The reaction that this destruction also can cause glucose that mitochondrion caused the PPAR-gamma agonist treatment or lactose substrate to increase reduces.Be expected among the APOE4 allele experimenter of 2 copies bigger than this effect in 1 copy allele experimenter, and bigger than this effect in not having the experimenter that copy carries in 1 APOE4 allele experimenter is arranged.

The experimenter carry 0,1 still the APOE4 of 2 copies allelic pre-determine can, for example, undertaken by APOE4 screening method described herein.

In one embodiment of the invention, the experimenter suffers from type ii diabetes.In another embodiment of the invention, the experimenter does not suffer from type ii diabetes.

Determining that APOE4 allele exists or the diagnosis screening method to the experimenter that lacks has itemized record in the literature, and within those skilled in the art's ability.

The allelic disappearance of APOE4 can directly be determined by the negative findings that shows the test that allele exists, or indirectly determine positive findings (thereby getting rid of probability that APOE4 allele exists) for example by showing the test that APOE2 and APOE3 allele exist.

Screening method is learned can be based on many methods for example (ApoE albumen itself or its code nucleic acid) isoelectrofocusing method, immunological method, immuno-chemical method or sequence measurement.Concrete grammar comprises the method for the PCR-based that uses restriction fragment enzyme or TaqMan primer.

Immunological method comprises that the ApoE isoform that uses the isoform specific antibody detects.Yet immunological detection method can be subjected to the interference of antibody cross reaction, influences result's reliability.

Immuno-chemical method comprises the method for describing in the International Patent Application WO 94/09155 (relevant with granted patent EP0625212, JP03265577 and US5508167), described international patent application discloses the method that ApoE4 exists or lacks that detects, thus diagnosis AD.The also use in the present invention of method that disclosed detection ApoE4 exists or lacks among the WO94/09155.In brief, contact with solid carrier, design described solid carrier and react with sulfydryl specifically from experimenter's sample (for example, blood sample).Fluid sample separates from solid carrier afterwards, and uses the existence of suitable antibody test ApoE.The existence of ApoE4 explanation experimenter is the allelic carrier of APOE4 in isolating sample.Therefore be different from ApoE2 and ApoE3, ApoE4 albumen does not comprise cysteine residues, with the solid carrier reaction and be not fixed on the solid carrier.After fluid sample flow through solid carrier, the existence of unconjugated ApoE explanation individuality was ApoE4+ in the fluid sample; After fluid sample flow through solid carrier, the immunocompetent disappearance explanation of ApoE individuality was ApoE-in the liquid-like.Because this method does not require the immunology differentiation of ApoE isoform, therefore avoided the problem of antibody specificity significantly by the method.

Sequence measurement comprises separation and the purification of the DNA of experimenter ApoE albumen or coding ApoE, uses conventional method to measure the comparison of aminoacid or DNA sequence and result and not homoallelic known amino acid or DNA sequence.

Preferred determine that the genotypic method of APOE comprises the method for using PCR-based-mainly the carry out PCR of part A POE gene, subsequently with the digestion with restriction enzyme of discerning DNA base (differentiation allele), and through gel electrophoresis or most recently used TaqMan real-time quantitative PCR.Especially, the APOE genotype can be used the Taqman method of having set up, and the Taqman method relies on the fluorescence detecting system of 5 '-nuclease for using allele specific fluorescent probe.These probes only just fluoresce when combining with template.This method is at people Eur J Clinical Investigation 200131 (7) such as Macleod: description is arranged among the 570-3.Be used for determining that the genotypic commercially available prod of APOE is on sale at LabCorp and Athena Diagnostics company.

The improvement of patient's cognitive function can be definite by one or more methods of having set up, for example ADAS-cog and/or CIBIC+ and/or DAD method (every kind of method details is other local description of this paper, and pertinent literature is incorporated herein by reference).Preferable methods is ADAS-cog.Through 24 all treatments phases, proper A DAS-cog is improved as at least 1 fen, especially at least 2 minutes.

Another kind of possible method is that Buschke selects to remind test (Buschke SelectiveReminding Test) people Neurology 198838:900-903 such as () Grober E.

" improvement of cognitive function " refers in the cognition treatment of after a while Drug therapy the improvement with respect to not treatment group individuality.Because dull-witted (for example AD) patient is cognitive function decline in time usually, " improvement of cognitive function " comprises that decline is slow or stops, also comprising absolute improvement.As shown in Example 2, the absolute improvement of cognitive function is to carry out the preferred method of the present invention to cause.

Rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt can exist with pharmacy acceptable solvent thing form, and this is clear and definite to those skilled in the art.

Suitable solvate comprises hydrate.

The suitable rosiglitazone and the pharmaceutically acceptable salt of donepezil comprise and salt organic and mineral acid or alkali formation.

The acceptable acid-addition salts of pharmacy comprises the salt that forms with following acid: hydrochloric acid, hydrobromic acid, sulphuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetone acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, sulfamic acid, p-anilinesulfonic acid., succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethyl sulfonic acid, aromatic sulfonic acid (p-methyl benzenesulfonic acid for example, benzenesulfonic acid, LOMAR PWA EINECS 246-676-2 or naphthalenedisulfonic acid), salicylic acid, 1,3-propanedicarboxylic acid, gluconic acid, tricarballylic acid, cinnamic acid, substituted cinnamic acid (for example, phenyl, methyl, the cinnamic acid that methoxyl group or halogen replace, comprise 4-methyl and 4-methoxy cinnamic acid), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (for example 1-or 3-hydroxyl-2-naphthoic acid), naphthalene acrylic acid (for example naphthalene-2-acrylic acid), benzoic acid, the 4-methoxybenzoic acid, 2-or 4-hydroxy benzoic acid, the 4-chlorobenzoic acid, the 4-Phenylbenzoic acid, cinnamic acid (for example 1,4-benzene diacrylate) and hydroxyethylsulfonic acid..

Pharmacy can accept alkali salt comprise ammonium salt, alkali metal salt for example sodium salt and potassium salt, alkali salt for example calcium salt and magnesium salt and with the organic base salt that forms of hexanamine and N-methyl D-glucamine for example.

Particularly preferably be, independently or merge the rosiglitazone use and be the rosiglitazone maleate form, and donepezil is a hydrochloric acid donepezil form.

Donepezil and its salt exist with polymorphic forms, and any form can be used for the present invention.

