CN104271125A - Method and formulation for treating sialic acid deficiencies - Google Patents

Method and formulation for treating sialic acid deficiencies Download PDF

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Publication number
CN104271125A
CN104271125A CN201380015020.XA CN201380015020A CN104271125A CN 104271125 A CN104271125 A CN 104271125A CN 201380015020 A CN201380015020 A CN 201380015020A CN 104271125 A CN104271125 A CN 104271125A
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sialic acid
slow releasing
releasing preparation
administration
pharmaceutically acceptable
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E·D·卡基
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Ultragenyx Pharmaceutical Inc
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Ultragenyx Pharmaceutical Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Abstract

The invention relates to an oral formulation for treating sialic acid deficiencies, which comprises sialic acid of an effective dose, or pharmaceutically acceptable salt, solvate or ester.

Description

Be used for the treatment of the anacid method and formulation of saliva
The cross reference of related application
This application claims the U.S. Provisional Application No.61/588 that the title submitted on January 18th, 2012 is " Methods and Formulations for Treating Sialic Acid Deficiencies ", 069, and the title of submission on October 4th, 2012 is the U.S. Provisional Application No.61/709 of " Methods and Formulations for Treating Sialic Acid Deficiencies ", the benefit of priority of 549.For all objects, the content of these applications is quoted with its entirety and is added herein.
Background
Sialic acid (SA) is the sugar containing net negative charge.It generally appears at the end side chain of N-polysaccharide, O-polysaccharide and glycosyl sphingolipid (ganglioside), and sometimes appear at GPI anchor add cap (capping) side chain.The sialic acid of cell surface molecule is modified at such as protein structure stability, cell adhesion regulates and play a role in many biological phenomenons of signal transduction.Such as Hereditary inclusion body myopathy (HIBM or 2 type HIBM), Nonaka myopathy and have the sialic acid deficiency symptom of Rimmed vacuoles distal myopathy (DMRV) to be produced by sialic acid to reduce the clinical disease that causes.
HIBM is the rare autosomal recessive neuromuscular disorder caused by the biosynthesis deficiency in sialic acid route of synthesis.The people such as Eisenberg, Nat.Genet.29:83-87 (2001).Described disease usually shows such as drop foot at the age of 20-40 and to ease up slow Progressive symmetric erythrokeratodermia muscle weakness and atrophy.Patient may walk in drop foot (walking with foot drop), grasp, suffer difficulty in the using and swallow of hands.Described disease is progressive; Most of ridden individuality LOM and dependance on wheel chair (wheelchair-confined) in 20 to three ten years.There is no available Therapeutic Method.
The position determining the sudden change relevant to HIBM of Iran-Jew's heredity isolation is chromosome 9p 12-13.The people such as Argov, Neurology 60:1519-1523 (2003).Through differentiating to cause the sudden change of HIBM in gene GNE, this gene code bifunctional enzyme UDP-N-acetylglucosamine-2-epimerase/ManNAc kinases (GNE/MNK).The people such as Eisenberg, Nat.Genet.29:83-87 (2001).DMRV is Japanese's variant, it and HIBM equipotential.The people such as Nishino, Neurology59:1689-1693 (2002).
Biosynthesis step and GNE/MNK feedback regulation is described in Fig. 1.Glycoconjugates produces sialic acid need N-acetyl-glucosamine (puting together with its vector nucleotide sugar UDP) to change into sialic acid.Sialic acid enters nucleus subsequently, puts together generation cmp sialic acid here with its nucleotide sugar support C MP, cmp sialic acid is used as the donor sugar of the glycosylation in cell.Cmp sialic acid is known GNE/MNK active regulator.The people such as Jay, Gene Reg. & Sys.Biol.3:181-190 (2009).HIBM patient produces not enough via the sialic acid of GNE/MNK enzyme, and described enzyme participates in the first two steps of this sequence.Report in the HIBM patient of different ethnic background close to 20 kinds of GNE sudden changes, in Iranian Jew and Japanese, had founder effect.The people such as Broccolini, Hum.Mutat.23:632 (2004).
Because sialic generation is the key reason that this sudden change causes disease, after this path genetic block, substitute metabolite can alleviate the anacid symptom of saliva in theory.The people such as Jay, Gene Reg.and Sys.Biology 3:181-190 (2009).But in fact, one or more compounds in sialic acid biosynthesis pathway of administration are great challenges in vivo.These compounds there is clearance rate quickly and they can by metabolism before drain in urine.
Summary of the invention
The invention provides treatment and need the anacid method of saliva in its individuality, it comprises oral administration sialic acid or its pharmaceutically acceptable salt, solvate or ester, and wherein said method provides the sialic acid for the treatment of effective dose in the time being greater than about four hours.
In some embodiments of the present invention, described sialic acid or its pharmaceutically acceptable salt, solvate or ester are in slow releasing preparation.In some embodiments of the present invention, described sialic acid or its pharmaceutically acceptable salt, solvate or ester are in slow releasing preparation and quick releasing formulation.
In some embodiments of the present invention, the average C that provides during stable state during dosing interval of described method minsialic acid is at least about 0.11mcg/ml.
In some embodiments of the present invention, the sialic mean plasma concentration that described method provides during stable state during dosing interval is at least about 0.16mcg/ml.
In some embodiments of the present invention, the sialic mean plasma concentration that the sialic mean plasma concentration that described method provides during stable state during dosing interval compares in the individuality before sialic acid described in administration or its pharmaceutically acceptable salt, solvate or ester is high at least about 50%.
In some embodiments of the present invention, described method on the feed under condition slow releasing preparation described in administration provide the absorption curve of improvement than administration in fasted condition.
In some embodiments of described method, it is lack relevant myopathy to sialic acid that described sialic acid lacks.
In some embodiments of described method, it is lack relevant myopathy to sialic acid that described sialic acid lacks.It is in some embodiments, described that to lack relevant myopathy to sialic acid be Hereditary inclusion body myopathy (HIBM), Nonaka myopathy and/or have Rimmed vacuoles distal myopathy (DMRV).
In some embodiments of described method, described slow releasing preparation is solid matrix form.
Accompanying drawing is sketched
Fig. 1 provides sialic acid metabolic map in born of the same parents.
Fig. 2 shows sialic particle size distribution.
Fig. 3 shows the particle size distribution figure of the final blend of ProCR sialic acid 250mg.
Fig. 4 shows the sialic acid 250mg of direct compression and the stripping curve (dissolution plot) of 325mg slow release (SR) tablet.
Fig. 5 shows the stripping curve (dissolution profile) of sialic acid 325mg and 500mg slow release (SR) uncoated tablets.
Fig. 6 shows the stripping curve of sialic acid 325mg and 500mg slow release (SR) coated tablet.
Fig. 7 shows the stripping curve of ManNAc 325mg tablet.
Fig. 8 to show after IV or oral administration in beasle dog serum sialic acid relative to the individual bulk concentration of time.Concentration after (A and B) administration TA-1 capsule; (C) concentration after administration TA-2 tablet; (D) concentration after administration TA-3 tablet; (E) concentration after administration TA-4 tablet; (F) concentration after administration TA-5 tablet; Concentration after (G and H) intravenous administration TA-6.
Fig. 9 is presented at sialic crossing research in the serum of the pharmacokinetic data of SA-ER relative to the SA API-oral administration SA-ER tablet of single dose in dog.
Figure 10 is presented at the result of repeat administration SA-ER in dog: the 0th day to the 7th day.Average (Gp is average) sialic acid concentration of group in the serum of oral administration SA-ER tablet (1625mg TID).Accumulation is to a certain degree there is in the time of 7 days.
Figure 11 is presented at the excretion level of comparison-each dog within the time of 24 hours of urine SA excretion in the crossing research of oral administration SA-ER in dog.Three qf oral administration dosage levels are relative to the last day of API relative to administration in 7 days.
Figure 12 shows average total urine SA excretion and compares-Total silicic acid in upon administration/24 hours periods in urine.Single dose compares with API and repeat administration on the 7th day.
The research approach that Figure 13 display is relevant to ER-SA people's clinical trial of embodiment 7.
Figure 14 shows the pharmacokinetic data obtained by the single dose ER-SA administration (650mg) of six different people patients.Open circles (open circle) represents the first day carrying out baseline monitoring; Filled circles (closed circle) represents second day of administration single dose under fasting.Free serum sialic acid concentration is in μ g/mL.
Figure 15 shows the pharmacokinetic data obtained by the single dose ER-SA administration (1,950mg) of six different people patients.Open circles represents the first day carrying out baseline monitoring; Filled circles represents second day of administration single dose under fasting.Free serum sialic acid concentration is in μ g/mL.
Figure 16 shows the pharmacokinetic data obtained by the single dose ER-SA administration (2,925mg) of two different people patients.Open circles represents the first day carrying out baseline monitoring; Filled circles represents second day of administration single dose under fasting.Free serum sialic acid concentration is in μ g/mL.
Figure 17 shows the pharmacokinetic data obtained by the single dose ER-SA administration (4,825mg) of a people patient.Open circles represents the first day carrying out baseline monitoring; Filled circles represents second day of administration single dose under fasting.Free serum sialic acid concentration is in μ g/mL.
Figure 18 shows the ER-SA repeat administration (650x3 by six different people patients; 1,950mg) pharmacokinetic data that obtains.Open circles represents the first day carrying out baseline monitoring; Filled circles represents that every day separates the data of the last day of 7 days of administration for three times.Free serum sialic acid concentration is in μ g/mL.
Figure 19 shows the ER-SA repeat administration (975x3 by five different people patients; 2,925mg) pharmacokinetic data that obtains.Open circles represents the first day carrying out baseline monitoring; Filled circles represents that every day separates the data of the last day of 7 days of administration for three times.Free serum sialic acid concentration is in μ g/mL.
Figure 20 is the diagram of I phase interim (interim) safety research dosage regimen.
Figure 21 display is depicted in the chart of the average free sialic acid concentration under single dose level (fasting and fed conditions).The individual mean P K curve of display 650mg, 1950mg, 2925mg, 4875mg and 6000mg dosage level is to compare fasting, feed and baseline SA level.The figure (Panel) of 650mg, 1950mg, 2925mg and 6000mg has the y-axis of formed objects, but the figure of 4875mg has larger y-axis (the higher level owing to obtaining).Baseline curve individual in each generation represents with open circles, and fasting levels is dark circles, and curve of taking food is Lycoperdon polymorphum Vitt circle.Group of individuals (fasting and fed conditions both) the baseline Sialic Acid Level of the 1st day illustrates on the same axis to present and compares can carry out range estimation to the Sialic Acid Level before treatment and after treatment.6000mg group administration 500mg tablet, and all the other dosage group administrations 325mg tablet.
Figure 22 is for being depicted in the chart of the average free sialic acid concentration under different single dose level (fasting state).Mean P K curve under display 650mg, 1950mg, 2925mg, 4875mg and 6000mg dosage level (fasting state) and standard deviation.6000mg group administration 500mg tablet, and all the other dosage group administrations 325mg tablet.
Figure 23 is for being depicted in the chart of the average free sialic acid concentration under different single dose level (fed conditions).Mean P K curve under display 650mg, 1950mg, 2925mg, 4875mg and 6000mg dosage level (fed conditions) and standard deviation.6000mg group administration 500mg tablet, and all the other dosage group administrations 325mg tablet.
Figure 24 A-F display is depicted in the chart of the free serum sialic acid concentration under different repeated doses levels.
Figure 25 shows description and continues 4 days by administration sialic acid slow releasing preparation, and then administration sialic acid slow releasing preparation adds the chart that sialic acid quick releasing formulation continues the free serum sialic acid concentration of 4 days.
Figure 26 shows description and continues 4 days by administration sialic acid slow releasing preparation, and then administration sialic acid slow releasing preparation adds the chart that sialic acid quick releasing formulation continues the free serum sialic acid concentration of 4 days.
Detailed Description Of The Invention
The application's providing package containing one or more compound or derivatives thereofs in sialic acid biosynthesis pathway sustained release pharmaceutical formulation and utilize described sustained release pharmaceutical formulation to treat and the anacid method of prevention saliva.The present invention relates to the method being designed for substrate and substituting, it provides stable and constant substituting with night in the daytime for suffering from the anacid individuality of saliva, and does not have high concentration crest in genotype and Various Tissues widely.The present invention can substitute and treatment benefit by using the combination of slow releasing preparation and one or more metabolite (comprising the combination of metabolite) optimally to realize this substrate.
Should be understood that described description refers to and includes the activating agent (compound as provided) of effective amount herein, it includes but not limited to compound included under title " therapeutic agent ".Therefore, should be understood that any slow releasing preparation described in detail can include the therapeutic agent of effective amount herein, as sialic acid or its pharmaceutically acceptable salt of effective dose.
Definition
Term " oral administration " and " orally ingestible " refer to for making to individual oral delivery pharmaceutical composition all conventionally forms that pharmaceutical preparation deposits at the gastrointestinal tract (comprising gastrointestinal stomach, i.e. stomach) of patient.Therefore, for example, oral administration and orally ingestible comprise actual picked-up solid or composition of liquid medicine, per os gavage (oral gavage) etc.
Term used herein " treatment " (" treating " and " treatment ") refers to for obtaining the method for result comprising the useful of clinical effectiveness or expect.For the purposes of the present invention, clinical effectiveness that is useful or that expect includes but not limited to following one or more: the seriousness and/or the frequency that reduce one or more symptoms caused by disease, reduce diseases range, make stable disease (such as prevent or delay disease progression), delay or slow down progression of disease, improve disease condition state, increase sialic acid, the generation of sialylated precursor cmp sialic acid (such as increasing sialic generation in born of the same parents) and the sialylation levels recovered in muscle and other oroteins, reduce the dosage of one or more other medicines needed for disease therapy and/or improve the quality of living.Management is comprised individual to suppress disease or the patient's condition or to make it disappear with preparation described herein " treatment " patient.
" prevention " or " prophylactic treatment " " or prophylactic treatment " refers to the appearance of prevention symptom and/or its potential cause, such as, disease or the patient's condition of the patient of (such as because heredodiathesis, environmental factors, susceptibility to disease or disease etc. have higher risk) disease or the patient's condition is easily suffered from prevention.The prevention chronic disease comprised in muscle changes irreversible HIBM myopathy, and animal model data show the treatment benefit of prevention.
" delaying " used herein progression of disease represents delay, hinders, slows down, blocks, stablizes and/or postpones advancing of disease.The individuality depending on history of disease and/or be treated, this delaying can have different time spans.
The individuality of " risky " used herein has the individuality suffered from sialic acid and lack risk.The individuality of " risky " can have and maybe can not have detectable disease, and can show before the Therapeutic Method described in this article or can not show detectable disease." risky " represents that individuality has one or more so-called risk factor, these risk factor be described herein with suffer from sialic acid and lack relevant measurable parameter.Compared with the individuality not having these risk factor, it is higher that the individuality with one or more these risk factor suffers from the anacid probability of saliva.
The amount of one or more compounds in sialic acid biosynthesis pathway that term " effective dose " refers to the amount being enough to obtain the therapeutic outcome expected.Effective dose can be included in one or many dosage, namely in order to reach the treatment terminal of expectation, may need single dose or multidose.
" treatment effective dose " refers to the amount of one or more compounds in sialic acid biosynthesis pathway being enough to produce the therapeutic outcome (such as reducing the seriousness of disease or the patient's condition) expected.In one embodiment, treat effective dose and refer to sialic treatment effective plasma level concentration." prevention effective dose " refers to when to susceptible individual and/or may be enough to prevent or reduce the amount comprising the pharmaceutical preparation of one or more compounds in sialic acid biosynthesis pathway of the seriousness of disease or the patient's condition in the future during the individual administration of disease or the patient's condition.
Term " slow release " refers to preparation containing medicine or its part, and the release of wherein said medicine is not immediately, i.e. administration " slow release " preparation can not cause medicine to the rapid release of absorption cell (absorption pool).In general, term used herein " slow release " comprises controlled release preparation, extended release preparation and delayed release preparation.
" pharmaceutically acceptable " represents that material is not biologically or undesirable in other side, namely described material can be mixed the pharmaceutical composition to patient's administration and other component of any described compositions not causing any significant less desirable biological effect or contain with it interacts in harmful mode.When term " pharmaceutically acceptable " is when being used in reference to pharmaceutical carrier or excipient, it represents that described carrier or excipient meet standard required by toxicology and production test or it is included in the Inactive Ingredient Guide formulated by U.S. food and drug administration.