That appropriate formulation comprises is oral, parenteral route (comprising subcutaneous, Intradermal, intramuscular, vein and intraarticular), suck and (comprise fine particles powder or mist agent, can decide aerosol, spray or inhaler that dosage exerts pressure and produce by various types of), the preparation of percutaneous (for example passing through skin patch), rectum and part (comprising skin, buccal, Sublingual and ophthalmic) administration, although only route of administration depends on for example receiver's situation.Preparation can exist with unit dosage forms easily, and can be by the well-known method preparation of pharmaceutical field.All methods comprise active component added and combine with the carrier that contains one or more accessory ingredients.General preparation is by adding active component equably and closely, the solid carrier of active component and liquid-carrier or segmentation or both are combined and prepares, and afterwards if desired, product made required preparation.

Being suitable for the preparation that oral administration uses in the present invention can discrete units exist, for example capsule, cachet or tablet, every kind of active component that comprises the amount of pre-determining; For example powder or granule; The for example solution of water or on-aqueous liquid or suspension; Or for example oil-in-water liquid emulsion or Water-In-Oil liquid emulsion.Active component also can pill, electuary or paste exist.

Can make tablet by compacting or press back, randomly, use one or more accessory ingredients.The tablet of compacting can be by stranglehold liquid form on suitable machine, the active component of powder or particle form for example, randomly, with binding agent, lubricant, inert diluent, surface activity or dispersant.Moulded tablet can pass through the mixture manufacturing at the powdered compounds of suitable machine patrix chine inert liquid diluent moistening.Randomly, but tablet coating or indentation, and can be mixed with the form that reactive compound in slow release or controlled release or the continuous release tablet is provided.

The preparation of parenteral administration comprises the sterile solution for injection of water and non-water, and injection can comprise antioxidant, buffer, antibacterial and make preparation and the isoosmotic solute of receiver's blood; Sterilization injection suspension with water and non-water can comprise suspending agent and thickening agent.Preparation may reside in unit dose or the multi-dose container, and for example Mi Feng peace is cutd open bottle and medicine bottle, and stores under lyophilization (lyophilizing) condition, only needs to add before use the liquid-carrier of sterilization, for example saline or water for injection.Interim injection solution and suspension can be by sterilizing powder, granule and the preparation tablets of describing before.

Can be present in for example medicated bag (cartridge) of capsule that uses in inhaler or the insufflator and for example gelatin, or for example thin aluminum foil cover by sucking the dry powder compositions that the part is transported to lung.The powder mixes preparation comprises the mixture of powders of the The compounds of this invention that is used to suck and suitable powder substrate (carrier/dilution/inert matter) for example monosaccharide, disaccharide or polysaccharide (for example lactose or starch) usually.The preferred lactose that uses.

Be used for can being formulated as and for example using aqueous solution or suspension or the aerosol of suitable liquefied propellant from the packing output of exerting pressure by sucking spray composite that the part is transported to lung, the described packing of exerting pressure is for example decided the inhaler of dosage.The aerosol compositions that is suitable for sucking can be suspension, also can be solution, and comprises formula (I) chemical compound usually, randomly with other therapeutic activity composition and suitable for example fluorocarbon or hydrogenous Chlorofluorocarbons (CFCs) or its mixture combination, particularly hydrogen fluoroalkane, for example dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane of propellant, particularly 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-seven fluoro-n-propanes or its mixture.Carbon dioxide or other suitable gas also can be used as propellant and use.The aerosol compositions can not have excipient or randomly comprises other formulation excipients well-known in the art, as surfactant, and oleic acid or lecithin and cosolvent ethanol for example for example.The preparation of exerting pressure is generally held in the jar of valve (for example quantitative valve) sealing (for example aluminium pot), and is incorporated with the actuating unit of interface.

Ideal medicine by inhalation has controlled particle diameter.The suitable particle diameter that is used to suck bronchi is generally 1-10 μ m, preferred 2-5 μ m.It is too big usually above the granule of 20 μ m to have particle diameter, can not suck to arrive stingy road.In order to realize this particle diameter, the granule of the active component of production can by conventional method for example micronization reduce size.Required part is come out by air classification (air classification) and sieving separating.Preferably, granule is a crystalline state.When using diluent/excipient for example during lactose, the size ratio suction medicine of the present invention of excipient is a lot of greatly usually.When excipient is lactose, exist with ground lactose usually, the MMD that wherein is no more than 85% lactose granule is 60-90 μ m and is no less than 15% granule MMD and is lower than 15 μ m.

The intranasal spray agent can make water or nonaqueous carrier, adds for example thickening agent, buffer salt or acid or alkali and regulates pH, isotonicity adjusting reagent or antioxidant preparation.

The solution that sucks by atomizing can use aqueous carrier, adds for example acid or alkali, buffer salt, isotonicity adjusting reagent or antibacterial preparation.Can by filter or in autoclave heat sterilization, or be sterile product.

Be used for rectally preparation can with common vector, for example cupu oil or Polyethylene Glycol exist as suppository.

Be used for for example preparation of buccal or sublingual administration of topical in the oral cavity, being included in flavoured base for example contains the lozenge of active component in sucrose and arabic gum or the Tragacanth and for example contains the pastille (pastilles) of active component in glycerin cement and glycerol or sucrose and the arabic gum in substrate.

Should understand the composition of describing especially except above, preparation of the present invention can comprise that the reagent that for example is suitable for oral administration can comprise flavoring agent for the conventional reagent in other relevant this area of required preparation type.

Preferred composition is formulated as the preparation of oral administration.

A challenge that occurs when being formulated as the compositions that comprises rosiglitazone and donepezil is that two kinds of medicines have different to a great extent pharmacokinetics features.In order to obtain the best pharmacokinetic profiles of rosiglitazone, the medicine that is formulated as fast dissolving dosage form is administered twice to the experimenter common every day.If the mitigation dosage form is provided, for example describe among the WO2005/013935 dosage form, medicine only needs be administered once every day.This file has instructed the preparation of rosiglitazone, and it includes the core of two different active compounds (quick releasing formulation and mitigation delivery formulations).Tablet is wrapped up by coating, and for example the ethyl cellulose coating penetrates by the coating hole, and a hole penetrates the bank of rapid release, and a hole penetrates relaxes the bank that discharges.This preparation guarantees to obtain the height controlled release of the rosiglitazone of best pharmacokinetic profiles.

On the other hand, donepezil has different pharmacokinetics features with rosiglitazone, and need not to provide the mitigation delivery formulations usually, to realize the administration of dosage once-a-day.

This means that any oral formulations that comprises rosiglitazone and donepezil should be designed to guarantee that two kinds of medicines reach acceptable pharmacokinetic profiles, particularly if desired once-a-day during dosage form.

What in addition the people was taken aback is, the inventor think produce to WO2005/013935 in similar preparation be possible, wherein donepezil is included in the quick releasing formulation, does not influence the release profile of rosiglitazone basically.This preparation becomes another aspect of the present invention.

Therefore, another aspect of the present invention provides peroral dosage form, comprises:

First compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, the preparation of rapid release when being configured to contact aqueous matrix; With

Second compositions comprises rosiglitazone or its pharmaceutically acceptable salt, relaxes the preparation that discharges when being configured to contact aqueous matrix.

Term " relaxes and discharges " and refers to be designed to produce the compositions of desirable pharmacokinetic profiles, and comprises delay pulse system and sustained release system independent or that merge.Yet common second compositions is formulated as sustained release formulation, and optional release with delay made up.

Peroral dosage form can, for example take tablet form, wherein first and second compositionss are arranged in two or more independent layers, and are preferably two-layer.

Perhaps first and second compositionss are many granules.

Many granules comprise coated drugs or comprise for example medicine of lactose ball of the blank pill heart (non-pareil) material.

When peroral dosage form comprised many granules, the granule of first compositions is coating not usually, the non-functional coating is perhaps arranged, and second compositions has functional coatings usually, for example enteric coating.In this embodiment, first compositions can comprise the pearl that contains or rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt coating are arranged, or comprise and contain or the pearl of rosiglitazone or its pharmaceutically acceptable salt coating is arranged and contain or have the mixture of the pearl of donepezil or its pharmaceutically acceptable salt coating.Many granules of this embodiment can incapsulate.

When immediate release composition was tablet form, suitable diluent comprised sucrose, for example lactose and maltose.More suitably, the compositions major part is a lactose, the optional for example magnesium stearate of other preparation adjuvant that adds.

Perhaps, as mentioned above, immediate release composition can be many particle form, and coating is not so that the rapid release of rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.

Postpone to discharge and can obtain easily by using stomach opposing formulation example such as Enteral formulations, said preparation can comprise many granules, and for example many granules ball uses stomach opposing polymer coating.Suitable stomach opposing polymer is well known in the art, and for example is listed among the WO2005/013935.Comprise polymer, for example methacrylate, cellulose acetate, carbomer, polyvinyl acetate phthalate and hydroxypropylmethyl cellulose phthalate.

Lasting release provides the release of active medicine during reaching a period of time of 26 hours, and suitable is 4 to 24 hours, be more preferably 12 to 24 hours.

Continuing to discharge is usually provided by the common lasting release matrix in tablet of use, and non-disintegrate is erosion property substrate maybe.

Lasting release matrix can be tablet.Suitable non-disintegrate substrate tablet is well-known in this area, and provides by for example one or more of methacrylate, cellulose acetate, carbomer and hydroxypropyl emthylcellulose being mixed tablet.

Perhaps, lasting release can be by preparation with for example many granules of ECN7NF coating (as the definition of above-mentioned institute) realization of semipermeable membrane.

Above-mentioned peroral dosage form can use the enteric coating coating, and therefore another aspect of the present invention provides peroral dosage form, and described peroral dosage form comprises the erosion property coating around erosion property core and the core, and its SMIS comprises:

First compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, the preparation of rapid release when being mixed with the contact aqueous matrix; With

Second compositions comprises rosiglitazone or its pharmaceutically acceptable salt, sustained release formulation when being configured to contact aqueous matrix.

Erosion property coating also can comprise one or more openings, opening passes through coating basically fully, but do not penetrate core, and make environment for use and core commissure, the rosiglitazone of its SMIS and donepezil discharge by described opening with by the erosion to coating under predetermined pH value condition basically.

Core can comprise every kind first and second compositions of monolayer.

Preferably, the erosion of coating is that pH value relies on, and partly or entirely disintegrate becomes porous or dissolves when contacting with environmental liquids, thereby liquid is contacted with core.Preferably, erosion property coating is an enteric coating, and promptly coating has clear and definite, predetermined pH value, and in this pH value coating dissolving, preferred pH is greater than 4.5, and preferred pH is 4.5 to 8, and most preferred pH is in 5 to 7 scope.Enteric coating be non-penetrative also be preferred.

The material and the material blends that are suitable for the erosion property coating that relies on as pH are well-known, and are for example describing among the WO2005/013935.The material that it is Eudragit L30 that specially suitable enteric-coating material comprises based on methacrylate polymer and for example commercially available trade mark of copolymer.

Once more, the general size of coating upper shed is described in WO2005/013935.Usually, the size about 0.19 to about 50.3mm ²Scope in, the diameter of corresponding circular open is in the scope of 0.5mm to 8mm, in preferred 2mm to the 4mm scope.The size of opening relies on the overall dimensions of tablet and required release rate.Except circle, opening can be Any shape, for example circle substantially or oval.

Opening can form according to the method for describing among the WO2005/013935, for example by using the boring of power auger or laser beam or perforator.Perhaps, opening can form by the coating original position that comprises pore-forming reagent, the material that promptly dissolves in the stomach can be on coating manufacturing hole.

Opening can be 0.25 to 70% of total surface, is more typically 10-70%.

Can provide a kind, 2 kinds or more coating openings, and when core comprised the independent layer of first and second compositionss, the embodiment of 2 kinds of openings was specially suitable.In this case, core and coating are set, thereby make first kind of opening that the release of first compositions is provided, second kind of opening provides the release of second compositions.

For the protective core material, prevent before the administration that by the pollution of opening the dosage form after it is desirable to core or hole formed provides conventional sealing coating.

Above-mentioned dosage form should make rosiglitazone and donepezil keep the mode of optimum level to discharge with interior two kinds of drug plasma concentrations during 24 hours, so that the dosage form once a day of combination becomes possibility.

As mentioned above, the inventor has shown rosiglitazone to not being that the homozygous experimenter's of APOE4 treatment is the most effective, and particularly the experimenter does not carry APOE4 allele.

Therefore, the merging purposes of above-mentioned rosiglitazone and donepezil and method comparable applications are in the present invention's specific peroral dosage form in this respect.