Term " disease " or " disease " are used interchangeably in this article, it refers to any change of the state of health or its one of organ and/or tissue, interrupts or upsets the usefulness (such as causing organ dysfunction) of organ dysfunction and/or function of organization and/or cause such as discomfort, dysfunction, painful symptom or even dead to the individuality suffering from described disease.
Term " individuality " or " patient " refer to animal (such as mammal) and include but not limited to people, cattle, horse, cat, dog, rodent or primate.Described individuality is preferably people.
Term used herein " derivant " comprises derivant, analog, prodrug and non-natural precursor.
Term " pharmaceutically acceptable salt " refers to the salt of biological effectiveness retaining compound, and its be not biologically or other side less desirable.
(and description) variant for described value or parameter itself is comprised to quoting of " about " certain value or parameter herein.Such as, the description to " X " is comprised to the description of " about X ".
Unless the context clearly determines otherwise, otherwise herein and the singulative " a " used in appending claims, " an " and " the " comprise plural referents.Should be understood that embodiment of the present invention described herein, aspect and variant comprise " comprise/comprise ", embodiment, aspect and the variant of " by ... composition " and/or " substantially by ... composition ".
Pharmacokinetic parameter describes feature in activating agent (i.e. free sialic acid) body in time, such as plasma concentration (C), C max, C n, C 24, T maxand AUC." C max" be the concentration of activating agent in the blood plasma measured when maximum concentration site." C n" be the concentration of activating agent in the blood plasma that after administration, about n hour measures." C 24" be the concentration of activating agent in the blood plasma that after administration, about 24 hours measure.Term " T max" refer to administration activating agent after time when the concentration of activating agent is the highest in the blood plasma measured." AUC " is concentration (normally plasma concentration) (by the point in time measurement) area under curve relative to the figure of time of the activating agent measured.Such as AUC 0-tthe area under curve of plasma concentration relative to the time of the t from the time 0 to the time.AUC 0-∞or AUC 0-INFthe area under curve of plasma concentration relative to the time of the infinitely great calculating from the time 0 to the time.
Slow releasing preparation
Providing package is containing as one or more compound or derivatives thereofs in sialic acid biosynthesis pathway of therapeutic agent or the sustained release pharmaceutical formulation of above-mentioned pharmaceutically acceptable salt herein.In one embodiment, described sustained release pharmaceutical formulation comprises the therapeutic agent and polymer that describe in detail herein.The slow releasing preparation comprising therapeutic agent and polymer also can comprise one or more other components, such as any one or plurality of diluent, excipient, antioxidant, lubricant, coloring agent, binding agent, disintegrating agent etc.Should understand, below to comprise one or more compound or derivatives thereofs in sialic acid biosynthesis pathway sustained release pharmaceutical formulation mention and describe to be exemplary, and this description is equally applicable to and comprises the sustained release pharmaceutical formulation comprising any one or multiple compound in sialic acid biosynthesis pathway.Will also be understood that, below to comprise any one or multiple compound in sialic acid biosynthesis pathway derivant mention and describe to be exemplary, and this description is equally applicable to and comprises the sustained release pharmaceutical formulation comprising any one or multiple derivant, analog, prodrug and/or non-natural precursor compound in described sialic acid biosynthesis pathway.
In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent) and comprises hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
therapeutic agent
Think that the administration of sialic acid or the compound or derivatives thereof in sialic acid biosynthesis pathway or pharmaceutically acceptable salt above-mentioned arbitrarily can as therapeutic agent (such as substituting as substrate) to suffering from or suspecting the individual administration suffering from sialic acid deficiency symptom.Providing package contains the slow releasing preparation of such compound or its pharmaceutically acceptable salt (as therapeutic agent) herein.On the one hand, described sialic acid or the compound or derivatives thereof in sialic acid biosynthesis pathway or pharmaceutically acceptable salt above-mentioned are arbitrarily sialic acid or its pharmaceutically acceptable salt.On the one hand, any slow releasing preparation described in detail herein can include the therapeutic agent of effective amount, as sialic acid or its pharmaceutically acceptable salt of effective dose.
In a variant, the compound or derivatives thereof in sialic acid biosynthesis pathway is the compound or its pharmaceutically acceptable salt that are in ManNAc in described sialic acid biosynthesis pathway or its downstream.In a specific variants, described therapeutic agent is the compound or its pharmaceutically acceptable salt that are in ManNAc in described sialic acid biosynthesis pathway or its downstream, and it describes in FIG.
In another variant, the compound or derivatives thereof in sialic acid biosynthesis pathway is the compound or its pharmaceutically acceptable salt that are in cmp sialic acid in described sialic acid biosynthesis pathway or its upstream.In a specific variants, described therapeutic agent is the compound or its pharmaceutically acceptable salt that are in cmp sialic acid in described sialic acid biosynthesis pathway or its upstream, and it describes in FIG.In such variant, described compound or derivatives thereof in sialic acid biosynthesis pathway does not comprise glucose or its pharmaceutically acceptable salt.
In a specific variants, compound or derivatives thereof described in a variant in sialic acid biosynthesis pathway is the compound or its pharmaceutically acceptable salt that meet following condition: (i) is in ManNAc in described sialic acid biosynthesis pathway or its downstream, and (ii) is in cmp sialic acid in described sialic acid biosynthesis pathway or its upstream.In such variant, described compound is the compound or its pharmaceutically acceptable salt that describe in Fig. 1.
Compound or derivatives thereof in sialic acid biosynthesis pathway includes but not limited to mannosamine, ManNAc (ManNAc), ManNac-6-phosphate ester (ManNAc-6-P), UDP-GlcNAc, N-acetyl-neuraminate (NeuAc), NeuAc-9-phosphate ester (NeuAc-9-P), sialic acid (i.e. 5-N-n acetylneuraminic acid n), cmp sialic acid and/or its derivant or above-mentioned pharmaceutically acceptable salt.
In some embodiments, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described comprise N-acetyl-neuraminate (NeuAc) or derivatives thereof.The structure of such NeuAc or derivatives thereof include but not limited to be defined by following formula those:
wherein R 1, R 2, R 3, R 5, R 6or R 7hydrogen, low-grade alkane acidyl (alkanoyl), carboxylic acid ester groups or low alkyl group independently of one another; And R 4low alkyl group, low-grade alkane acidyl alkyl or low alkyl group alkanoyl oxygen base.
In some embodiments, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described comprise ManNAc or derivatives thereof.Such ManNAc and the structure of derivant thereof include but not limited to be defined by following formula those:
Wherein R 1, R 3, R 4or R 5hydrogen, low-grade alkane acidyl, carboxylic acid ester groups or low alkyl group independently of one another; And R 2low alkyl group, low-grade alkane acidyl alkyl or low alkyl group alkanoyl oxygen base.
Term lower alkyl refers to (C 1-C 6) alkyl.Low alkyl group comprises methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, 3-amyl group, hexyl and (C 3-C 6) group of naphthene base (such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl), (C 3-C 6) cycloalkyl (C 1-C 6) alkyl (such as Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, 2-cyclopropylethyl, 2-CYCLOBUTYLETHYL, 2-cyclopentyl ethyl or 2-cyclohexyl-ethyl), (C 1-C 6) alkoxyl (such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, amoxy, 3-amoxy or hexyloxy), (C 2-C 6) thiazolinyl (such as vinyl, pi-allyl, 1-acrylic, 2-acrylic, 1-butylene base, crotyl, 3-cyclobutenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl), (C 2-C 6) alkynyl (such as acetenyl, 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base or 5-hexin base), (C 1-C 6) alkanoyl (such as acetyl group, propiono or bytyry), halo (C 1-C 6) alkyl (such as iodomethyl, bromomethyl, chloromethyl, methyl fluoride, trifluoromethyl, 2-chloroethyl, 2-fluoro ethyl, 2,2,2-trifluoroethyls or pentafluoroethyl group), hydroxyl (C 1-C 6) alkyl (such as methylol, 1-ethoxy, 2-ethoxy, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyl butyl, 4-hydroxyl butyl, 1-hydroxyl amyl group, 5-hydroxyl amyl group, 1-hydroxyl hexyl or 6-hydroxyl hexyl), (C 1-C 6) alkoxy carbonyl group (such as methoxycarbonyl group, carbethoxyl group, the third oxygen carbonyl, butyloxycarbonyl, butoxy carbonyl, penta oxygen carbonyl or own oxygen carbonyl), (C 1-C 6) alkylthio group (such as methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio, penta sulfenyl or own sulfenyl) and/or (C 2-C 6) alkanoyl oxygen base (such as acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, penta acyloxy or hexylyloxy).
In some embodiments, R 2methyl, and R 1, R 3, R 4and R 5each hydrogen naturally.In some embodiments, described ManNAc or derivatives thereof is ManNAc (ManNAc).In some embodiments, described ManNAc or derivatives thereof is N-levulinic acyl group mannosamine (levulinoylmannosamine, ManLev) or N-azido acetylmannosamine (ManNAz).
In a variant, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described are esters of the compound in sialic acid biosynthesis pathway.On the one hand, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described are esters of sialic acid or MaNAc.In a specific variants, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described are sialic esters.On the one hand, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described are sialic prodrugs.For the derivant of the compound in sialic acid biosynthesis pathway, see also WO 2010/131712 disclosed in 18 days November in 2010, it is quoted with its entirety and adds herein, and specifically relate to the compound (derivant of the compound such as in sialic acid biosynthesis pathway) wherein described in detail.
On the one hand, the derivant (derivant of such as sialic acid or MaNAc) of one or more compounds in sialic acid biosynthesis pathway be such as suffer from or suspect suffer from sialic acid deficiency symptom individuality in sialic effective substrate substitute.The derivant (derivant of such as sialic acid or MaNAc) of one or more compounds in sialic acid biosynthesis pathway or the slow releasing preparation of derivant (derivant of such as sialic acid or MaNAc) comprising one or more compounds in sialic acid biosynthesis pathway can show in following characteristic any one or multiple: (i) can through for about or be greater than about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, arbitrary time in 19 or 20 hours is to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, (ii) can through for about or one or more compound or derivatives thereofs in described sialic acid approach from the treatment effective dose of substantial constant to its individuality of needs that send of the arbitrary time being greater than about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours, (iii) can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach during each dosing interval, T maxfor about 2-6 hour, 2-5 hour or any one in 3-6 hour, (iv) can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor about 0.1-0.9 μ g/mL, 0.1-100 μ g/mL, 0.2-0.3 μ g/mL or 0.5-100 μ g/mL, v () can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, paddy level is about 0.05-0.2 μ g/mL, 0.05-0.3 μ g/mL, 0.1-0.3 μ g/mL or 0.1-20 μ g/mL, (vi) to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, any one be less than in about 10%, 20%, 30%, 40%, 50%, 60% or 70% can after one hour, be drained, (vii) can to need its individuality send about 0.01-750mg/kg/ days, 0.5-500mg/kg/ days, 1-250mg/kg/ days, one or more compound or derivatives thereofs in described sialic acid approach of 2.5-100mg/kg/ days or any one in 5-50mg/kg/ days or above-mentioned pharmaceutically acceptable salt, (viii) can to need its individuality send about 0.01-750mg/kg/ days, 0.5-500mg/kg/ days, 1-250mg/kg/ days, one or more compound or derivatives thereofs in described sialic acid approach of 2.5-100mg/kg/ days or any one in 5-50mg/kg/ days or above-mentioned pharmaceutically acceptable salt, (ix) there is the absolute bioavailability of about 1% to about 50%, x () has the bioavailability based on the Sialic Acid Level about 0.5% to about 100% in urine, and (xi) has the mean residence time (MRT) at least about 3.5 hours.
In some embodiments, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described comprise sialic acid or derivatives thereof.In some embodiments, described sialic acid or derivatives thereof is sialic acid.In some embodiments, described sialic acid or derivatives thereof is sialic acid analogue, such as N-levulinic acyl group sialic acid (SiaLev) or N-azido acetyl group sialic acid (SiaNAz).In some embodiments, described sialic acid is combined into glycoconjugates.In some embodiments, described sialic acid or derivatives thereof is non-natural precursor, such as sialyllactose (sialylactose).
In some embodiments, described slow releasing preparation comprises about a kind of, two kinds, three kinds or four kinds of compound or derivatives thereofs in sialic acid biosynthesis pathway arbitrarily.In some embodiments, described slow releasing preparation comprises two kinds of compound or derivatives thereofs in sialic acid biosynthesis pathway.Therefore, such as, described slow releasing preparation can comprise ManNAc or derivatives thereof and sialic acid or derivatives thereof.More particularly, described slow releasing preparation can comprise ManNAc and sialic acid.
In the embodiment of any described slow releasing preparation, the amount of one or more in described slow releasing preparation compound or derivatives thereof in sialic acid biosynthesis pathway effectively increases the amount that sialic acid produces and/or increase sialylated (such as sialylated maximum recovery).
In some embodiments, the ratio of two or more compound or derivatives thereof in sialic acid biosynthesis pathway is the minimized ratio of feedback suppression making described sialic acid biosynthesis pathway.In some embodiments, the ratio of two or more compound or derivatives thereof in sialic acid biosynthesis pathway described is the ratio allowing effectively to send to myocyte two or more compound or derivatives thereof in sialic acid biosynthesis pathway described.In some embodiments, the ratio of two or more compound or derivatives thereof in sialic acid biosynthesis pathway described is the ratio feedback suppression of described sialic acid biosynthesis pathway being minimized and allows effectively to send to myocyte two or more compound or derivatives thereof in sialic acid biosynthesis pathway described.In some embodiments, two or more compound or derivatives thereof in sialic acid biosynthesis pathway described is ManNAc or derivatives thereof and sialic acid or derivatives thereof.Such as, in some embodiments, ManNAc and sialic ratio the feedback suppression of described sialic acid biosynthesis pathway are minimized and allow effectively to send ManNAc and/or sialic ratio to myocyte.Described combination can optimally expand intermediate and substitute, and strengthens the Optimal Distribution to all cells type with different metabolic.The method of the optimal ratio using external HIBM myocyte to test sialylated recovery and measure two or more compound or derivatives thereof in sialic acid biosynthesis pathway described is known in the art.See such as, the people such as Noguchi S., J.Bio.Chem.279 (12): 11402-7 (2004).It is sialylated that this may relate to the optimum evaluating muscle-derived albumen, soluble form (the people such as Ricci of such as nerve cell adhesion molecule (NCAM), Neurology 66:755-758 (2006), sialic acid metabolite in evaluation of tissue sample or cmp sialic acid level, or assess the sialylated protein on muscle surface or other cell.The people such as Noguchi S., J.Bio.Chem.279 (12): 11402-7 (2004).
Comprise in the embodiment of two kinds of compound or derivatives thereofs in sialic acid biosynthesis pathway at described slow releasing preparation, the weight of two kinds of compounds in described slow releasing preparation and the percentage ratio of weight can be any one in about 5%-95%: 95%-5%, 5%-50%: 95%-50% or 10%-40%: 90%-60%.The weight of two kinds of compounds in described slow releasing preparation and the percentage ratio of weight can be any one in about 90%: 10%, 80%: 20%, 70%: 30%, 60%: 40%, 50%: 50%, 40%: 60%, 30%: 70%, 20%: 80% or 10%: 90%.In some embodiments, the weight of two kinds of compounds in described slow releasing preparation and the percentage ratio of weight are about 50%: 50%.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Therefore, such as, described slow releasing preparation can comprise ManNAc and sialic acid, and wherein the percentage ratio of ManNAc and sialic weight and weight is any one in about 90%: 10%, 80%: 20%, 70%: 30%, 60%: 40%, 50%: 50%, 40%: 60%, 30%: 70%, 20%: 80% or 10%: 90%.
polymer
The described slow releasing preparation comprising one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described herein can comprise one or more polymer.Described polymer can be natural polymer (such as polysaccharide or protein), modified natural polymers and/or synthetic polymer.Described polymer can be such as hydrophobic polymer, hydrophilic polymer, hydrogel, soluble polymer, biodegradable polymer, not biodegradable polymer and/or Mucoadhesive polymers.