Although preferred rosiglitazone and the common preparation of donepezil, they are the independent compositions of administration simultaneously or in a sequence.Usually when rosiglitazone and donepezil not during administration simultaneously, they are administration within a certain period of time, and the described time refers to that they have section overlapping time for the treatment of effective plasma levels.Suitably, in the compositions that does not comprise donepezil, during administration, rosiglitazone is formulated as the preparation of administration once a day when rosiglitazone.When every kind of active component was formulated as the preparation of administration once a day, it was enough taking every kind of active component every day.

Dosage every day in the scope of 0.01mg to 12mg (for example every day 2mg, 4mg or 8mg) usually that rosiglitazone (for example rosiglitazone maleate) is suitable.Every day, the dosage of 8mg or more (for example 8mg) was especially suitable.In the application of the present invention to the APOE4 heterozygote, the rosiglitazone (for example 4mg or more, for example 4mg or 8mg) that gives higher dosage appears as useful.

Donepezil (for example hydrochloric acid donepezil) suitable every day dosage usually in the scope of 2-15mg, for example 5mg or 10mg.

Therefore, suitable dosage form can comprise the donepezil (for example hydrochloric acid donepezil) of 2mg, 4mg or 8mg rosiglitazone (for example rosiglitazone maleate) and 5mg or 10mg according to the present invention.

Should understand the combination of medicine of the present invention, can be used for prevention and (being more suitable for) treatment and suffer from mild cognitive damage, Alzheimer or other dementia.

The present invention will further describe in embodiment that quotes and chart:

Fig. 1 represents to treat in the colony of embodiment 2, and the ADAS-cog of model tuning (model adjusted) is from the change of baseline.

Fig. 2 represents that the ADAS-cog of model tuning is from the change of baseline in the genotype colony of embodiment 2 of different therapeutic schemes and APOE allele state.

Fig. 3 is illustrated in the APOE4 heterozygote (" Het ") and APOE4 homozygote (" Homo ") colony of embodiment 2, and the ADAS-cog of model tuning is from the change of baseline.

Embodiment

Embodiment 1 and 2 relates to the preparation that comprises rosiglitazone maleate, and shows that the treatment of using rosiglitazone is the most effective in not having the allelic patient of APOE4, and has minimum therapeutic effect in APOE4 allele homozygote patient.

Embodiment 3 relates to and comprises the various preparations that rosiglitazone merges donepezil.

The preparation of embodiment 1-rosiglitazone maleate slow release (extended release) tablet

The slow releasing tablet that comprises the PPAR-gamma agonist rosiglitazone (maleate form) of 2mg, 4mg or 8mg prepares (corresponding to embodiment 3) according to the method for describing among the WO05/013935.

(a) The agent of 2mg rosiglitazone slow-release tablet

Following compositions forms label:

Table 2-2mg rosiglitazone tablet first compositions (release layer).

Composition	Ratio (%w/w)
		Rosiglitazone (maleate)	1.99
Lactose	97.48
		Yellow iron oxide	0.03
Magnesium stearate	0.5

Second compositions of table 3-2mg rosiglitazone tablet (relax and discharge (modified release) layer).

Composition	Ratio (%w/w)
		Rosiglitazone (maleate)	1.1
HPMC	30.0
		Lactose	66.9
Silicon dioxide	0.5
		Magnesium stearate	1.5

Form the double-deck 200mg tablet (the mitigation releasing layer of the release layer of 50mg and 150mg) of the conventional concave surface of 7mm by compacting.

Label is with the end clothing of HPMC base with at the soluble polymethacrylate resin coating of pH5.5 ad pond om 217.3mg.

The opening of drill diameter 3.0mm penetrates coating on two main surperficial every of coated cores, to expose the sheet wicking surface.

Final tablet comprises the rosiglitazone of 0.75mg in 2mg rosiglitazone-release layer and relaxes the rosiglitazone of 1.25mg in the releasing layer.

(b) The agent of 4mg rosiglitazone slow-release tablet

Following compositions forms label:

Table 4-4mg rosiglitazone tablet first compositions (release layer).

Composition	Ratio (%w/w)
		Rosiglitazone (maleate)	3.98
Lactose	95.49
		Yellow iron oxide	0.03
Magnesium stearate	0.5

Table 5-4mg second kind of compositions of rosiglitazone tablet (mitigation releasing layer).

Composition	Ratio (%w/w)
		Rosiglitazone (maleate)	2.2
HPMC	30.0
		Lactose	65.8
Silicon dioxide	0.5
		Magnesium stearate	1.5

Form the double-deck 200mg tablet (the mitigation releasing layer of the release layer of 50mg and 150mg) of the conventional concave surface of 7mm by compacting.

Label is with the end clothing of HPMC base with at the soluble polymethacrylate resin coating of pH5.5 ad pond om 217.3mg.

The opening of drill diameter 3.0mm penetrates coating on two main surperficial every of coated cores, to expose the sheet wicking surface.

Final tablet comprises the rosiglitazone of 1.5mg in 4mg rosiglitazone-release layer and relaxes the rosiglitazone of 2.5mg in the releasing layer.

(a) The rosiglitazone maleate slow releasing tablet of 8mg

Following compositions forms label:

Table 6-8mg rosiglitazone tablet first compositions (release layer).

Composition	Ratio (%w/w)
		Rosiglitazone (maleate)	7.95
Lactose	91.52
		Yellow iron oxide	0.03
Magnesium stearate	0.5

Table 7-8mg rosiglitazone tablet second compositions (mitigation releasing layer).

Composition	Ratio (%w/w)
		Rosiglitazone (maleate)	4.4
HPMC	30.0
		Lactose	63.6
Silicon dioxide	0.5
		Magnesium stearate	1.5

Form the double-deck 200mg tablet (the mitigation releasing layer of the release layer of 50mg and 150mg) of the conventional concave surface of 7mm by compacting.

Label is with the end clothing of HPMC base with at the soluble polymethacrylate resin coating of pH5.5 ad pond om 217.3mg.

The opening of drill diameter 3.0mm penetrates coating on two main surperficial every of coated cores, to expose the sheet wicking surface.

Final tablet comprises the rosiglitazone of 3mg in 8mg rosiglitazone-release layer and relaxes the rosiglitazone of 5mg in the releasing layer.

Embodiment 2-PPAR-gamma agonist (rosiglitazone maleate) in treatment Alzheimer patient to the effect of ADAS-cog and CIBIC+.

Method

It is the analysis of purpose (ITT) colony fully with the treatment that 511 experimenters are carried out, a kind of in experimenter's random assortment to four kind of particular treatment dosage regimen.ITT colony to 63% (323/511) carries out gene type assay.

Patient colony comprises white man's masculinity and femininity, age is at 50-85 between year, suffered from slightly to moderate AD by diagnosis, patient colony does not accept anyly may cause dysgenic medicine (for example PPAR-gamma agonist and conventional AD medicine) and not suffer from other possible unfavorable disease (for example diabetes or main mental sickness) research.

The patient accepts the rosiglitazone of the slow release of placebo or three kinds of dosage levels (2mg, 4mg and 8mg tablet as described in example 1 above) once a day.Use Alzheimer to assess cognitive scale (ADAS-cog; More information is seen people Am.J.Psychiatry.1984141:1356-1364 such as Rosen WG) and follow the doctor of caregiver's information to speak face to face impression change (CIBIC+; More information is seen people Neurology 1994 44:2315-2321 such as Knopman DS) the detection patient; And use: dull-witted disabled assessment (DAD, more information is seen people Am J Occup Ther 199953:471-81 such as Gelinas L) and neural spiritual application form (NPI, more information is seen people such as Cummings (1994) Neurology 44, and 2308-2314) (after treating 8 weeks, 16 weeks and 24 weeks) carries out the secondary evaluation in research beginning (baseline) and research process.

Hereinafter the APOE genotype uses the method based on TaqMan PCR among the people 2001 such as McLeod to measure.

All statistical datas reflection last observations carry down (last observed assessment carriedforward) (LOCF) measure.

Table 8 and 9 has been summed up the age and the sex of genotype and complete ITT colony by therapeutic scheme.

Table 8-genotype colony sums up

The complete therapeutic purposes of table 9-colony sums up

The result

It should be noted that higher ADAS-cog scoring shows decline of cognitive function.Therefore the negative change from baseline shows improvement in the research process, and shows decline from the just change of baseline.In brief, minus treatment difference represents that this treatment is compared with placebo group and causes improving, and positive treatment difference is represented that this treatment is compared with placebo group and caused decline.

Higher CIBIC+ scoring shows the reduction of big level, and scoring is lower than 4 expression clinical improvementses and scoring is higher than the clinical decline of 4 expressions.Therefore minus this treatment of CIBIC+ treatment difference expression is compared with placebo group and is caused improving, and positive treatment difference shows that this treatment is compared with placebo group and causes decline.

ITT colony

Table 10 has been summed up in ITT colony change and the CIBIC+ result after the experiment of 24 weeks from baseline to the ADAS-cog of every kind of model tuning in 4 kinds of therapeutic schemes.During Fig. 1 represents to study in ITT colony the ADAS-cog of model tuning from the change of baseline (analysis comprise to the effect of baseline scores regulate, counting (country), small-sized mental status detect examination and baseline body mass index).

Use the treatment of PPAR-gamma agonist rosiglitazone, the ADAS-cog data in table 10 and Fig. 1 are supported the clinical improvements trend negative change of baseline (that is, from).At all time points, clean improvement is arranged in the analyzed as a complete unit colony.Yet this trend of statistical results show of rosiglitazone being treated AD patient's effect does not have statistical significance.CIBIC+ result in 24 weeks does not have significant difference between treatment group and placebo group.

The ADAS-cog of table 10-treatment group 24 week back model tuning sums up from the change of baseline

(LOCF-ITT colony)

Variable	Therapeutic scheme	LS average (SE)	Treat poor (95% confidence interval) rosiglitazone-placebo	Treatment difference P-value
					ADAS-cog	Placebo (n=122) rosiglitazone 2mg (n=126) rosiglitazone 4mg (n=128) rosiglitazone 8mg (n=130)	-0.4(0.55) -0.2(0.54) -0.9(0.54) -0.7(0.53)	0.25(-1.19，1.68) -0.46(-1.90，0.97) -0.27(-1.70，1.16)	0.74 0.52 0.71
CIBIC+	Placebo (n=122) rosiglitazone 2mg (n=126) rosiglitazone 4mg (n=128) rosiglitazone 8mg (n=130)	4.0(0.10) 3.8(0.10) 3.8(0.10) 3.8(0.10)	-0.16(-0.44，0.11) -0.16(-0.43，0.11) -0.22(-0.49，0.05)	0.23 0.24 0.11

Genotype colony

Table 11 and table 11a (having reflected other 2 experimenters' adding) show the result that APOE4 allele is measured in genotype colony.Before measuring, distributes in APOE4 allele therapeutic scheme; however; because statistical average, genotype distributes better usually between each group, though some more not general genotype show gathering (the APOE4 homozygote that vast scale is for example arranged in the 8mg rosiglitazone treatment group).

The APOE allele situation of table 11-treatment group is summed up

The APOE allele situation of table 11a-treatment group is summed up

^*An experimenter does not have available genotype information

After following table 12 has represented that APOE allele situation and therapeutic scheme research carried out for 24 weeks, the statistics that ADAS-cog changes.

Predetermined to APOE carry situation and change from the ADAS-cog overall score in baseline to 24 week between the detection of mutual relation be (P=0.0194) that significance is arranged.Exploration subsequently detects the patient who discloses APOE4-(not having APOE4 allele), after 24 weeks, show the overall improvement trend that PPAR-gamma agonist rosiglitazone treatment causes cognitive function, rosiglitazone dosage treatment group that evidence suggests the highest 8mg is compared with placebo and can be caused function to improve (P=0.027).

APOE4 heterozygote (single APOE4 allele is arranged) does not show any discernible trend.Although accepting some decline of 2mg rosiglitazone group, 4mg and 8mg dosage group all almost do not show change, and the neither one point has obvious significance after 24 weeks of treatment.

APOE4 homozygote (2 APOE4 allele are arranged) shows the relatively large just change that rosiglitazone is treated the ADAS-cog scoring that is caused.Although sample number is less, evidence suggests that this decline after 24 weeks of treatment is because the treatment (not proofreading and correct P＜0.05) of all 3 dosage levels.Yet the degree of the clinical decline that treatment is caused descends with the increase of dosage level.The clinical decline that it be unclear that in the treatment group is that rosiglitazone causes, or Alzheimer nature process caused.