In some embodiments, described polymer is hydrophobic polymer.The example of hydrophobic polymer comprises polyethylene, polrvinyl chloride, ethyl cellulose or acrylate polymer and copolymer thereof.
In some embodiments, described polymer is hydrophilic polymer.The example of hydrophilic polymer comprises a) cellulose derivative, such as methylcellulose (MC), hydroxyethyl-cellulose, hydroxypropyl emthylcellulose (HPMC) or sodium carboxymethyl cellulose, b) the natural or semi synthetic polymer of non-cellulose, as the polysaccharide of agar, carob, alginate, molasses, mannose and galactose or chitosan and modified starch and c) acrylic acid polymer, such as carbomer polymer.
In some embodiments, described polymer is hydrogel.The example of hydrogel includes but not limited to poly-hydroxyethyl acrylic acid methyl ester. (PHEMA), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), poly(ethylene oxide) (PEO) or polyacrylamide (PA).In some embodiments, described hydrogel is poly(ethylene oxide) (such as Polyox tMwater-soluble resin, Dow Chemical Company, Mich., USA).
In some embodiments, described polymer is soluble polymer.The example of soluble polymer includes but not limited to Polyethylene Glycol (PEG), PVA, PVP or HPMC.
In some embodiments, described polymer is biodegradable polymer.The example of biodegradable polymer includes but not limited to polylactic acid (PLA), polyglycolic acid (PGA), poly-(lactic acid/glycolic) (PLGA), polycaprolactone (PCL), polyanhydride or poe.
In some embodiments, described polymer is not biodegradable polymer.The example of not biodegradable polymer includes but not limited to polyethylene vinylacetate, polydimethylsiloxane (PDS), poly(ether-urethane) (PEU), polrvinyl chloride (PVC), cellulose acetate (CA) or ethyl cellulose (EC).
In some embodiments, described polymer is Mucoadhesive polymers.The example of Mucoadhesive polymers includes but not limited to polycarbophil, sodium carboxymethyl cellulose, polyacrylic acid, Tragacanth, methylcellulose, pectin, natural gum, xanthan gum, guar gum or karaya.
In some embodiments, described sustained release pharmaceutical formulation comprises two kinds of polymer.In some embodiments, described polymer is not polylactic acid (polylactide).In some embodiments, described polymer is not the copolymer of poly lactic acid of such as PLGA.
In some embodiments, described slow releasing preparation comprises one or more and is selected from following polymer: a) water-swellable, non-TCP friendly flow polymer, b) anion, pH dependency, gel formation copolymer, c) cationic polymer and d) hydrocolloid polymer.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
The example of water-swellable, non-TCP friendly flow polymer includes but not limited to carbohydrate based polymer, such as, hypromellose (being originally called hydroxypropyl emthylcellulose family), Cellulose ethyl hydroxypropyl ether, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose or other composition.The grade being generally used for these hypromellose copolymers of the present invention comprises E and K series, such as Dow Chemical Company (Midland, or E4M, E10M, K100LV, K4M, K15M, K25M, K100M, K200M of Aqualon (being positioned at Wilmington, the Del. of North American) and the mixture of various molecular weights and grade Mich.USA).The grade of hydroxyethyl-cellulose comprises the Natrasol polymer HHX (molecular weight 1 of such as Aqualon, 300,000), HX (molecular weight 1,000,000), H (molecular weight 1,000,000), M (molecular weight 720,000) and G (molecular weight 1,150,000) and composition thereof.The grade of hydroxypropyl cellulose comprises HPC polymer MF and MXF (molecular weight 580,000) and KF and HXF (molecular weight 1,150,000) and composition thereof of such as Aqualon.The grade of ethyl cellulose comprises Ethocel polymer 7FP, 10FP and 100FP of such as Dow Chemical Company and polymer T10EC, N7, N10, N17, N22, N50, N100 and N200 and composition thereof of Aqualon.In some embodiments, described water-swellable, non-TCP friendly flow polymer are hypromellose (such as hypromellose models 2208).In some embodiments, described water-swellable, non-TCP friendly flow polymer are (such as k 100MPremium CR, Colorcon).
The example of anion, pH dependency, gel formation copolymer includes but not limited to monovalence alginate (sodium salt of such as alginic acid, potassium salt or ammonium salt or its combination) and sodium carboxymethyl cellulose etc., or the mixture of one or more alginate and carboxymethyl celluloses etc.In some embodiments, described anion, pH dependency, gel formation copolymer be sodium alginate (such as fMC BioPolymer).
The material that the example of cationic polymer comprises such as chitosan or derivatives thereof (comprising such as N-trimethyl chitosan TMC and n-trimethyl chitosan chloride (quartermised chitosan)) and chitosan derivative (comprises such as in U.S. Patent No. 5,747, in 475 instruction those).High molecular or low-molecular-weight chitosan product can be used in pharmaceutical preparation of the present invention, and can easily from these chitosan products being positioned at global supplier and obtaining pharmaceutical grade.
The hydrocolloid polymer used in preparation of the present invention can be carrageenan.Available carrageenan has ι, κ and λ carrageenan, and ι carrageenan the most often uses, and λ carrageenan the most seldom uses.Also can use the multiple salt form of carrageenan, it comprises such as carrageenan sodium.The grade of normally used ι carrageenan comprises and is not limited to carrageenan NF AEP board colloid (Hadley, N.Y.USA) FD433 (1% viscosity; 300-400cps) with FD384 (1% viscosity; About 100cps).The viscosity of other carrageenan product is in the scope of about 50cps to about 4000cps.In some embodiments, described carrageenan is λ carrageenan (such as Viscarin GP-209, FMC BioPolymer).In some embodiments, the viscosity of described carrageenan is about 1500-2000cPs.In some embodiments, the viscosity of described carrageenan is about 1600cPs.
Preparation useful in described slow releasing preparation and polymer further describe in U.S. Patent application 2010/0159001 disclosed in U.S. Patent application disclosed in 24 days June in 2010 2010/0160363 and 24 days June in 2010, described application is quoted with its entirety and adds herein, and specifically the polymer wherein provided is provided.
In some embodiments, described slow releasing preparation comprises water-swellable, non-TCP friendly flow polymer (such as hypromellose).In some embodiments, described slow releasing preparation also comprises anion, pH dependency, gel formation copolymer (such as alginate).In some embodiments, described slow releasing preparation also comprises hydrocolloid polymer (such as carrageenan).In some embodiments, described slow releasing preparation comprises water-swellable, non-TCP friendly flow polymer (such as hypromellose), anion, pH dependency, gel formation copolymer (such as alginate) and hydrocolloid polymer (such as carrageenan).In some embodiments, described slow releasing preparation comprises hypromellose (such as hypromellose model 2208 or Methocel K100M), sodium alginate (such as Protanal) and λ carrageenan (such as Viscarin GP-209).In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent) and comprises hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
In some embodiments, described slow releasing preparation comprises hydrogel (such as poly(ethylene oxide)).In some embodiments, described slow releasing preparation also comprises anion, pH dependency, gel formation copolymer (such as alginate).In some embodiments, described slow releasing preparation also comprises hydrocolloid polymer (such as carrageenan).In some embodiments, described slow releasing preparation comprises hydrogel (such as poly(ethylene oxide)), anion, pH dependency, gel formation copolymer (such as alginate) and hydrocolloid polymer (such as carrageenan).In some embodiments, described slow releasing preparation comprises poly(ethylene oxide) (such as Polyox WSR), sodium alginate (such as Protanal) and λ carrageenan (such as Viscarin GP-209).In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent) and comprises hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
In a variant, described slow releasing preparation comprises: (i) hydrocolloid polymer; (ii) anion, pH dependency, gel formation copolymer and (iii) water-swellable, non-TCP friendly flow polymer or hydrogel.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.Slow releasing preparation in a variant comprises the therapeutic agent (such as sialic acid) and (i) hydrocolloid polymer that describe in detail herein; (ii) anion, pH dependency, gel formation copolymer and (iii) water-swellable, non-TCP friendly flow polymer or hydrogel.Exemplary sustained release preparation comprises those that list in Table A, wherein should understand slow releasing preparation can comprise with polymer 1,2, at least one of any one in 3A or 3B combine described in any one of therapeutic agent listed, as the combination specifically and individually listing each and each therapeutic agent and polymer or combination of polymers.Although specific preparation can comprise the therapeutic agent of Table A and any one or the multiple polymer being selected from the polymer 1,2 and 3 (A and/or B) of Table A, in a specific variants, slow releasing preparation comprises the therapeutic agent of Table A, the polymer 1 of Table A, the polymer 2 of Table A and the polymer 3A of Table A or the polymer 3B of Table A, as the combination specifically and individually listing each and each therapeutic agent and combination of polymers.Such as, should be understood that on the one hand, slow releasing preparation comprise sialic acid, carrageenan (such as λ carrageenan, such as Viscarin GP-209), alginate (such as sodium alginate, such as lF 120M) and (i) hypromellose (such as hypromellose model 2208) or (ii) poly(ethylene oxide) (such as Polyox) or pharmaceutically acceptable salt above-mentioned arbitrarily.
Table A. the exemplary compositions used in slow releasing preparation.
In a variant, slow releasing preparation comprises polymer 3A or the polymer 3B of the therapeutic agent of Table A, the polymer 1 of Table A, the polymer 2 of Table A and Table A, and wherein said compositions comprises therapeutic agent and the polymer of any one of the weight percentage ranges described in table B.
The example weight percentage ratio of some component that table B. uses in slow releasing preparation.
In another variant, described slow releasing preparation comprises therapeutic agent (the compound or derivatives thereof in sialic acid biosynthesis pathway or salt above-mentioned arbitrarily, the any compound such as described in detail herein, be included in Table A) and polymer, wherein said polymer comprises: (i) hydrocolloid polymer; (ii) anion, pH dependency, gel formation copolymer and (iii) water-swellable, non-TCP friendly flow polymer or hydrogel, and wherein polymer (i): (ii): the percentage by weight of (iii) is about 1: 5: 5 or about 1: 5: 6.
It is believed that (i) hydrocolloid polymer; (ii) combination of anion, pH dependency, gel formation copolymer and (iii) water-swellable, non-TCP friendly flow polymer or hydrogel provides unique combination, described combination is advantageous particularly for the preparation of peroral dosage form because described combination produce in following characteristics any one or multiple: (i) provides firm preparation (such as tablet formulation); I () is that non-pH is dependent; And (iii) contribute to granulating and not affecting stripping curve.
Other description of slow releasing preparation and formulation components at full text and hereinafter can find.
Should be understood that to mentioning of relative weight percents be suppose that the summation of all components percentage by weight in preparation adds up to 100.Should be further understood that, the relative weight percents of one or more components can be heightened or turned down make the percentage by weight of the component in compositions be total up to 100.On the one hand, the percentage by weight described in detail herein refers to the percentage by weight (be such as mixed with the amount before the unit dose of such as tablet, it can adjust further, such as, by adding tablet coating) of preparation blend.On the other hand, the percentage by weight described in detail herein refers to the percentage by weight of the unit dose of preparation, wherein said preparation be certain form and/or through packaging for individual administration (such as there is the tablet of coating).
Relative to one or more compound or derivatives thereofs in described sialic acid approach described in 100 weight portions, the amount being present in the polymer in described slow releasing preparation can in the scope of 5 to 40 weight portions, 10 to 20 weight portions.In some embodiments, by weight, one or more the compound or derivatives thereofs in described sialic acid approach comprised in such preparation are the about 0.1-99.9% of described preparation.In some embodiments, one or more the compound or derivatives thereofs in described sialic acid approach comprised in such preparation are any one about in 20%-30%, 30%-40%, 40%-50% or 20%-50%.In some embodiments, by weight, described slow releasing preparation comprises the polymer of any one in about 40%-50%, 50%-60%, 60%-70% or 50%-70%.
In some embodiments, the drug loading of one or more in described slow releasing preparation compound or derivatives thereof in described sialic acid approach accounts for about 20% to 80%w/w.In some embodiments, the drug loading of one or more in described slow releasing preparation compound or derivatives thereof in described sialic acid approach accounts for any one in about 20%-60%w/w, 20%-50%w/w, 20%-40%w/w, 15%-60%w/w, 15%-50%w/w, 15%-40%w/w, 25%-60%w/w, 25%-50%w/w, 25%-40%w/w, 30%-60%w/w, 30%-50%w/w, 30%-45%w/w, 35%-60%w/w, 35%-50%w/w or 35%-45%w/w.In some embodiments, the drug loading of one or more in described slow releasing preparation compound or derivatives thereof in described sialic acid approach accounts for any one at least about 25%w/w, 30%w/w, 35%w/w, 40%w/w, 45%w/w or 50%w/w.In some embodiments, the drug loading of one or more in described slow releasing preparation compound or derivatives thereof in described sialic acid approach accounts for about 33%w/w.In some embodiments, the drug loading of one or more in described slow releasing preparation compound or derivatives thereof in described sialic acid approach accounts for about 43%w/w.
In some embodiments, described slow releasing preparation comprises water-swellable, the non-TCP friendly flow polymer (such as hypromellose) of about 20 to about 50 or about 20 to about 40 or about 20 to about 30%w/w.In some embodiments, described slow releasing preparation comprises water-swellable, the non-TCP friendly flow polymer (such as hypromellose) of about 25%w/w.In some embodiments, described slow releasing preparation also comprises anion, pH dependency, the gel formation copolymer (such as alginate) of about 20-25%w/w.In some embodiments, described slow releasing preparation also comprises anion, pH dependency, the gel formation copolymer (such as alginate) of about 21%w/w.In some embodiments, described slow releasing preparation also comprises the hydrocolloid polymer (such as carrageenan) of about 1-5%w/w.In some embodiments, described slow releasing preparation also comprises the hydrocolloid polymer (such as carrageenan) of about 4%w/w.In some embodiments, described slow releasing preparation comprises the hydrocolloid polymer (such as carrageenan) of the water-swellable of about 20-30%w/w, non-TCP friendly flow polymer (such as hypromellose), the anion of about 20-25%w/w, pH dependency, gel formation copolymer (such as alginate) and about 1-5%w/w.In some embodiments, described slow releasing preparation comprises about 20-30%w/w hypromellose (such as hypromellose model 2208 or Methocel K100M), about 20-25%w/w sodium alginate (such as Protanal) and about 1-5%w/w λ carrageenan (such as Viscarin GP-209).In some embodiments, described slow releasing preparation comprises the hydrocolloid polymer (such as carrageenan) of the water-swellable of about 25%w/w, non-TCP friendly flow polymer (such as hypromellose), the anion of about 21%w/w, pH dependency, gel formation copolymer (such as alginate) and about 4%w/w.In some embodiments, described slow releasing preparation comprises about 25%w/w hypromellose (such as hypromellose model 2208 or Methocel K100M), about 21%w/w sodium alginate (such as Protanal) and about 4%w/w λ carrageenan (such as Viscarin GP-209).
In some embodiments, described slow releasing preparation comprises the hydrogel (such as poly(ethylene oxide), Polyox WSR) of about 20 to about 50 or about 20 to about 40 or about 20 to about 20-30%w/w.In some embodiments, described slow releasing preparation comprises the hydrogel (such as poly(ethylene oxide), Polyox WSR) of about 25%w/w.In some embodiments, described slow releasing preparation also comprises anion, pH dependency, the gel formation copolymer (such as alginate) of about 20-25%w/w.In some embodiments, described slow releasing preparation also comprises anion, pH dependency, the gel formation copolymer (such as alginate) of about 21%w/w.In some embodiments, described slow releasing preparation also comprises the hydrocolloid polymer (such as carrageenan) of about 1-5%w/w.In some embodiments, described slow releasing preparation also comprises the hydrocolloid polymer (such as carrageenan) of about 4%w/w.In some embodiments, described slow releasing preparation comprises the hydrocolloid polymer (such as carrageenan) of the hydrogel (such as poly(ethylene oxide)) of about 20-30%w/w, the anion of about 20-25%w/w, pH dependency, gel formation copolymer (such as alginate) and about 1-5%w/w.In some embodiments, described slow releasing preparation comprises about 20-30%w/w poly(ethylene oxide) (such as Polyox WSR), about 20-25%w/w sodium alginate (such as Protanal) and about 1-5%w/w λ carrageenan (such as Viscarin GP-209).In some embodiments, described slow releasing preparation comprises the hydrocolloid polymer (such as carrageenan) of the hydrogel (such as poly(ethylene oxide)) of about 25%w/w, the anion of about 21%w/w, pH dependency, gel formation copolymer (such as alginate) and about 4%w/w.In some embodiments, described slow releasing preparation comprises about 25%w/w poly(ethylene oxide) (such as Polyox WSR), about 21%w/w sodium alginate (such as Protanal) and about 4%w/w λ carrageenan (such as Viscarin GP-209).
other formulation components
The sustained release pharmaceutical formulation comprising one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described herein also can comprise diluent, excipient, antioxidant, lubricant, coloring agent, binding agent, disintegrating agent etc.Should understand, any slow releasing preparation (including but not limited to those (any preparations of such as Table A or B) of listing for title with " slow releasing preparation ") described in detail herein also can comprise the diluent, excipient, antioxidant, lubricant, coloring agent, binding agent, disintegrating agent etc. that describe in detail herein, as specifically and individually listed each and each slow releasing preparation also comprising such component.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
Select diluent with the biological activity making it not affect described combination.The example of such diluent is distilled water, buffered water, normal saline, PBS, ringer's solution (Ringer ' s solution), glucose solution and Chinese krebs solution (Hank ' s solution).Described pharmaceutical preparation can also comprise other material with close to physiological conditions, such as pH regulator and buffer agent, toxicity modifiers, wetting agent and detergent.Described pharmaceutical preparation can also comprise any one in plurality of stable agent.Other guidance relevant with pharmaceutical preparation being suitable for multiple administration fashion can at Remington:The Science and Practice of Pharmacy, 20th edition, Baltimore, MD:Lippincott Williams & Wilkins, finds in 2000.
Described excipient can be selected from lactose, microcrystalline Cellulose, corn starch, potato starch, wheaten starch, sucrose, PEARLITOL 25C, winnofil, dextrin, pregelatinized Starch and combination thereof.If existed, the amount of the excipient that can contain is to about 90 weight portions based on tablet total weight amount about 10.In some embodiments, by weight, described slow releasing preparation comprises the excipient of any one in about 40%-50%, 50%-60%, 60%-70% or 50% to 70%.In some embodiments, described excipient is microcrystalline Cellulose.In some embodiments, described excipient be microcrystalline Cellulose and silica sol (such as sMCC HD90).In some embodiments, described slow releasing preparation comprises the microcrystalline Cellulose of about 1-10%w/w and silica sol (such as sMCC HD90).In some embodiments, described slow releasing preparation comprises the microcrystalline Cellulose of about 5%w/w and silica sol (such as sMCC HD90).
Described binding agent can be selected from hydroxypropyl cellulose, the microcrystalline Cellulose of direct compression, HPMC, MC, hydroxyethyl-cellulose, hydroxy methocel, carboxymethyl cellulose and other cellulose derivative, PVP, PVA, paste, Radix Acaciae senegalis, dextrin, gelatin, alginate and combination thereof.If existed, the amount of operable binding agent is to about 60 weight portions based on the gross weight about 2 of tablet.
Described disintegrating agent can be selected from primojel, polyvinylpolypyrrolidone (crosspovidone), cross-linked carboxymethyl cellulose sodium, the hydroxypropyl cellulose of low replacement, starch, carboxymethylcellulose calcium, calcium carbonate, sodium bicarbonate and combination thereof.If existed, the amount of the disintegrating agent that can comprise is to about 32 weight portions based on the gross weight about 0.1 of tablet composition.
Described lubricant can be selected from magnesium stearate, calcium stearate, Talcum, light anhydrous silicic acid and solid polyethylene glycol and combination thereof.If existed, the amount of the lubricant that can comprise is to about 20 weight portions based on the gross weight about 0.1 of tablet.In some embodiments, described lubricant be magnesium stearate (such as ).In some embodiments, described slow releasing preparation comprises about 0.1-1%w/w magnesium stearate (such as ).In some embodiments, described slow releasing preparation comprises about 0.5%w/w magnesium stearate (such as ).
For described coloring agent, described tablet can comprise the kind that at least one can be selected from titanium dioxide, ferrum oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum color lake (such as blue No. 1 aluminum color lake, red No. 40 aluminum color lakes) etc.
In another variant, the slow releasing preparation (including but not limited to those (any preparations of such as Table A and B) of listing for title with " slow releasing preparation ") described in detail herein also comprises excipient.In a specific variants, described excipient comprises microcrystalline Cellulose.In another variant, described excipient comprises microcrystalline Cellulose and silica sol.In variant so arbitrarily, the slow releasing preparation also comprising excipient (such as comprising the excipient of microcrystalline Cellulose and silica sol) comprises about 1 to about 20 or about 1 to about 15 or about 1 to about 10 or about 1 to about 5 or about 5 to about 20 or about 5 to about 15 or about 5 to about 10 or about 1,2,3,4,5,6,7,8, the excipient of any one in 9 or 10 percentage by weights.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
In another variant, the slow releasing preparation (including but not limited to those (any preparations of such as Table A and B) of listing for title with " slow releasing preparation ") described in detail herein also comprises lubricant.In a specific variants, described lubricant comprises stearate, such as magnesium stearate.In variant so arbitrarily, the slow releasing preparation also comprising lubricant (such as stearate, such as magnesium stearate) comprises about 0.1 to about 2 or about 0.1 to about 1.5 or about 0.1 to about 1.0 or about 0.01 to about 0.09-5 or about 0.1 to about 0.8 or about 0.1 to about 0.7 or about 0.1 to about 0.6 or about 0.1 to about 0.5 or about 0.2 to about 0.8 or about 0.3 to about 0.7 or about 0.4 to about 0.6 or about 0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8, the lubricant of any one in 0.9 or 1.0 percentage by weights.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
In another variant, the slow releasing preparation (including but not limited to those (any preparations of such as Table A and B) of listing for title with " slow releasing preparation ") described in detail herein also comprises excipient and lubricant.In variant so arbitrarily, the preparation also comprising excipient and lubricant comprises about 1 to about 20 or about 1 to about 15 or about 1 to about 10 or about 1 to about 5 or about 5 to about 20 or about 5 to about 15 or about 5 to about 10 or about 1, 2, 3, 4, 5, 6, 7, 8, the excipient (such as comprising the excipient of microcrystalline Cellulose and silica sol) of any one in 9 or 10 percentage by weights, and comprise about 0.1 to about 2 or about 0.1 to about 1.5 or about 0.1 to about 1.0 or about 0.01 to about 0.09-5 or about 0.1 to about 0.8 or about 0.1 to about 0.7 or about 0.1 to about 0.6 or about 0.1 to about 0.5 or about 0.2 to about 0.8 or about 0.3 to about 0.7 or about 0.4 to about 0.6 or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, lubricant (the such as stearate of any one in 0.9 or 1.0 percentage by weights, such as magnesium stearate).In another variant, the excipient (such as comprising the excipient of microcrystalline Cellulose and silica sol) that the preparation also comprising excipient and lubricant comprises and the percentage by weight of lubricant (such as stearate, such as magnesium stearate) are any one in about 1: 10 or 1: 11 or 1: 9 or 1: 10.5.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
Specific slow releasing preparation comprise table C in list those, wherein said compositions comprises therapeutic agent, polymer 1, polymer 2, polymer 3A or polymer 3B, excipient and lubricant, should understand each combination intention with these components each with specifically with to list each individually identical with each combination.
Table C. exemplary sustained release preparation compositions.
In a variant, slow releasing preparation is the compositions described in detail in table C, and wherein said compositions comprises the formulation components of any weight percentage ranges of the description of table D.Should be understood that the combination intention of each and these components each and percentage by weight with specifically with to list each individually identical with the combination of percentage by weight with each component.
The example weight percentage ratio of some component that table D. uses in slow releasing preparation.
In another variant, provide slow releasing preparation, wherein said preparation comprises the therapeutic agent of table C, the polymer 1 showing C, the polymer 2 of table C, the polymer 3A of table C or polymer 3B, the excipient of table C and the lubricant of table C, and the percentage by weight being wherein present in the component in described compositions is as follows.On the one hand, lubricant: polymer 1: excipient: polymer 2: polymer 3A or 3B: the percentage by weight of therapeutic agent is about 1: 8: 10: 40: 50: 85 or about 1: 8.5: 10.5: 42.5: 51: 86.5 or about 1: 8.4: 10.6: 42.4: 51: 86.6.
In any preparation (including but not limited to any preparation in Table A-D) described in detail in this article, on the one hand, described therapeutic agent is the combination of sialic acid or ManNAc or its pharmaceutically acceptable salt or sialic acid or ManNAc.The particular aspects of any preparation (including but not limited to any preparation in Table A-D) described in detail in this article, described therapeutic agent is sialic acid or its pharmaceutically acceptable salt.
Sialic specific slow releasing preparation provides in table E.In a variant, the sialic acid in the preparation of ManNAc substitution list E can be used.
The sialic exemplary sustained release preparation of table E..
Component for preparing described sustained release pharmaceutical formulation is preferably high-purity and essentially no potential noxious pollutant (being at least such as state food (NF) level, is at least generally AG, is at least more generally pharmaceutical grade).In addition, the pharmaceutical preparation being intended to use in body is normally aseptic.If given compound must synthesize before the use, so the product of gained generally there is no any genotoxic potential agent that may exist during synthesis or purge process.Compositions for parental generation (parental) administration is also aseptic, substantially isotonic and prepares under gmp conditions.
The blend of described slow releasing preparation can have most of granule by the granularity of the sieve size reservation of 45 μm.In some embodiments, the blend of described slow releasing preparation has the granule of any one at least 10%, 30%, 40%, 50% by the granularity of the sieve size reservation of 45 μm.
Sustained release pharmaceutical formulation described herein can be mixed with solid, semisolid, liquid or gas form preparation, such as tablet, capsule, powder, granule, ointment, solution, suppository, injection, inhalant, gel, microsphere and aerosol.In some embodiments of any sustained release pharmaceutical formulation described in this article, described sustained release pharmaceutical formulation is through preparation by number of ways administration, and described approach comprises in oral, parenteral (comprising subcutaneous, intravenous, intramuscular and intraperitoneal), rectum, skin, percutaneous, intrathoracic, lung and intranasal (breathing) approach.In some embodiments, described sustained release pharmaceutical formulation is used for oral administration through preparation.
In a variant, any slow releasing preparation described in detail herein can through preparation for oral administration.Such as, any preparation (including but not limited to any preparation that Table A-E, embodiment 6 or embodiment 7 propose) provided for title with " slow releasing preparation " in a variant can be the preparation being suitable for oral administration.The preparation being suitable for oral administration can be formulated as solid oral dosage form, such as tablet or comprise the capsule of preparation of powder form.On the one hand, the solid oral dosage form of slow releasing preparation is provided, wherein said solid oral dosage form comprises any preparation (including but not limited to any preparation proposed in Table A-E, embodiment 6 or embodiment 7) provided of tablet form herein, and wherein said tablet also comprises coating (such as Opadry-II white).In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
For oral administration, sialic acid biosynthesis pathway or derivatives thereof described herein can with solid dosage forms (such as capsule, tablet and powder) administration or liquid dosage form (such as elixir, syrup and suspensoid) administration.
In some embodiments, described pharmaceutical preparation comprises enteric coating.Eurypalynous acid resistant enteric coated coating is perhaps had to use.The example of acidproof coating comprises acetylcellulose phthalate, polyvinyl acetate phthalate, lac, acrylate homopolymer or copolymer, methacrylic acid homo thing or copolymer, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate or its combination.The copolymer of some methacrylic acids is known in the art and has commercially available.The example of such polymer is the copolymer of methyl methacrylate and methacrylic acid and the copolymer of ethyl acrylate and methacrylic acid, and sells with trade name Eudragit (Rohm GmbH & Co.KG): example comprises l 100-55, l 30D-55, l 100, s 100-55 and fS 30D.In some embodiments, described enteric coating comprises one or more titanium dioxide, polydextrose, hypromellose, acetin and Polyethylene Glycol/PEG.In some embodiments, described enteric coating is iI white.In some embodiments, described enteric coating (such as iI white) account for described slow releasing preparation and be about 1-5%w/w.In some embodiments, described enteric coating (such as iI white) account for described slow releasing preparation and be about 1-5%w/w.
Enteric coating also can be the coating of time delay release (time-release).The coating of described time delay release with the degradation rate of relative constancy until coat dissolves breaks to the coating being enough to make described time delay discharge.Therefore, described enteric coating breaks (i.e. the thickness) of the time mainly time dependence needed, and mainly non-TCP friendly flow.The example of the coating material of time delay release comprises cellulose acetate, cellulose acetate-butyrate, cellulose-acetate propionate, EC and has the acrylate of quaternary ammonium group and the copolymer of methacrylate, such as rL and rS and nE30-D.
Further film coating process can be carried out to described sustained release pharmaceutical formulation.For film coating agent, enteric or non-enteric film coating agent can be used, described enteric film coating agent can be acetylcellulose phthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylate polymers (Eudragit L, etc., and described non-enteric film coating agent can be hydroxypropyl cellulose (HPC), MC, EC, HPMC, polyvidone, PVA, CA, lac etc. S).Cotton seeds can be undertaken by such as pan coating method, fluidized bed coating, compression coating etc.
The coated tablet of the described slow releasing preparation of sizes can be prepared.Such as, described coated tablet can have the length of about 16-20mm, the width of about 7-12mm and the thickness of about 5-8mm.In some embodiments, described coated tablet has the length of about 17.7mm, the width of about 9.1mm and the thickness of about 6.7mm.In some embodiments, described coated tablet has the length of about 19.3mm, the width of about 9.7mm and the thickness of about 8.0mm.
In the embodiment of any described method, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, the water-swellable of about 20-30%w/w, non-TCP friendly flow polymer (such as hypromellose), the anion of about 20-25%w/w, pH dependency, gel formation copolymer (such as alginate), the hydrocolloid polymer (such as carrageenan) of about 1-5%w/w, the microcrystalline Cellulose of about 1-10%w/w and silica sol (such as sMCC HD90), about 0.1-1%w/w/ magnesium stearate (such as ) and about 1-5% enteric coating (such as iI white).In some embodiments, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, about 20-30%w/w hypromellose (such as hypromellose model 2208 or Methocel K100M), about 20-25%w/w sodium alginate (such as Protanal), about 1-5%w/w λ carrageenan (such as Viscarin GP-209), the microcrystalline Cellulose of about 1-10%w/w and silica sol (such as sMCC HD90), about 0.1-1%w/w/ magnesium stearate (such as ) and about 1-5% enteric coating (such as iI white).In some embodiments, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, the water-swellable of about 25%w/w, non-TCP friendly flow polymer (such as hypromellose), the anion of about 21%w/w, pH dependency, gel formation copolymer (such as alginate), the hydrocolloid polymer (such as carrageenan) of about 4%w/w, the microcrystalline Cellulose of about 5%w/w and silica sol (such as sMCC HD90), about 0.5%w/w/ magnesium stearate (such as ) and about 3.5% enteric coating (such as iI white).In some embodiments, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, about 25%w/w hypromellose (such as hypromellose model 2208 or Methocel K100M), about 21%w/w sodium alginate (such as Protanal), about 4%w/w λ carrageenan (such as Viscarin GP-209), the microcrystalline Cellulose of about 5%w/w and silica sol (such as sMCC HD90), about 0.5%w/w/ magnesium stearate (such as ) and about 3.5% enteric coating (such as iI white).