The ADAS-cog of table 12-APOE4 allele situation and treatment group (PGx ITT colony) 24 week back model tuning sums up from the change of baseline

The APOE4 copy	Therapeutic scheme	LS average (SE)	Treat poor (90% confidence interval) rosiglitazone-placebo	The P-value of treatment difference
					0	Placebo (n=43) rosiglitazone 2mg (n=49) rosiglitazone 4mg (n=45) rosiglitazone 8mg (n=42)	1.01(0.95) -1.38(0.90) -1.25(0.90) -1.85(0.94)	-2.39(-4.43，-0.36) -2.26(-4.32，-0.20) -2.86(-4.98，-0.74)	0.053 0.071 0.027
1	Placebo (n=30) rosiglitazone 2mg (n=32) rosiglitazone 4mg (n=28) rosiglitazone 8mg (n=24)	-0.57(1.10) 2.02(1.10) -0.21(1.15) -0.34(1.25)	2.59(0.10，5.08) 0.36(-2.18，2.90) 0.23(-2.42，2.87)	0.087 0.82 0.89
					2	Placebo (n=5) rosiglitazone 2mg (n=4) rosiglitazone 4mg (n=6) rosiglitazone 8mg (n=12)	-4.58(2.70) 5.67(2.98) 3.16(2.44) 1.91(1.73)	10.26(3.64，16.87) 7.75(1.79，13.71) 6.50(1.28，11.71)	0.011 0.033 0.041

Fig. 2 represents to analyze colony by therapeutic scheme and APOE allele situation (1 and 2 APOE4 allele carrier shows) the gauged ADAS-cog of the model of fit change from baseline together.Fig. 3 represents a kind of match, and wherein APOE4 homozygote (be expressed as ' Homo E4+ ') data and APOE4 heterozygote (be expressed as ' Het E4+ ') data are different.

The visible trend that the cognition that the rosiglitazone treatment causes improves is obvious especially in the APOE4-individuality.Show the lasting decline of cognitive function in all time points (8,16 and 24 week) placebo group, yet use the treatment group of the PPAR-gamma agonist of 2mg, 4mg or 8mg to show significant improvement.

Situation for the APOE4+ individuality is not fully aware of.After 8 weeks of treatment, accept the slight decline that placebo group shows cognitive function, yet all are accepted rosiglitazone group (2mg, 4mg or 8mg) slight improvement are arranged.After 16 weeks of treatment, accept the lasting decline that placebo group shows cognitive function, although use the treatment group of 4mg and 8mg to show identical or clinical condition preferably.Using 2mg rosiglitazone treatment group to show than placebo group descends greatly.Finally, after 24 weeks of treatment, in accepting the APOE4 carrier of placebo, observe big and astonishing improvement.Significantly improvement may be that the experimenter who is subjected to minority to have unexpected and big ADAS-cog scoring improvement influences.All three rosiglitazone treatment groups finish with clinical decline, and because the rare improvement of some placebo group at this moment, as if the rosiglitazone treatment compared with placebo group and shown clinical decline.Observed clinical decline may be because normal AD clinical course in some APOE4+ groups.

Fig. 3 represents that APOE4 homozygote result is different with APOE4 heterozygote result.Although APOE4 homozygote quantity is little, can see the APOE4 homozygote of useful rosiglitazone treatment experienced clinical decline, yet the APOE4 heterozygote of accepting the rosiglitazone (4,8mg) of higher dosage keeps near baseline in research process.

Use dull-witted disabled assessment (DAD) to detect people Am J Occup Ther 199953:471-81 such as () Gelinas L and obtain similar result.Predetermined detection to mutual relation between the APOE4 in 24 weeks carrier situation and DAD scoring is (P=0.006) that significance is arranged.Detection subsequently shows that result and ADAS-cog result are qualitative similar: promptly, to DAD, APOE4-experimenter shows improvement, yet APOE4+ experimenter does not have improvement.

Use neural spiritual application form (NPI) to detect that (people (1994) Neurology 44 such as Cummings 2308-2314) obtains similar result.Predetermined detection to mutual relation between the APOE4 in 24 weeks carrier situation and NPI scoring is (P=0.086) that significance is arranged.Detection subsequently shows that result and ADAS-cog result are qualitative similar: promptly, to NPI, APOE4-experimenter shows improvement, yet APOE4+ experimenter does not have improvement.

Table 13 and table 13a (for considering the replacement analysis that adds the experimenter) show the CIBIC+ result after 24 weeks, press APOE4 allele situation and the classification of treatment dosage regimen.There is not evidence to show mutual relation between treatment and APOE4 copy, so following difference between subgroup is likely because random error, rather than the diversity effect.

APOE4-(do not have APOE allelic) patient all shows slight improvement in 24 weeks, observe maximum improve (not proofreading and correct P=0.052) in the rosiglitazone treatment group of 2mg.

Use APOE4 heterozygote (the allelic patient of single APOE4 is arranged) the performance decline (P=0.056) of the rosiglitazone treatment of 2mg.Show less decline in the rosiglitazone group of accepting 4mg, and show slight improvement the (although in exploratory analysis, not having) near the comparison that significance is arranged in the rosiglitazone group of accepting 8mg.

APOE4 homozygote (2 allelic patients of APOE4 are arranged) is compared the slight improvement that all shows with placebo group in CIBIC+ after 24 weeks of treatment, although the improvement degree descends with therapeutic dose.

Table 13-sums up at the model tuning CIBIC+ of 24 all back APOE4 allele situations and treatment group (PGx ITT colony).

The APOE4 copy	The treatment dosage regimen	LS average (SE)	Treat poor (90% confidence interval) rosiglitazone-placebo	The P-value of treatment difference
					0	Placebo (n=41) rosiglitazone 2mg (n=45) rosiglitazone 4mg (n=43) rosiglitazone 8mg (n=42)	3.95(0.19) 3.47(0.18) 3.76(0.18) 3.76(0.18)	-0.49(-0.89，-0.08) -0.19(-0.60，0.22) -0.19(-0.61，0.22)	0.051 0.44 0.44
1	Placebo (n=28) rosiglitazone 2mg (n=28) rosiglitazone 4mg (n=25) rosiglitazone 8mg (n=23)	3.88(0.22) 4.47(0.23) 4.11(0.23) 3.68(0.25)	0.59(0.08，1.11) 0.23(-0.28，0.74) -0.20(-0.73，0.34)	0.056 0.45 0.54
					2	Placebo (n=5) rosiglitazone 2mg (n=4) rosiglitazone 4mg (n=6) rosiglitazone 8mg (n=12)	4.34(0.53) 3.42(0.58) 3.95(0.47) 4.27(0.34)	-0.92(-2.20，0.37) -0.39(-1.55，0.77) -0.07(-1.08，0.95)	0.24 0.58 0.91

Table 13a-sums up at the model tuning CIBIC+ of 24 all back APOE4 allele situations and treatment group (PGx ITT).