In the embodiment of any described method, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, the hydrogel (such as poly(ethylene oxide)) of about 20-30%w/w, the anion of about 20-25%w/w, pH dependency, gel formation copolymer (such as alginate), the hydrocolloid polymer (such as carrageenan) of about 1-5%w/w, the microcrystalline Cellulose of about 1-10%w/w and silica sol (such as sMCC HD90), about 0.1-1%w/w/ magnesium stearate (such as ) and about 1-5% enteric coating (such as iI white).In some embodiments, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, about 20-30%w/w poly(ethylene oxide) (such as Polyox WSR), about 20-25%w/w sodium alginate (such as Protanal), about 1-5%w/w λ carrageenan (such as Viscarin GP-209), the microcrystalline Cellulose of about 1-10%w/w and silica sol (such as sMCC HD90), about 0.1-1%w/w/ magnesium stearate (such as ) and about 1-5% enteric coating (such as iI white).In some embodiments, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, the hydrogel (such as poly(ethylene oxide)) of about 25%w/w, the anion of about 21%w/w, pH dependency, gel formation copolymer (such as alginate), the hydrocolloid polymer (such as carrageenan) of about 4%w/w, the microcrystalline Cellulose of about 5%w/w and silica sol (such as sMCC HD90), about 0.5%w/w/ magnesium stearate (such as ) and about 3.5% enteric coating (such as iI white).In some embodiments, described slow releasing preparation comprises the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, about 25%w/w poly(ethylene oxide) (such as Polyos WSR), about 21%w/w sodium alginate (such as Protanal), about 4%w/w λ carrageenan (such as Viscarin GP-209), the microcrystalline Cellulose of about 5%w/w and silica sol (such as sMCC HD90), about 0.5%w/w/ magnesium stearate (such as ) and about 3.5% enteric coating (such as iI white).
the embodiment of preparation
In one embodiment, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, solvate or the ester of about 25% to about 50%w/w; One or more water-swellables of about 20% to about 40%w/w, non-TCP friendly flow polymer or one or more hydrogels form polymer; One or more aniones, pH dependency, the gel formation polymer of about 15% to about 30%w/w; One or more hydrocolloid polymer of about 3% to about 8%w/w or one or more cationic polymers.
In one embodiment, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, solvate or the ester of about 25% to about 50%w/w; The hypromellose of about 20% to about 30%w/w; The carrageenan of about 3% to about 8%w/w; And the sodium alginate of about 20% to about 25%w/w.In one embodiment, described slow releasing preparation comprises the sialic acid of about 30% to about 45%w/w.In one embodiment, described slow releasing preparation comprises the hypromellose of about 22% to about 27%w/w.In one embodiment, described slow releasing preparation comprises the carrageenan of about 4% to about 6%w/w.In one embodiment, described slow releasing preparation comprises the carrageenan of about 20% to about 23%w/w.In one embodiment, described slow releasing preparation also comprises about 1% to the microcrystalline Cellulose of about 10%w/w and the mixture of silica sol; And the magnesium stearate of about 0.1% to about 1%w/w.
In one embodiment, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, solvate or the ester of about 25% to about 50%w/w; At least one in about 20% to the Polyethylene Glycol and poly(ethylene oxide) of about 30%w/w; The carrageenan of about 3% to about 8%w/w; And the sodium alginate of about 20% to about 25%w/w.In one embodiment, described slow releasing preparation comprises the sialic acid of about 30% to about 45%w/w.In one embodiment, described slow releasing preparation comprises at least one in about 22% to the Polyethylene Glycol and poly(ethylene oxide) of about 27%w/w.In one embodiment, described slow releasing preparation comprises the carrageenan of about 4% to about 6%w/w.In one embodiment, described slow releasing preparation comprises the carrageenan of about 20% to about 23%w/w.In one embodiment, described slow releasing preparation also comprises about 1% to the microcrystalline Cellulose of about 10%w/w and the mixture of silica sol; And the magnesium stearate of about 0.1% to about 1%w/w.
In a specific embodiment, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, solvate or the ester of about 43.3%; The hypromellose of about 25.5%w/w; The carrageenan of about 4.2%w/w; The sodium alginate of about 21.1%w/w; The microcrystalline Cellulose of about 5.3% and silica sol; And the magnesium stearate of about 0.5%.In another embodiment, described slow releasing preparation is the dosage form of 325mg and 500mg.
therapeutic use
The invention provides and be used for the treatment of the anacid method of saliva in its individuality of needs.Described method comprises oral administration sialic acid or its pharmaceutically acceptable salt, solvate or ester, and provides the sialic acid for the treatment of effective dose in the time being greater than about four hours.
In one embodiment, described sialic acid or its pharmaceutically acceptable salt, solvate or ester in slow releasing preparation, all as described in this article those.In another embodiment, described sialic acid or its pharmaceutically acceptable salt, solvate or ester are in slow releasing preparation (all as described in this article those) and quick releasing formulation.Described slow releasing preparation and quick releasing formulation can be independent dosage form, and administration in a coordinated fashion.Such as, individuality can walk abreast and take the dosage form of slow releasing preparation and the dosage form of quick releasing formulation.Or, described slow releasing preparation and quick releasing formulation can be formulated as single dosage form.Such as, the single dosage form of sialic acid or its pharmaceutically acceptable salt, solvate or ester can comprise release sustaining component and immediate release component.
In an embodiment of this method, described sialic acid or its pharmaceutically acceptable salt, solvate or ester are to have the metronomic dosing regimens administration of one or more dosing interval every day.Such as described sialic acid or its pharmaceutically acceptable salt, solvate or ester can be administered once every day, twice, three times or four times.In one embodiment, described sialic acid or its pharmaceutically acceptable salt, solvate or ester are administered three times (TID) every day.
In one embodiment, this method provides the sialic acid for the treatment of effective dose in the time that every day is greater than about eight hours.In some embodiments, this method provides the sialic acid for the treatment of effective dose in the time that every day is greater than about ten, 12,14,16 or 18 hours.Such as, this method in every day about eight to about ten, about eight to about 12, about eight to about 14, about eight to about 16, about ten to about 14, about 12 to the time of about 16 or about 16 to about 20 hours provide treatment effective dose sialic acid.
In one embodiment, the average C that provides during stable state during described dosing interval of this method minsialic acid is at least about 0.11mcg/ml.In some embodiments, the average C that provides during stable state during described dosing interval of this method minsialic acid is at least about 0.12mcg/ml, about 0.13mcg/ml, about 0.14mcg/ml, about 0.15mcg/ml, about 0.16mcg/ml, about 0.17mcg/ml.
In one embodiment, the sialic mean plasma concentration that this method provides during stable state during described dosing interval is at least about 0.16mcg/ml.In some embodiments, the sialic mean plasma concentration that this method provides during stable state during described dosing interval is at least about 0.17mcg/ml, about 0.18mcg/ml, about 0.19mcg/ml, about 0.20mcg/ml, about 0.21mcg/ml, about 0.22mcg/ml, about 0.23mcg/ml, about 0.24mcg/ml.
In one embodiment, the sialic mean plasma concentration that the sialic mean plasma concentration that this method provides during stable state during dosing interval compares in the individuality before sialic acid described in administration or its pharmaceutically acceptable salt, solvate or ester is high at least about 50%.In some embodiments, the sialic mean plasma concentration that the sialic mean plasma concentration that this method provides during stable state during dosing interval compares in the individuality before sialic acid described in administration or its pharmaceutically acceptable salt, solvate or ester is high at least about 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%.
In one embodiment, this method provide stable state time sialic blood plasma concentration curve make the sialic minimum plasma concentration during described dosing interval be maximal plasma concentration during described dosing interval at least about 35%.In some embodiments, this method provide stable state time sialic blood plasma concentration curve make the sialic minimum plasma concentration during described dosing interval be maximal plasma concentration during described dosing interval at least about 40%, 45%, 50%, 55% or 60%.
In one embodiment, this method on the feed under condition slow releasing preparation described in administration provide the absorption curve of improvement than administration in fasted condition.In one embodiment, the absorption curve of described improvement comprises the average C measured in the fasted state maxhigher than the average C measured under state on the feed max.The average C such as measured in the fasted state maxthan the average C measured under state on the feed maxheight about 10%, 15%, 20%, 25%, 30% or 35%.In one embodiment, the average T that measures under being included in fed conditions of the absorption curve of described improvement maxhigher than the average T measured in the fasted state max.The average T such as measured under state on the feed maxthe average T measured in the fasted state maxratio be about 1.2: 1; 1.3: 1; 1.4: 1; 1.5: 1; 1.6: 1; 1.7: 1; 1.8: 1; 1.9: 1 or 2: 1.
In one embodiment of the invention, the slow releasing preparation (including but not limited to those (any preparations in such as Table A-E, embodiment 6 or embodiment 7) of describing in detail for title with " slow releasing preparation " and " other formulation components ") described in detail herein can show that describe in detail with following any characteristic herein.In a specific variants, any slow releasing preparation described in detail herein can show in following characteristic any one or multiple: (i) can through for about or be greater than arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours to its one or more of individual delivery treatments effective dose compound or derivatives thereof in described sialic acid approach of needs; (ii) can through for about or one or more the compound or derivatives thereofs in described sialic acid approach being greater than that arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours sends the treatment effective dose of substantial constant to its individuality of needs; (iii) can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, at each dosing interval period T maxfor about 2-6 hour, 2-5 hour or the arbitrary time in 3-6 hour; (iv) can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor about 0.1-0.9 μ g/mL, 0.1-100 μ g/mL, 0.2-0.3 μ g/mL or 0.5-100 μ g/mL; V () can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, paddy level is about 0.05-0.2 μ g/mL, 0.05-0.3 μ g/mL, 0.1-0.3 μ g/mL or 0.1-20 μ g/mL; (vi) to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, any one be less than in about 10%, 20%, 30%, 40%, 50%, 60% or 70% can after one hour, be drained; (vii) can to need its individuality send about 0.01-750mg/kg/ days, 0.5-500mg/kg/ days, 1-250mg/kg/ days, one or more compound or derivatives thereofs in described sialic acid approach of 2.5-100mg/kg/ days or any one in 5-50mg/kg/ days or above-mentioned pharmaceutically acceptable salt; (viii) can to need its individuality send about 0.01-750mg/kg/ days, 0.5-500mg/kg/ days, 1-250mg/kg/ days, one or more compound or derivatives thereofs in described sialic acid approach of 2.5-100mg/kg/ days or any one in 5-50mg/kg/ days or above-mentioned pharmaceutically acceptable salt; (ix) there is the absolute bioavailability of about 1% to about 50%; X () has the bioavailability based on the Sialic Acid Level about 0.5% to about 100% in urine; (xi) there is the mean residence time (MRT) at least about 3.5 hours.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.
In the embodiment of any described slow releasing preparation, described slow releasing preparation can through being greater than the arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours to its one or more of individual delivery treatments effective dose compound or derivatives thereof in described sialic acid approach of needs.In some embodiments, described slow releasing preparation can through time of being greater than about 12 hours or being greater than about 24 hours to its one or more of individual delivery treatments effective dose compound or derivatives thereof in described sialic acid approach of needs.In the embodiment of any described slow releasing preparation, described slow releasing preparation can through about 6-10 hour, 8-12 hour, 10-16 hour or the arbitrary time in 12-20 hour is to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach.In the embodiment of any described slow releasing preparation, described slow releasing preparation can arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach.In some embodiments, described slow releasing preparation can through the time of about 12 hours or about 24 hours to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach.In some embodiments, described treatment effective dose is delivered in individual blood flow.In some embodiments, described treatment effective dose is delivered in individual muscular tissue.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, described slow releasing preparation can through about 6-10 hour, 8-12 hour, 10-16 hour or the arbitrary time in 12-20 hour is to the ManNAc of the muscular tissue delivery treatments effective dose needed in its individuality and/or sialic acid.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation can through one or more the compound or derivatives thereofs in described sialic acid approach being greater than that the arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours treats effective dose to (namely not having the large prominent deficiency releasing (large burst) and drug availability of drug availability to blood and/or destination organization) that its individuality of needs sends substantial constant.In the embodiment of any described slow releasing preparation, described slow releasing preparation can through about 6-10 hour, 8-12 hour, 10-16 hour or the arbitrary time in 12-20 hour is to one or more the compound or derivatives thereofs in described sialic acid approach needing its individuality to send the treatment effective dose of substantial constant.In the embodiment of any described slow releasing preparation, described slow releasing preparation can arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours to one or more the compound or derivatives thereofs in described sialic acid approach needing its individuality to send the treatment effective dose of substantial constant.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, described slow releasing preparation can through about 6-10 hour, 8-12 hour, 10-16 hour or the arbitrary time in 12-20 hour to send ManNAc and/or the sialic acid of the treatment effective dose of substantial constant to the muscular tissue needed in its individuality.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor about 0.1-0.9 μ g/mL, 0.1-100 μ g/mL, 0.2-0.3 μ g/mL or 0.5-100 μ g/mL.In some embodiments, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor any one in about 0.5-80 μ g/mL, 0.5-60 μ g/mL, 0.5-40 μ g/mL or 0.5-20 μ g/mL.In some embodiments, described slow releasing preparation can to needing its one or more compound or derivatives thereofs in described sialic acid approach of individual delivery treatments effective dose, C maxfor about 0.5-40 μ g/mL.In some embodiments, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor about 0.5-35 μ g/mL, 0.5-30 μ g/mL, 0.5-25 μ g/mL, 1-40 μ g/mL, 2.5-40 μ g/mL, 5-40 μ g/mL, 0.5-35 μ g/mL, 1-35 μ g/mL, 2.5-35 μ g/mL, 5-35 μ g/mL, 0.5-30 μ g/mL, 1-30 μ g/mL, 2.5-30 μ g/mL, 5-30 μ g/mL, 0.5-25 μ g/mL, 0.1-0.3 μ g/mL, 0.1-0.8 μ g/mL, 0.2-0.4 μ g/mL, 0.2-0.5 μ g/mL, 0.2-0.8 μ g/mL, 0.1-1 μ g/mL, 1-25 μ g/mL, any one in 2.5-25 μ g/mL or 5-25 μ g/mL.In some embodiments, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor about 0.5-20 μ g/mL.In some embodiments, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor about 0.1-1 μ g/mL.In some embodiments, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, C maxfor any one in about 0.5-15 μ g/mL, 0.5-10 μ g/mL, 1-20 μ g/mL, 2.5-20 μ g/mL, 5-20 μ g/mL, 0.5-15 μ g/mL, 1-15 μ g/mL, 2.5-15 μ g/mL, 5-15 μ g/mL, 0.5-10 μ g/mL, 1-10 μ g/mL, 2.5-10 μ g/mL or 5-10 μ g/mL.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc and/or sialic acid.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise sialic acid.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, and paddy level is about 0.05-0.2 μ g/mL, 0.05-0.3 μ g/mL, 0.1-0.3 μ g/mL or 0.1-20 μ g/mL.In the embodiment of any described slow releasing preparation, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, paddy level is about 0.05-0.2 μ g/mL, 0.05-0.3 μ g/mL, 0.1-0.2 μ g/mL, 0.1-0.3 μ g/mL, 0.2-0.3 μ g/mL, 0.1-15 μ g/mL, 0.1-10 μ g/mL, 0.1-5 μ g/mL, 0.5-20 μ g/mL, 0.5-15 μ g/mL, 0.5-10 μ g/mL, 0.5-5 μ g/mL, 1-20 μ g/mL, 1-15 μ g/mL, any one or about 0.1 in 1-10 μ g/mL or 1-5 μ g/mL, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, any one in 14 or 15 μ g/mL.In the embodiment of any described slow releasing preparation, described slow releasing preparation can to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, and paddy level is about 0.05-0.3 μ g/mL.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc and/or sialic acid.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise sialic acid.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In one embodiment of the invention, by described slow releasing preparation administration every day 3 times (TID) to provide the therapeutic effect of whole day (namely about 24 hours).Such as, patient can take described slow releasing preparation approximately every 8 hours of every day.In one embodiment, described slow releasing preparation is from the about 0.5 little sialic mean maximum plasma concentration providing about 0.1 μ g/mL to about 1 μ g/mL up to about 6 hours average after first time administration.In another embodiment, described slow releasing preparation is from the about 1 little sialic mean maximum plasma concentration providing about 0.15 μ g/mL to about 0.85 μ g/mL up to about 5.5 hours average after first time administration.In another embodiment, described slow releasing preparation is from the about 1.5 little sialic mean maximum plasma concentration providing about 0.2 μ g/mL to about 0.7 μ g/mL up to about 5 hours average after first time administration.In another embodiment, described slow releasing preparation is from the about 2 little sialic mean maximum plasma concentration providing about 0.25 μ g/mL to about 0.55 μ g/mL up to about 4.5 hours average after first time administration.In another embodiment, described slow releasing preparation is from the about 2.5 little sialic mean maximum plasma concentration providing about 0.3 μ g/mL to about 0.5 μ g/mL up to about 4 hours average after first time administration.In one embodiment, described slow releasing preparation average about 6 little sialic average minimum plasma concentration that about 0.1 μ g/mL to about 0.5 μ g/mL was provided up to about 8 hours after approximately every 8 hours repeat administrations to limit.In another embodiment, described slow releasing preparation average about 6 little sialic average minimum plasma concentration that about 0.15 μ g/mL to about 0.45 μ g/mL was provided up to about 8 hours after approximately every 8 hours repeat administrations to limit.In one embodiment of the invention, described slow releasing preparation average about 6 little sialic average minimum plasma concentration that about 0.2 μ g/mL to about 0.4 μ g/mL was provided up to about 8 hours after approximately every 8 hours repeat administrations to limit.In one embodiment of the invention, described slow releasing preparation average about 6 little sialic average minimum plasma concentration that about 0.25 μ g/mL to about 0.35 μ g/mL was provided up to about 8 hours after approximately every 8 hours repeat administrations to limit.
In some embodiments of the present invention, when by described slow releasing preparation with the dosage regimen of rule to patient's administration time, provide therapeutic effect in the dosage regimen time of described rule continuously to patient.Namely after first time administration once obtain described therapeutic effect, it is lasting during the dosage regimen of rule comprising multiple dosing interval.The scheme of described rule can be the dosage regimen that the description of being enclosed by described slow releasing preparation product provides.Such as such dosage regimen can be take every day once, every day take twice, taken three times a day or take the described slow releasing preparation of four fixed amounts or variable every day.
In one embodiment, every day is that about 650mg is to the sialic acid of about 6000mg or its pharmaceutically acceptable salt, solvate or ester with the dosage regimen of rule to patient's administration total amount.In another embodiment, every day is that about 1950mg is to the sialic acid of about 6000mg or its pharmaceutically acceptable salt, solvate or ester with the dosage regimen of rule to patient's administration total amount.In one embodiment, the dosage regimen of described rule refers to and to be administered once with approximately equal dosing interval in each dosage period or repeatedly.The such as dosage regimen of every day three times (TID) represents that every day was with the dosing interval administration medicine three times of about eight hours.In one embodiment, to be administered once every day the sialic acid of about 650mg or its pharmaceutically acceptable salt, solvate or ester to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester of 650mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester of 650mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester (total amount is be about 1950mg every day) of 650mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester (total amount is be about 2925mg every day) of 975mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester (total amount is be about 3000mg every day) of 1000mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester (total amount is be about 4500mg every day) of 1500mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester (total amount is be about 4875mg every day) of 1625mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester (total amount is be about 6000mg every day) of 2000mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, be about sialic acid or its pharmaceutically acceptable salt, solvate or the ester (total amount is be about 12000mg every day) of 4000mg with the Dosage Regimens Dosage of three times every day to patient.In one embodiment, to patient with the sialic acid of the sialic acid of the about 2000mg of the dosage regimen administering drug combinations of three times every day in slow releasing preparation or its pharmaceutically acceptable salt, solvate or ester and the about 2000mg in quick releasing formulation or its pharmaceutically acceptable salt, solvate or ester (total amount is be about 12000mg every day).
In embodiments of the invention, when to patient with described in the Dosage Regimens Dosage of rule during slow releasing preparation, it provides the sialic blood plasma concentration curve of relatively flat when stable state, wherein in the blood plasma concentration curve of relatively flat, there is no substantial peak or paddy, and sialic minimum plasma concentration is enough to provide therapeutic effect to patient in the blood plasma concentration curve of described relatively flat.
In one embodiment of the invention, when to patient with described in the Dosage Regimens Dosage of rule during slow releasing preparation, it provides the sialic blood plasma concentration curve of relatively flat when stable state, make average C during dosing interval min/ C maxsialic acid ratio be about 0.40 to about 1.0, about 0.45 to about 1.0, about 0.5 to about 1.0, about 0.55 to about 1.0, about 0.6 to about 1.0 or about 0.65 to about 1.0 or about 0.7 to about 1.0 or about 0.75 to about 1.0 or about 0.8 to about 1.0 or about 0.85 to about 1.0 or about 0.9 to about 1.0 or about 0.95 to about 1.0, and C minbe enough to provide therapeutic effect.
In one embodiment of the invention, when to described in patient's administration during slow releasing preparation every day three times (TID), it is at the average C provided during stable state after patient's administration 8/ C maxsialic acid ratio be about 0.40 to about 1.0, about 0.45 to about 1.0, about 0.5 to about 1.0, about 0.55 to about 1.0, about 0.6 to about 1.0 or about 0.65 to about 1.0 or about 0.7 to about 1.0 or about 0.75 to about 1.0 or about 0.8 to about 1.0 or about 0.85 to about 1.0 or about 0.9 to about 1.0 or about 0.95 to about 1.0.
In one embodiment of the invention, described every day, the slow releasing preparation of three (TID) dosage form provided therapeutic effect to patient, continue about 8 hours, and the sialic blood plasma concentration curve of relatively flat is provided when stable state, make sialic minimum plasma concentration during dosing interval be about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of maximal plasma concentration during dosing interval.
In one embodiment of the invention, described every day, the slow releasing preparation of three (TID) dosage form provided therapeutic effect to patient, continue about 8 hours, and the sialic blood plasma concentration curve of relatively flat is provided when stable state, make sialic maximal plasma concentration during dosing interval be about 155%, 150%, 145%, 140%, 135%, 130%, 125%, 120%, 115%, 110% or 105% of minimum plasma concentration during dosing interval.
In the embodiment of any described slow releasing preparation, described slow releasing preparation to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, can drain any one be less than in about 10%, 20%, 30%, 40%, 50%, 60% or 70% after one hour.In the embodiment of any described slow releasing preparation, described slow releasing preparation to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, can drain any one be less than in about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% after four hours.In the embodiment of any described slow releasing preparation, described slow releasing preparation to the compound or derivatives thereof needing its one or more of individual delivery treatments effective dose in described sialic acid approach, can drain any one be less than in about 2%, 3%, 4% or 5% after 12 hours.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc and/or sialic acid.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise sialic acid.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation can to need its individuality send about 0.1-50g/ days, 0.5-25g/ days, 1-15g/ days, 1-10g/ days or any one in 2-5g/ days one or more compound or derivatives thereofs in described sialic acid approach.In some embodiments, described slow releasing preparation can to one or more the compound or derivatives thereofs in described sialic acid approach needing its individuality to send about 2g/ days to 5g/ days.In the embodiment of any described slow releasing preparation, one or more of any one during described slow releasing preparation can send about 0.01-750mg/kg, 0.5-500mg/kg, 1-250mg/kg, 2.5-100mg/kg or 5-50mg/kg to needing its individuality compound or derivatives thereof in described sialic acid approach.In some embodiments, described slow releasing preparation can to one or more the compound or derivatives thereofs in described sialic acid approach needing its individuality to send about 5mg/kg to 50mg/kg.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, described slow releasing preparation can to ManNAc and/or the sialic acid needing its individuality to send about 5mg/kg to 50mg/kg.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation can to need its individuality send about 0.01-750mg/kg/ days, 0.5-500mg/kg/ days, 1-250mg/kg/ days, 2.5-100mg/kg/ days or any one in 5-50mg/kg/ days one or more compound or derivatives thereofs in described sialic acid approach.In some embodiments, described slow releasing preparation can to one or more the compound or derivatives thereofs in described sialic acid approach needing its individuality to send about 5mg/kg/ days to 50mg/kg/ days.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, described slow releasing preparation can to ManNAc and/or the sialic acid needing its individuality to send about 5mg/kg/ days to 50mg/kg/ days.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation has the absolute bioavailability of about 1-50%.In some embodiments, described slow releasing preparation has the absolute bioavailability of any one in about 1-45%, 1-40%, 1-35%, 1-30%, 1-20%, 1-10%.In some embodiments, described slow releasing preparation has the absolute bioavailability of about 1-25%.In some embodiments, described slow releasing preparation has the absolute bioavailability of any one in about 5%, 10%, 15%, 20%, 25% or 50%.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise sialic acid or derivatives thereof.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation has the bioavailability being about 0.5-100% based on the Sialic Acid Level in urine.In some embodiments, described slow releasing preparation has the bioavailability being about any one in 0.5-2.5%, 1-2.5%, 2-8%, 2-12%, 2.5-20%, 2.5-40%, 2.5-80%, 2.5-100% based on the Sialic Acid Level in urine.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
In the embodiment of any described slow releasing preparation, described slow releasing preparation has the mean residence time (MRT) at least about 3.5 hours.In some embodiments, described slow releasing preparation has the MRT at least about the arbitrary time in 3,4,4.5,5,5.5 or 6 hours.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise sialic acid or derivatives thereof.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).
The combination of slow releasing preparation described herein and/or slow releasing preparation and quick releasing formulation can be sialic acid reference agent (Reference Drug).Term " reference agent ", at Federal Food and drug administration (FDA) orange paper, defines in Approved Drug Products with Therapeutic Equivalence Evaluations.The present invention includes any bioequivalence as the slow releasing preparation of reference agent and/or the combination of slow releasing preparation and quick releasing formulation.
" bioequivalence " represents when in the research of suitable design during administration, and speed and the degree of surrogate markers arrival (available) action site of the active substance in pharmacy equivalent or pharmacy substitute or active substance do not have significant difference.In one embodiment, bioequivalence is that its that extend arbitrarily that (successor) mechanism issues by U.S. food and drug administration or its defines arbitrarily.In one embodiment, bioequivalence measures according to the guide of Federal Drug Administration and standard, described guide and standard comprise from U.S.Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), " GUIDANCE FOR INDUSTRY BIOAVAILABILITY AND BIOEQUVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS-GENERAL CONSIDERATIONS " (in March, 2003 that drug evaluation and research center (CDER) obtain, revise 1), and " GUIDANCE FOR INDUSTRY STATISTICAL APPROACHES TO ESTABLISHING BIOEQUIVALENCE " DHHS, FDA, CDER (January calendar year 2001), the two is quoted with its entirety and adds herein.In another embodiment, bioequivalence measures according to the file " Note for Guidance on the Investigation of Bioavailability and Bioequivalence " (July 26 calendar year 2001 is issued, and obtains from EMEA) of European Medicines Agency (EMEA).
In one embodiment, the invention provides the preparation of sialic acid or its pharmaceutically acceptable salt, solvate or ester, the Logarithm conversion AUC of wherein said preparation display said preparation 0-tgeometric average and the Logarithm conversion AUC of sialic acid reference agent 0-tthe ratio of geometric average be about 0.80 to about 1.25.
In one embodiment, the invention provides the preparation of sialic acid or its pharmaceutically acceptable salt, solvate or ester, the Logarithm conversion AUC of wherein said preparation display said preparation 0-∞geometric average and the Logarithm conversion AUC of sialic acid reference agent 0-∞the ratio of geometric average be about 0.80 to about 1.25.
In one embodiment, the invention provides the preparation of sialic acid or its pharmaceutically acceptable salt, solvate or ester, the Logarithm conversion C of wherein said preparation display said preparation maxgeometric average and the Logarithm conversion C of sialic acid reference agent maxthe ratio of geometric average be about 0.80 to about 1.25.
Described sustained release pharmaceutical formulation can be used for parenteral (such as by injection through preparation, as bolus injection or continuous infusion), and can exist by the unit dosage form in ampoule, prefilled syringe, small size infusion container or multi-dose container.Described sustained release pharmaceutical formulation can form suspensoid, solution or Emulsion in oiliness or aqueous coal Jie thing.Or, one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described and other composition can be by the aseptic separation of sterile solid or the powder type by obtaining from solution lyophilizing, and described powder type builds by suitable vehicle (such as aseptic, pyrogen-free water) before the use.
As known in the art, for topical, described sustained release pharmaceutical formulation can be prepared for being directly applied to target area.The form being mainly used in local application takes following form, such as ointment, Emulsion (milk), gel, dispersant or microemulsion, the lotion thickening to greater or lesser degree, impregnated pads (impregnated pad), ointment or stick (stick), aerosol formulation (such as spray or foam), soap, detergent, lotion or soap-cake.Other conventionally form for this object comprises wound dressing, wraps by binder or other polymer covering, ointment, ointment, lotion, paste, jelly, spray and aerosol.Described sustained release pharmaceutical formulation can be sent via for the patch of transdermal administration or binder.Such as, ointment and ointment can add suitable thickening agent and/or gellant water or oil matrix and prepare.The drop of such as eye drop or nasal drop can with one or more compound or derivatives thereof preparations in sialic acid biosynthesis pathway in aqueous or non-aqueous base.Liquid spray can be sent easily from pressurized package.Drop can be sent via simple eye drop bottle with cover or via the plastic bottle being applicable to dropwise sending (closure via special shape) liquid contents.
In addition, in some embodiments, the sustained release pharmaceutical formulation comprising one or more compound or derivatives thereofs in sialic acid biosynthesis pathway can also use with other therapeutic combination.
Prepare the method for slow releasing preparation
Additionally provide the method for the slow releasing preparation that preparation is described in detail herein.On the one hand, combination and mix preparation component (is optionally pulverized (delump) and screening for expectation particle size range) to provide uniform preparation blend, it can be further used for preparing specific dosage form (such as tablet or capsule), such as, for oral administration.Once prepare specific dosage form, can improve to provide final medicine further it, such as, coating be carried out to the tablet formed by slow releasing preparation blend.The preparation of described slow releasing preparation can be realized by known technology, such as direct pressing, dry granulation and wet granulation.
Direct pressing can by pulverizing formulation components and screening realizes for the granularity of scope expected, described granularity can measure-alike or different from single formulation components.Subsequently by component blending, this can by one or a series of admixing step until realize all formulation components blending.If expected, by the preparation direct compression of blending, thus can provide the product of expectation, described product can be the dosage form of applicable oral administration, such as tablet.The preparation of blending can also be filled into capsule or be used in other form of administered in solid dosage forms (such as oral administration).
Can also use dry granulation to prepare the slow releasing preparation described in detail herein, and described dry granulation can be used for improving flowing or other characteristic that will form the formulation components blend of final medicine.An example of dry granulation comprises to be pulverized and/or screening formulation components, blending formulation components and blend is fed in such as chaser (roller compactor), described chaser produces the product tape of compacting, grinds the product tape of gained subsequently.Subsequently can as mentioned above by the compacting of the product of grinding or suppress with other formulation components blending further.
Wet granulation can also be used to prepare described slow releasing preparation.Such as, formulation components can be pulverized and sieve as desired size, and blending.Standard schedule can be used to add in suitable fluid bed processor by the blend of gained, and described fluid bed processor is furnished with spray gun, and it is for making the formulation components fluidisation of mixing.The particle drying (such as in fluid bed) of gained is crushed to the particle size range of expectation, and it may be used for preparing final preparation.High shear wet granulation can also be used to carry out wet granulation (during granulating, spray solvent (being generally water or other water solvent) to agglomerate, the mixing of the component of blending also repeatedly shredded simultaneously).
At where applicable, the slow releasing preparation of tablet form is preferably pressed into enough hardness, enters too early and surface indentation during preventing coating and breaking to prevent medium (such as aqueous medium).
Should understand, provide slow releasing preparation blend, such as comprise the final preparation blend (such as comprising the blend of therapeutic agent, polymer, excipient and lubricant) of therapeutic agent and all formulation components in the final product, and the intermediate preparation blend of a part containing all formulation components in the final product (such as comprise therapeutic agent and polymer but do not comprise the blend of excipient or lubricant, wherein final products contain excipient and lubricant).