The APOE4 copy	The treatment dosage regimen	LS average (SE)	Treat poor (90% confidence interval) rosiglitazone-placebo	The P-value of treatment difference
					0	Placebo (n=43) rosiglitazone 2mg (n=49) rosiglitazone 4mg (n=44) rosiglitazone 8mg (n=43)	3.97(0.18) 3.51(0.17) 3.75(0.17) 3.75(0.18)	-0.46(-0.85，-0.07) -0.22(-0.62，0.18) -0.22(-0.62，0.19)	0.052 0.37 0.38
1	Placebo (n=30) rosiglitazone 2mg (n=31) rosiglitazone 4mg (n=29) rosiglitazone 8mg (n=23)	3.92(0.21) 4.32(0.21) 3.97(0.22) 3.70(0.24)	0.39(-0.09，0.87) 0.04(-0.44，0.53) -0.22(-0.74，0.29)	0.18 0.88 0.48
					2	Placebo (n=5) rosiglitazone 2mg (n=4) rosiglitazone 4mg (n=6) rosiglitazone 8mg (n=12)	4.38(0.52) 3.46(0.57) 3.93(0.47) 4.29(0.33)	-0.91(-2.19，0.36) -0.45(-1.59，0.70) -0.09(-1.09，0.92)	0.24 0.52 0.89

APOE copy * treatment mutual relation P-value=0.21

Discuss

The result of embodiment 2 shows the integral body improvement trend of using PPAR-gamma agonist rosiglitazone treatment AD patient to cause not statistically significant as a complete unit in ITT colony.

In the colony of detecting, evidence suggests does not have the cognition of APOE4 allele patient's 8mg rosiglitazone group to improve (as measuring among the ADAS-cog).In not having APOE4 allele patient's 8mg rosiglitazone group, placebo group on average changed into-2.86, P=0.027 through 24 weeks.

In detecting colony, not having evidence to show to carry has cognition to improve (as measuring among the ADAS-cog) among the allelic patient of APOE4.Yet the patient who carries a copy is different with the allelic patient of the APOE4 that carries two copies, (yet this may be because the nature process of disease to show the cognition decline (measuring in as ADAS-cog) that maximum is arranged in carrying the APOE4 allele patient of 2 copies, rather than because rosiglitazone), and in the allelic patient of the APOE4 that carries 1 copy, there is not remarkable trend (for example, possible the stablizing of cognitive function).

Embodiment 3-comprises the peroral dosage form of rosiglitazone (for example maleate) and donepezil (for example hydrochlorate)

Preparation A

Preparation A has double-deck label, comprises release layer and relaxes releasing layer, and is as shown in table 14.This tablet coating and boring afterwards forms DiffCORE tablet (using the method for describing among the similar WO2005/013935).

Table 14: the composition of donepezil/rosiglitazone DiffCORE preparation

Label uses the end clothing of HPMC base and is 5.5 o'clock soluble polymethacrylate resin coatings at pH.

The opening that drills through diameter respectively on two of coated cores main surfaces on every and be 3.0mm penetrates coating, to expose the sheet wicking surface.

Final tablet comprises the rosiglitazone (being respectively the rosiglitazone of in release layer 0.75mg, 1.5mg or 3mg and the rosiglitazone of 1.25mg, 2.5mg or 5mg in relaxing releasing layer) of 2mg, 4mg or 8mg, together with the donepezil of 5mg in the release layer or 10mg.

Preparation B

Preparation B is an enteric substrate controlled release bilayer tablet.

Donepezil is mixed tablet in may combination range release layer in the following Table 15.

Table 15: the composition of donepezil/rosiglitazone enteric substrate tablet agent formulation

Final tablet comprises the rosiglitazone (being respectively the rosiglitazone of in release layer 0.75mg, 1.5mg or 3mg and the rosiglitazone of 1.25mg, 2.5mg or 5mg in relaxing releasing layer) of 2mg, 4mg or 8mg, together with the donepezil of 5mg in the release layer or 10mg.

Formulation C

Formulation C comprises the coated drugs piller (pellet) that incapsulates.The mixture of in capsule, packing into and forming by rapid release rosiglitazone, rapid release donepezil and enteric coating rosiglitazone piller.Pellets preparation sees Table 16:

Table 16: the donepezil/capsular composition of rosiglitazone pellets preparation

Rosiglitazone and donepezil release pills are used the end clothing coating of HPMC base.The piller of part end clothing coating uses the enteric coating at pH value 5.5 soluble polymethacrylates.

Final tablet comprises the rosiglitazone (be respectively the rosiglitazone of in release pills 0.75mg, 1.5mg or 3mg and relaxing the rosiglitazone that discharges 1.25mg, 2.5mg in the piller or 5mg) of 2mg, 4mg or 8mg, together with the donepezil of 5mg in the release pills or 10mg.

All lists of references in this application comprise patent and patent application, all quote at this to expose as a reference fully.

In whole description and following claim, unless requirement in the literary composition, otherwise the speech that " comprises (comprise) ", for example " comprise (comprises) " with the variation speech and " comprising (comprising) " will be understood that to represent to comprise described integral body, step, whole group or the group of step, and do not get rid of other any integral body, step, the group of integral body or the group of step.

Claims (47)

1. compositions, it comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, and pharmacy can be accepted diluent or carrier.

2. compositions, it comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, and pharmacy can accept diluent or carrier, and described compositions is used to improve the cognitive function of suffering from or easily suffering from mild cognitive damage, Alzheimer or other dull-witted experimenter.

3. improve and suffer from or easily suffer from the method for mild cognitive damage, Alzheimer or other dull-witted experimenter's cognitive function, this method comprises the compositions to experimenter's administration safety and effective dose, and described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.

4. compositions is used for improving the purposes of suffering from or easily suffering from the medicine of mild cognitive damage, Alzheimer or other dull-witted experimenter's cognitive function in preparation, and described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.

5. the combination of rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, the two is used to improve the cognitive function of suffering from or easily suffering from mild cognitive damage, Alzheimer or other dull-witted experimenter simultaneously, respectively or use in order.

6. according to the compositions of claim 2, the method for claim 3, the purposes of claim 4 or the combination of claim 5, wherein said experimenter is not an APOE4 allele homozygote.

7. according to the compositions of claim 2, the method for claim 3, the purposes of claim 4 or the combination of claim 5, wherein said experimenter does not carry APOE4 allele.