Treatment and the anacid method of prevention saliva
Also provide herein and treat and/or prevent by the compound or derivatives thereof of one or more in any slow releasing preparation described in this article of effective dosage in described sialic acid approach the anacid method of saliva needed in its individuality.Described method can comprise any preparation described in detail of effective dosage herein, any preparation (including but not limited to any preparation in Table A-E and embodiment 12 and 13) that to comprise with " slow releasing preparation " be title.Therefore, although detail some preparation below, it should be understood that in any means provided in this article and can use any slow releasing preparation described herein.In a variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt and MaNAc or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises the prodrug of one or more compounds in sialic acid biosynthesis pathway, such as sialic prodrug or its pharmaceutically acceptable salt (as therapeutic agent).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt (as therapeutic agent), and comprise hydrocolloid polymer, anion, pH dependency gel formation copolymer and water-swellable, non-TCP friendly flow polymer, and optionally also comprise lubricant and/or excipient.In a specific variants, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate and hypromellose or poly(ethylene oxide).In another variant, described slow releasing preparation comprises sialic acid or its pharmaceutically acceptable salt, carrageenan, sodium alginate, hypromellose or poly(ethylene oxide), magnesium stearate and microcrystalline Cellulose and silica sol.On the one hand, described slow releasing preparation is the preparation of table E.On the other hand, described slow releasing preparation is the preparation of table 8.On the other hand, described slow releasing preparation is the preparation of embodiment 6.On the other hand, described slow releasing preparation is the preparation of embodiment 7.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, provide herein and treat and/or prevent by the ManNAc in any slow releasing preparation described in this article of effective dosage and sialic acid the anacid method of saliva needed in its individuality.In some embodiments, treat and/or prevent the anacid method of saliva and increase sialic generation.In some embodiments, treat and/or prevent the anacid method of saliva and increase the sialylated of affected tissue.In some embodiments, treat and/or prevent the anacid method of saliva to comprise administration and comprise the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, the hypromellose (such as hypromellose model 2208 or Methocel K100M) of about 20-30%w/w, the sodium alginate (such as Protanal) of about 20-25%w/w, the λ carrageenan (such as Viscarin GP-209) of about 1-5%w/w, the microcrystalline Cellulose of about 1-10%w/w and silica sol (such as sMCC HD90), the magnesium stearate of about 0.1-1%w/w/ (such as ) and about 1-5% enteric coating (such as iI white) slow releasing preparation.In some embodiments, treatment or prevention saliva anacid method comprise administration and comprise the drug loading (such as sialic acid and/or ManNAc) of about 30-60%, the poly(ethylene oxide) (such as Polyox WSR) of about 20-30%w/w, the sodium alginate (such as Protanal) of about 20-25%w/w, the λ carrageenan (such as Viscarin GP-209) of about 1-5%w/w, the microcrystalline Cellulose of about 1-10%w/w and silica sol (such as sMCC HD90), the magnesium stearate of about 0.1-1%w/w/ (such as ) and about 1-5% enteric coating (such as iI white) slow releasing preparation.
Also provide herein and increase by the compound or derivatives thereof of one or more in any slow releasing preparation described in this article of effective dosage in described sialic acid approach the method needing the sialic acid in its individuality (such as increasing the sialic generation in muscular tissue) and the generation for glycosylated contiguous substrate (cmp sialic acid).In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, the method being produced (such as increasing the sialic generation in muscular tissue) by the ManNAc in any slow releasing preparation described in this article of effective dosage and the sialic acid sialic acid increased in the individuality needing it is provided herein.
The sialylated method being increased the muscular tissue in the individuality needing it by the compound or derivatives thereof of one or more in any slow releasing preparation described in this article of effective dosage in described sialic acid approach is also provided herein.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, the sialylated method being increased the muscular tissue in the individuality needing it by the ManNAc in any slow releasing preparation described in this article of effective dosage and sialic acid is provided herein.
The method being improved the muscle function in the individuality needing it by the compound or derivatives thereof of one or more in any slow releasing preparation described in this article of effective dosage in described sialic acid approach is also provided herein.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, the method being improved the muscle function in the individuality needing it by the ManNAc in any slow releasing preparation described in this article of effective dosage and sialic acid is provided herein.
In some embodiments, relevant to the one or more genetic defectes in the sialic acid approach patient's condition also can be treated by being used in one or more in any slow releasing preparation described herein compound or derivatives thereof (no matter being current known or still undiscovered) in described sialic acid biosynthesis pathway.As shown in Figure 1; UDP-GlcNAc is changed into N-acetyl mannosamine (ManNAc) by uridine diphosphate-N-acetyl base glycosamine-2-epimerase (UDP-GlcNAc-2-epimerase), and it generates N-acetyl mannosamine-6-phosphate ester (ManNAc-6-P) by ManNAc tyrosine phosphorylation under ATP exists.By Neu5Ac-9-phosphonate ester synthetase, ManNAc-6-P is converted into N-acetyl-neuraminate-9-phosphate ester (NeuAc-9-P), passes through Neu5Ac-9-phophate phosphatase subsequently by NeuAc-9-P dephosphorylation to produce Neu5Ac (sialic acid).Then sialic acid enters nucleus, and changes into cytidine monophosphate-sialic acid (cmp sialic acid) by CMP-Neu5Ac synzyme.In some embodiments, any about ManNAc kinases, Neu5Ac-9-phosphonate ester synthetase or Neu5Ac-9-phophate phosphatase or its genetic defect combined or the patient's condition relevant with it, can treat with the compound or derivatives thereof of one or more in any slow releasing preparation described in this article of effective dose in described sialic acid biosynthesis pathway.Such as, in some embodiments, the compound that administration is such obtains the treatment to the patient's condition relevant with the defect about this certain enzyme to block specific enzyme step in described approach.Therefore, there is provided treatment to suffer from the method for the individuality of the patient's condition relevant with the genetic defect about the enzyme (such as ManNAc kinases, Neu5Ac-9-phosphonate ester synthetase or Neu5Ac-9-phophate phosphatase or its combine) in described sialic acid approach herein, described method comprises to the compound or derivatives thereof in described sialic acid biosynthesis pathway in any slow releasing preparation described in this article of described individual effective dosage.
In some embodiments, the patient's condition relevant with the defect in described sialic acid biosynthesis pathway that can be used on the treatment of the compound or derivatives thereof in described sialic acid biosynthesis pathway in any slow releasing preparation described herein includes but not limited to saliva Aciduria, glomerule low sialylated (hyposialylation), glomerular hematuria, albuminuria foot foot cytopathy, kidney condition (comprising the albuminuria because the sufficient foot cytopathy of glomerular basement membrane and/or segmental division (segmental splitting) cause and hematuria), minimal change nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis, idiopathic nephrotic syndrome and glycosylation defect (such as congenital glycosylation obstacle or muscular dystrophy).In some embodiments, relevant with the ManNac kinase deficiency patient's condition is selected from low sialylated, glomerular hematuria, the albuminuria foot foot cytopathy of saliva Aciduria, glomerule, kidney condition (comprising because the sufficient foot cytopathy of glomerular basement membrane and/or segmental divide the albuminuria and hematuria that cause), MCN, focal and segmental glomerulosclerosis, membranous glomerulonephritis and idiopathic nephrotic syndrome.In some embodiments, relevant with the Neu5Ac-9-phosphate phospho enzyme defect patient's condition is glycosylation defect (such as congenital glycosylation obstacle or muscular dystrophy).
In some embodiments, the minimizing that sialic acid lacks, sialic acid produces or sialylated PYLL analysis affects the genetic defect that sialic acid approach regulates: namely affect sialic acid generation or sialylated genetic defect is not limited to the genetic defect of direct enzyme in sialic acid approach.Like this, in some embodiments, sialic acid approach regulate in relate to affect sialic acid produce (such as defect cause sialic acid produce reduce or cause sialic acid to lack) or any potential genetic defect of sialylated (such as defect causes sialylated reduction) can treat with the compound or derivatives thereof in described sialic acid biosynthesis pathway in any slow releasing preparation described in this article of effective dose.In some embodiments, reduce sialic acid generation or reduce sialylated genetic defect (such as by affecting adjustment or the sialic acid approach other side of GNE/MNK) the compound or derivatives thereof in described sialic acid biosynthesis pathway that can be used in any slow releasing preparation described herein and treat.Therefore, there is provided treatment to suffer from and the method for individuality reducing sialic acid and produce or reduce the relevant patient's condition of sialylated genetic defect (adjustment of all GNE/MNK of defective effect as described therein or sialic acid approach other side) herein, described method comprises to the compound or derivatives thereof in described sialic acid biosynthesis pathway in any slow releasing preparation described in this article of described individual effective dosage.
Sialic acid is important concerning the suitable growth of many Organ and tissues and function, lacks sialic acid and may produce many dissimilar diseases and the patient's condition.It is important that the muscle disease of other type also shows glycosylation for muscle function.Nishino and Ozawa, Curr.Opin.Neurol.15:539-544 (2002).In some embodiments, described sialic acid lacks is myopathy, amyotrophy and/or duchenne muscular dystrophy.Rimmed vacuoles distal myopathy (Nonaka myopathy) and duchenne muscular dystrophy Hereditary inclusion body myopathy (HIBM) can be also included by the myopathy of the compositions and methods of the invention treatment.In some embodiments, the method treated and/or prevented increases the sialylated of muscular tissue.In some embodiments, as by the creatine kinase blood plasma level after measured motion, the method treated and/or prevented is improved muscle function and is reduced the muscle injury because body movement causes.In some embodiments, treatment or prevention muscle dysfunction method by independent for improvement ambulation, stair climbing, drop foot, from chair stand up and walk, grasped and operation and pulmonary function.In some embodiments, the described method genotype or expression also comprised by measuring gene GNE differentiates to need its individuality.
In some embodiments, described sialic acid lacks is the kidney patient's condition and disease (such as relate to albuminuria and hematuria those).Albuminuria relates to protein from blood leakage to urine.If the amount of the protein in urine is very high, the so this patient's condition is often called nephrotic syndrome.The disease display albuminuria symptom of a few types, comprises hypertension, infection, reflux nephropathy, diabetes and polytype glomerulonephritis (comprising minimal change nephropathy).Hematuria only represents the blood (such as gross hematuria or microscopic hematuria) in urine.In some embodiments, the method treated and/or prevented increases the sialylated of renal tissue.
In the embodiment of any described method, provide one or more compound or derivatives thereofs in described sialic acid approach for the treatment of effective dose through the arbitrary time be greater than in about 8,9,10,11,12,13,14,15,16,17,18,19,20 hours.In some embodiments, the time through being greater than about 12 hours or being greater than about 24 hours provides one or more compound or derivatives thereofs in described sialic acid approach for the treatment of effective dose.In the embodiment of any described method, through about 6-10 hour, 8-12 hour, 10-16 hour or the arbitrary time in 12-20 hour one or more compound or derivatives thereofs in described sialic acid approach of providing treatment effective dose.In the embodiment of any described method, the arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours provides one or more compound or derivatives thereofs in described sialic acid approach for the treatment of effective dose.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach that treatment effective dose is provided through about 12 hours or time of being greater than about 24 hours.In some embodiments, the blood flow to individuality provides described treatment effective dose.In some embodiments, the muscular tissue to individuality provides described treatment effective dose.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, through about 6-10 hour, 8-12 hour, 10-16 hour or the arbitrary time in 12-20 hour to provide ManNAc and/or the sialic acid for the treatment of effective dose to the muscular tissue of individuality.
In the embodiment of any described method, through one or more the compound or derivatives thereofs in described sialic acid approach being greater than that arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours provides (namely not the having the large prominent of drug availability to release the deficiency with drug availability to blood and/or destination organization (such as muscular tissue)) of substantial constant to treat effective dose to its individuality of needs.In the embodiment of any described method, through about 1-24 hour, 4-24 hour, 6-24 hour, 8-24 hour or the arbitrary time in 12-24 hour is to one or more the compound or derivatives thereofs in described sialic acid approach needing its individuality to provide the treatment effective dose of substantial constant.In the embodiment of any described method, the arbitrary time in about 8,9,10,11,12,13,14,15,16,17,18,19 or 20 hours is to one or more the compound or derivatives thereofs in described sialic acid approach needing its individuality to provide the treatment effective dose of substantial constant.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, through about 6-10 hour, 8-12 hour, 10-16 hour or the arbitrary time in 12-20 hour to provide ManNAc and/or the sialic acid of the treatment effective dose of substantial constant to the muscular tissue of the individuality needing it.
In the embodiment of any described method, one or more the compound or derivatives thereofs in described sialic acid approach being less than any one about 10%, 20%, 30%, 40%, 50%, 60% or 70% from individuality excretion after a hour.In the embodiment of any described method, one or more the compound or derivatives thereofs in described sialic acid approach being less than any one about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% from individuality excretion after four hours.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc and/or sialic acid.
In the embodiment of any described method, to need its individual administration be about 0.1-50g/ days, 0.5-25g/ days, 1-15g/ days, 1-10g/ days, 2-5g/ days, 0.2-25g/ days, 0.3-12g/ days, 0.4-10g/ days, 0.5-8g/ days and any one in 0.7-6g/ days one or more compound or derivatives thereofs in described sialic acid approach.In some embodiments, administration one or more compound or derivatives thereofs in described sialic acid approach of being about 2g/ days to 5g/ days.In the embodiment of any described method, one or more the compound or derivatives thereofs in described sialic acid approach being about any one in 0.01-750mg/kg, 0.5-500mg/kg, 1-250mg/kg, 2.5-100mg/kg or 5-50mg/kg to needing its individual administration.In some embodiments, to one or more the compound or derivatives thereofs in described sialic acid approach needing its individual administration to be about 5mg/kg to 50mg/kg.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, to the ManNAc and/or the sialic acid that need its individual administration to be about 5mg/kg to 50mg/kg.
In the embodiment of any described method, to need its individual administration be about 0.01-750mg/kg/ days, 0.5-500mg/kg/ days, 1-250mg/kg/ days, 2.5-100mg/kg/ days or any one in 5-50mg/kg/ days one or more compound or derivatives thereofs in described sialic acid approach.In some embodiments, to one or more the compound or derivatives thereofs in described sialic acid approach needing its individual administration to be about 5mg/kg/ days to 50mg/kg/ days.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.Such as, in some embodiments, to the ManNAc and/or the sialic acid that need its individual administration to be about 5mg/kg/ days to 50mg/kg/ days.
In some embodiments, be administered once every day, one or more in any slow releasing preparation compound or derivatives thereof in described sialic acid approach of twice, three times or four times effective dose.
Suitably can select according to the seriousness etc. of the age of body absorption speed, deactivation rate, discharge rate, patient, sex and the patient's condition, disease according to the amount of embodiment of the present invention to the slow releasing preparation of human administration.Clinicist can use animal model or this area can other test macro easily measure these factors.
Depend on the physiological condition of such as receptor, administration object is therapeutic or preventative and experienced doctor is known other factors, can with single dose, multidose, continuously or the mode administration be interrupted according to therapeutic agent of the present invention.The administration of one or more compound or derivatives thereofs in described sialic acid approach can be carried out or can the dosage at many intervals carry out by the time basic continous through selecting in advance.In topical and Formulations for systemic administration are all encompassed in.
In one embodiment, the invention provides treatment and need the anacid method of saliva in its individuality, it is included in slow releasing preparation described in patient's administration under fed condition, and wherein slow releasing preparation described in administration provides the absorption curve of improvement than administration in fasted condition under condition on the feed.In some embodiments, described absorption curve is by plasma concentration v. time area under curve (AUC) (relevant to the amount of absorbed medicine or bioavailability), the C through time of 8,12 or 24 hours max(medicine Cmax in blood) and T max(reach C maxtime) describe.In one embodiment, the absorption curve of improvement represents concentration-time curve that is not sharper keen and more even shape.The absorption curve of such as described improvement can represent the AUC of slightly low, slightly high or substantially the same value but have lower C maxhigher T max.In one embodiment, the average A UC measured under state is on the feed substantially similar or higher than it to the average A UC measured at fasting state.The average C measured under state on the feed maxlower than the average A UC measured in the fasted state.In another embodiment, the average C measured under state on the feed maxlower than the average A UC measured in the fasted state.In another embodiment, the average T measured under state on the feed maxhigher than the average A UC measured in the fasted state.
Unit dose and goods
Goods and the unit dose of the slow releasing preparation comprised containing one or more compound or derivatives thereofs in described sialic acid approach described herein are also provided herein.
Providing package is containing following goods or medicine box herein: (a) comprises the container of the sustained release pharmaceutical formulation containing one or more compound or derivatives thereofs in sialic acid biosynthesis pathway described herein; (b) there is the package insert being used for the treatment of and/or preventing the anacid guidance of the saliva of patient.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.