8. be used to improve the method for suffering from or easily suffering from MCI, Alzheimer or other dull-witted experimenter's cognitive function, described experimenter is not an APOE4 allele homozygote, and described method comprises the following steps:

I) examination experimenter determines that the experimenter is not an APOE4 allele homozygote; Then

Ii) to the compositions of experimenter's administration safety and effective dose, described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt.

9. method according to Claim 8, wherein said examination step (i) comprise determines that the experimenter carries the APOE4 allele of single copy.

10. method according to Claim 8, wherein said examination step (i) comprise determines that the experimenter is APOE4-.

11. each method in 10 according to Claim 8, wherein said experimenter suffers from or easily suffers from MCI (particularly forgeing type MCI).

12. each method in 10 according to Claim 8, wherein said experimenter suffers from or easily suffers from Alzheimer.

13. examination suffers from or easily suffer from MCI, Alzheimer or other dull-witted experimenter's method, this method helps to predict that the experimenter is to giving the reaction of compositions, described compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, and described method comprises examination to determine whether the experimenter carries the APOE4 allele of 0 or 1 copy.

14. according to the method for claim 13, described method comprises that examination is to determine whether the experimenter is APOE4-.

15. test kit, it comprises the compositions that (i) contains rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, (ii) instruct the description to experimenter's administration PPAR-gamma agonist (being generally pharmaceutical compositions), described experimenter is not an APOE4 allele homozygote.

16. according to each compositions, method, purposes, combination or test kit in the claim 1 to 15, wherein said rosiglitazone is the rosiglitazone maleate form.

17. according to each compositions, method, purposes, combination or test kit in the claim 1 to 15, wherein said donepezil is a hydrochloric acid donepezil form.

18. according to each compositions in the claim 1,2,16 or 17, that described compositions is formulated as is oral, parenteral route (comprising subcutaneous, Intradermal, intramuscular, intravenous and intraarticular), suck the preparation of (comprise fine particles powder or mist agent, can by aerosolizer, aerosol apparatus or the insufflator generation of various types of meterings pressurizations), percutaneous (for example passing through skin patch), rectum and part (comprising skin, buccal, Sublingual and ophthalmic) administration.

19. peroral dosage form, it comprises:

First compositions comprises rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt, rapid release when described compositions is formulated as the contact aqueous medium; With

Second compositions comprises rosiglitazone or its pharmaceutically acceptable salt, and described compositions relaxes when being formulated as the contact aqueous medium and discharges.

20. according to the peroral dosage form of claim 19, wherein said first and second compositionss are many granules.

21. according to the peroral dosage form of claim 20, wherein said many granules are coated drugs or pastille lactose ball.

22. according to the peroral dosage form of claim 20 or 21, the many granules that wherein comprise first compositions are coating not, and the many granules that comprise second compositions have enteric coating.

23. according to each peroral dosage form in the claim 20 to 22, during wherein said many granules incapsulate.

24. according to the peroral dosage form of claim 19, this peroral dosage form is taked tablet form, wherein first and second compositionss are placed in two or more independent layers.

25. according to the peroral dosage form of claim 24, wherein first and second compositionss are placed in two independent layers.

26. according to the peroral dosage form of claim 24, wherein said immediate release composition comprises sucrose.

27. according to the peroral dosage form of claim 26, wherein said immediate release composition comprises lactose, and the optional magnesium stearate that comprises.

28. according to each peroral dosage form in the claim 19 to 27, wherein said mitigation discharges to comprise and postpones and/or continue to discharge.

29. according to each peroral dosage form in the claim 24 to 27, wherein said second compositions is included in the sustained-release composition in the tablet.

30. according to each peroral dosage form in the claim 20 to 23, wherein said second compositions comprises the sustained-release composition with many particle form of semipermeable membrane coating.

31. according to each peroral dosage form in the claim 19 to 30, this oral formulations uses enteric coating coating.

32. peroral dosage form, the erosion property coating that it comprises erosion property core and centers on this core, described core comprises according to each peroral dosage form in the claim 19 to 30, wherein said erosion property coating comprises one or more and connects described coating basically fully but the opening that do not penetrate core, and core is communicated with environment for use, wherein rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt be under predetermined pH value condition, discharges from core by described opening and the erosion by coating basically.

33. according to the peroral dosage form of claim 32, the erosion of wherein said coating is that pH is dependent.

34. according to the peroral dosage form of claim 33, wherein said erosion property coating is an enteric coating.

35. according to each peroral dosage form in the claim 32 to 34, the opening in the wherein said coating about 0.19 to about 50.3mm ²Scope in, the diameter of corresponding circular open is in 0.5mm to 8mm scope.

36. according to each peroral dosage form in the claim 32 to 35, wherein said core comprises the isolating layer of first and second compositionss, and coating is provided with two kinds of openings, thereby makes first kind of opening that the release of first compositions is provided, and second kind of opening provides the release of second compositions.

37. according to each peroral dosage form in the claim 19 to 36, it is used to improve the cognitive function of suffering from or easily suffering from mild cognitive damage, Alzheimer or other dull-witted experimenter.

Suffer from or easily suffer from the method for mild cognitive damage, Alzheimer or other dull-witted experimenter's cognitive function 38. improve, described method comprises each described peroral dosage form in experimenter's administration claim 19 to 36.

39. according to the method for claim 38, wherein said experimenter is not an APOE4 allele homozygote.

40. according to the method for claim 38, wherein said experimenter does not carry APOE4 allele.

41. be used to improve the method for suffering from or easily suffering from MCI, Alzheimer or other dull-witted experimenter's cognitive function, described experimenter is not an APOE4 allele homozygote, described method comprises the following steps:

I) examination experimenter determines that the experimenter is not an APOE4 allele homozygote; Then

Ii) each peroral dosage form in described experimenter's administration claim 19 to 36.

42. according to the method for claim 41, wherein said examination step (i) comprises determines that the experimenter carries the APOE4 allele of single copy.

43. according to the method for claim 41, wherein said examination step (i) comprises determines that the experimenter is APOE4-.

44. according to each method in the claim 38 to 43, wherein said experimenter suffers from or easily suffers from MCI (particularly forgeing type MCI).

45. according to each method in the claim 38 to 43, wherein said experimenter suffers from or easily suffers from Alzheimer.

46. according to each method in the claim 19 to 36, wherein said rosiglitazone is the rosiglitazone maleate form.

47. according to each method in the claim 19 to 36, wherein said donepezil is a hydrochloric acid donepezil form.

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