Described goods comprise container and on the container or the label be associated with described container or package insert.Suitable container comprises such as bottle, bottle, syringe etc.Described container can be made up of the material of such as glass or plastics.Described container is equipped with or contains preparation and can have sterile access port (such as described container can be parenteral solutions bag or the bottle with the stopper that can be pierced through by hypodermic needle).At least one activating agent is in the composition polypeptide.Label or package insert indicate the purposes of described compositions in individuality, and about polypeptide and the dosage of any other medicines provided and the concrete guide at interval.Described goods also can be included in business and user and it seems and comprise other buffer, diluent, filter, syringe needle and syringe by other desirable material.In some embodiments, described container is syringe.In some embodiments, described syringe is included in injection device further.In some embodiments, described injection device is automatic injector.
" package insert " refers to the description in the commercial packing being generally comprised within treatment product, and it contains about indication, usage, dosage, administration, contraindication, treats product with other of product mix of packaging and/or relate to the information that these treat the warning of the use of product.
Go back the unit dose of providing package containing the slow releasing preparation containing the compound or derivatives thereof in described sialic acid approach herein.In some embodiments, one or more compound or derivatives thereofs in described sialic acid approach described comprise ManNAc or derivatives thereof and/or sialic acid or derivatives thereof.
Describe the unit dosage forms comprising any slow releasing preparation described herein, described slow releasing preparation includes but not limited to those preparations described in detail for title with " slow releasing preparation ", any preparation in such as Table A-E, embodiment 6 or embodiment 7.These unit dosage forms can be stored in the suitable package of single or multiple unit dose, and can further by sterilizing and sealing.For the purpose of the convenience of patient compliance and simplification, the form of unit dosage forms can send described slow releasing preparation, can to unit dosage forms described in individual administration.In a variant, described slow releasing preparation is solid matter and its unit dosage forms can be prepared to tablet, capsule, wafer (sachet) and chewable tablet or not be used for the form of the tablet chewed.On the one hand, described dosage form is the form of capsule or tablet, preferably tablet form.In some embodiments, described dosage form is the form of the tablet not being used for chewing.In some embodiments, described dosage form is the form of tablet not being used for crushing.In some embodiments, described dosage form is not used for the form of the tablet chewed or crush.
The preparation of described unit dosage forms is usually directed to by volume or weight prepares the step of blend filler.Such as in the preparation of Tablet and Capsula agent, by volume slow releasing preparation blend is filled in punch die or capsule respectively.On the one hand, a collection of unit dosage forms has the same performance (medication amount of each unit dosage forms) in permissible range, described in a variant permissible range be less than 6% relative standard deviation (RSD), in another variant, be less than 8.0% or 7.8%.
Embodiment
Following examples are proposed to provide how to prepare and use complete disclosure and description of the present invention to persons skilled in the art, be not intended restriction the present inventor and be considered as its scope of invention, be also not intended to represent that following experiment is the whole or only experiments carried out.
Embodiment 1
Dry blending preparation method is used to prepare sialic acid 250mg content (strength) tablet
Experiment/material
Sialic acid (Food & Bio Research center, Inc.Kyoto Japan) is stored in aluminium foil bag at-20 DEG C.But operation and the process of prototype are carried out all at ambient room temperature.Process in which materials and tablet desiccant in bulk are stored in double-layer polyethylene bag.Evaluate sialic physical property, comprise form, granularity (passing through screen analysis), bulk density and tap density.
In order to evaluate the dissolution as one-level screening, using pocket type blending, filled by hand and hands to turn tabletting machine and preparing 50 grams of laboratory scales batch.ProCR platform is used to prepare tablet.Its formula is listed in following table 1 and 2.
The quantitative formula of table 1. sialic acid, ProCR hypromellose 250mg tablet:
Table 2. sialic acid ProCR Polyox, the quantitative formula of 250mg tablet:
Use #20USA standard screen that sialic acid, hypromellose model 2208, sodium alginate, carrageenan and microcrystalline Cellulose and silica sol are pulverized and weighed according to quantitative formula.Composition is merged in little zippered bag and blending 15 minutes.Use #40USA standard screen (screen) magnesium stearate to be pulverized, weigh according to quantitative formula and add in the blending composition in sack.By the blending three minutes again of described composition.Use bulk density, tap density, size exclusion, Ka Shi compressibility index (Carr ' s Compressibility Index) and minimum critical hole (minimum critical orifice) characterize final blend and unsized sialic acid.Korsch PH100 tablet machine is suppressed the final blend of each prototype.The stripping test of gained tablet is carried out in assay laboratory.
sialic acid characterizes
Sialic visual characteristic is the flour of white fluffy.Its bulk density is 0.293g/mL, and its tap density is 0.419g/mL.Ka Shi compressibility index is 30%, and minimum critical aperture is 18mm.Sialic size exclusion (table 3) display coarse granule as shown in Figure 2 and the distribution of medium-sized particles.Sialic acid is processed into suitable dimension (sized) before blending to promote even blend.
The sialic particle size distribution of table 3.
Screen size (sieve size (um)) Not sieved sialic acid (N-acetyl-neuraminate)
20(850) 34.16
40(425) 26.87
60(250) 15.57
100(150) 10.75
200(75) 9.3
325(45) 1.77
Pot (< 45) 1.45
ProCR sialic acid, 250mg CR tablet
Two kinds of prototype blends (ProCR hypromellose and ProCR Polyox) are pressed into tablet by the 0.3300X0.7100 inch improved ellipse shape mould of the tablet using target to be 750mg weight and 17 to 20Kp hardness range.During tabletting, observe the powder bridging (powder bridging) of ProCR hypromellose in die cavity.This shows that blend needs to increase density to improve the mobility on tablet machine.It is larger and seem on tablet machine, have better mobility that ProCR Polyox shows density.But as shown in table 4, the Ka Shi compressibility exponential sum minimum critical aperture result of ProCR Polyox shows that it also needs the process of such as granulating further.Show in table 5 and Fig. 3, the particle size distribution of Polyox prototype seems more to disperse on multiple screen size compared with hypromellose prototype.
The sialic physical characterization result of table 4.250mg
Table 5.ProCR sialic acid, the particle size distribution of 250mg tablet.
The compacting of tablet causes the weight fluctuation of the 3-5% of 750mg target.Variation is mainly due to filled by hand and poor mobility.Although weight has variation, tablet appearance and hardness are good, in the scope (as listed in table 6) of 13 to 18Kp.As shown in table 7 and Fig. 4, dissolution results shows the first order extended release curve through 12 hours.
The physical data of table 6. sialic acid 250 and 325mg tablet
ND: undetermined
The dissolution results of table 7. direct pressing prototype
* the final time point in chart is represented
Embodiment 2
Sialic acid 325mg and 500mg researches and develops the preparation of prototype
At first, two little 50 grams of dry blends batch (drug loading is increased to 43%w/w by 33%w/w) are prepared, to verify that drug release patterns is acceptable.Two kinds of compositionss are listed as hypromellose and Polyox in table 8.As described above, filled by hand in die cavity is used to carry out tabletting.
The quantitative formula of table 8. sialic acid 325mg and 500mg slow releasing tablet prototype:
Wet granulation preparation method
In order to avoid the mobility of the bridge joint during compacting and difference, batch will be extended to 1800 grams from 50 grams, and will prepare 325mg and 500mg dosage level under the tabletting characteristics using high shear method of granulating simultaneously to keep good.325mg and 500mg dosage level uses identical blend, separates before pressing.Prepare two kinds of tablet sizes: 325mg dosage level tablet has the thickness of the length of 17.7mm, the width of 9.1mm and 6.7mm; With 500mg dosage level tablet, there is the thickness of the length of 19.3mm, the width of 9.7mm and 8.0mm.Use following equipment and method to prepare these tablets.
Experiment/material
The form that whole raw material all receives by the supplier listed from table 8 uses.Batch is 1800 grams.Use following equipment:
Fielder PP1 high shear granulator
Niro-Aeromatic MP-1 multiprocessor
FitzMill JT Homoloid, is furnished with forward cutter (knives forward), 0.079 " round-hole mesh 4 Qt PK blender
Korsch PH100 tablet machine, is furnished with 0.350 " x0.6875 " improved ellipse shape mould (for 750mg tablet) and 0.374 " x0.7480 " improved ellipse shape mould (for 1154mg tablet)
Accela-cota type 24MK III (24 " coating pan)
Whole raw materials are except for magnesium stearate added PP-1 granulator and premixing 3 minutes (without shredder bar) under 300rpm impeller speed.Carry out baseline loss on drying mensuration, recording water in the hypromellose preparation of not granulating is 3.4%, and Polyox preparation is 2.9%.When mixing under 300rpm and slow chopping speed, with about 200 gram/minute water sprays.Spraying mixing is after 2 minutes, and hypromellose preparation 1.8kg batch uses the water (water spray 778g) of 43%, and Polyox preparation has sprayed the water (water spray 905g) of 52%.Granulated product to be transferred in MP-1 fluid bed and dry under the inlet temperature of 75 DEG C, until loss on drying (LOD)≤3%; Be equal to or slightly lower than the baseline moisture of preparation of not granulating.By dry granulated product by #4 order rider.Be separated and be discarded in the bulky grain that #4 sieve aperture retains.Remaining granule is processed into suitable dimension by the FitzMill of low speed, forward cutter.Subsequently blend magnesium stearate is lubricated 3 minutes.Use Korsch rotary tablet machine that final blend is pressed into tablet.Obtain after dissolution results, by non-functional Opadry II white by core tablet coating to the weightening finish of about 4.5%w/w.
Leaching condition is summarized as follows:
900mL dissolution medium: 50mM phosphate, pH 6.8
100RPM hanging basket
37℃
Time point: 2,4,6,8,12,16 or 24 hours
Carry out the blending based on the preparation of hypromellose and granulation reposefully.Hypromellose preparation processing is good, and produce the final blend with fabulous mobility, its compressibility on tablet machine is good.Batch has fabulous productive rate (96%) on a small scale.
Preparation based on poly(ethylene oxide) (Polyox) is not so easily granulated.Polyox preparation is granulated excessively (over-granulated).Can in future by alleviating granulation excessively to spray less granulation water compared with slow rate.The granulated product of a great deal of is lost when the granulated product of part drying to be divided the caking of the large excessively granulation removed can not be dry in fluid bed through 4 mesh sieves.Therefore, batch productive rate is poor 83%.But the described batch of part retained produces fabulous final blend.Its mobility and compressibility in tableting processes is good and produce the second best in quality tablet.Known Polyox is difficult to granulate, and therefore this does not expect completely.But, fabulous granulated product can be obtained with suitable grain made parameter.
The physical data of the final blend of sialic acid 325mg, sialic acid 325mg tablet and sialic acid 500mg tablet is shown respectively in table 9,10 and 11.The analysis result of sialic acid 325 and 500mg tablet (non-coating) is shown in table 12.
Table 9. sialic acid, the physical data of the final blend of 325mg:
The physical data of the sialic acid 325mg tablet of table 10. different hardness
Annotation: the meansigma methods of 10 tablets
The physical data of the final blend of table 11. sialic acid 500mg and tablet
Annotation: the meansigma methods of 10 tablets
* ND: undetermined
The analysis result of table 12. sialic acid 325mg and 500mg SR tablet (non-coating)
Two kinds of dosage level and ProCR hypromellose and the dissolution results both ProCR Polyox (Fig. 5) display were through the first order extended release curve of 12 hours.In addition, these results show, are used in the common blend of 750 and 1154 tablet final weight, and described dose ratio method successfully can provide dose flexibility.
Embodiment 3
The coating of sialic acid 325mg and 500mg SR tablet ProCR hypromellose and ProCR Polyox
Preparation method
Eight kilograms of core tablets (the active tablet of about 1.5kg and 6.5kg "false" placebo combine and reach certain volume) are loaded and are furnished with 24 " the Accela-Cota coating equipment in sugar production line of coating pan and two spray guns.Non-functional film coating is the Opadry-II white (Colorcon Corporation preparation Y-22-7719) of 20% solid concentration.Film-coated object is to improve aesthetic property and in the future contributing to improving the compliance of patient's swallow tablet.Target endpoint is the weightening finish of 3-5%.
The parameter of coating method is as follows:
Pot speed: target 12-16rpm
Inlet temperature: 70-85 DEG C
Outlet temperature: 39-42 DEG C
Bed temperature: 33-45 DEG C
Atomizing pressure: 40psi
Spray rate: 50-60g/min
Air-flow: approximately 200cfm
Rifle-bed distance: 5 "
Tablet coating is good and have no problem.The coating weight gain of about 4% is just enough to cover tablet label well.
Prototype stability
The sialic acid white film coated tablet (325mg and 500mg dosage level) use ProCR hypromellose and ProCR Polyox prepared is with every bottle of 30 (30) unit packagings, add a bag MiniPax desiccant, use Lepak Jr without a ball of string (coil) tMinduction lid sealing system induction sealing.Table 13 lists the package component of use.Pack whole acceptable tablet and in 12 months prototype stability programs under being placed on ICH condition, test the stability 0,1,3,6 and 12 months under the condition of 25 DEG C and 60% relative humidity (RH) and 40 DEG C and 75%RH.After tested and monitor the outward appearance of tablet, dissolution, moisture, assay and related substance, and initial stability result is displayed in Table 14.The stripping curve of 325mg and the 500mg tablet of coating shows in figure 6.
The list of table 13. package component
Assembly Material describes AAI?RM#
Bottle 100cc circular white HDPE (38/400) PC-3714
Closure 38mm CRC w paillon foil closure MI liner PC-3982
Desiccant MiniPax w 1.00g silica gel bag PC-2637
The analysis result of table 14. sialic acid 325mg and 500mg SR tablet (coating) initial stability
Described preparation development activities successfully determines for the sialic two kinds of different slow release prototypes of 325mg and 500mg dosage level.In the aqueous medium of pH 6.8, In Vitro Dissolution release profiles shows the first-order release through 12 hours.Use slow release ProCR platform.The unique combination of this inert polymer provides sane preparation, and it is that non-pH is dependent and be applicable to pelletization treatment and do not affect stripping release profiles.Be exactly this situation for sialic acid 325mg and 500mg dosage level SR tablet, wherein wet granulation process realizes densification and good tablet compressibility is necessary.
About chemical stability, sialic acid 325mg and 500mg ProCR hypromellose and ProCR Polyox SR tablet show acceptable assay, dissolution and content concordance and easily have passed USP testing standard.These prototypes are monitored through the ICH stability study of 12 months.
As illustrated in Figures 5 and 6, sialic acid ProCR hypromellose and the non-coating of ProCR Polyox are consistent with the stripping curve of coated tablet.Application iI white film coating does not change significantly through the elution profiles of the release of 12 hours.The analysis result of assay and related substance is acceptable, and this shows that wet granulation, drying and the art for coating chemical integrity on medicine does not affect.
Embodiment 4
ManNAc 325mg researches and develops the preparation of prototype
ManNAc title preparation is prepared according to the above method described in detail for sialic acid.The stripping curve of ManNAc 325mg tablet is shown in Fig. 7.
Core tablet result
Embodiment 5
Pharmacokinetics after male dogs single oral or intravenous administration sialic acid preparation
The object of this research is the pharmacokinetics after evaluating male dogs single oral or intravenous administration sialic acid.
From PCS-SHG group obtain altogether six male beagle dogs (domesticated dog) (at first from Beijing Marshall Biotechnology Co., Ltd.) and carry out whole body health check-up with ensure begin one's study before have normal health status.All animals are all considered to be suitable for use, and by identifying each animal in the front side of an auricle uniquely by permanent skin tattoo numeral and/or letter.In order to make animal be accustomed to laboratory environment, allow shift animal and start to have between treatment the laundering period of five days.
Before starting administration, all animals are weighed and distributes treatment group.When treatment starts, animal be the 7-16 monthly age and weight in the scope of 6.4-9.4kg.Animal is raised separately in the Rotating Stainless Steel Cage being furnished with net type floor and automatic water feeding valve.Except during the operation of specifying, every day provides the granule commercialization dog of a standard authentication to eat (dog food 5C07, PMI Nutrition International, the Inc. of about 400g certification) to each animal.Control the maximum allowable concentration (such as heavy metal, aflatoxin, organic phosphate, chlorinated hydrocabon, PCB) of contaminants in food and carry out routine analysis by manufacturer.It is believed that do not have in described food can the known contaminant of the Study of Interference object.During the operation of specifying, freely can obtain municipal tap water (it is through softening, by reverse osmosis purification and be exposed to ultraviolet light).It is believed that do not have in described water can the known contaminant of the Study of Interference object.Except between the active stage of specifying, provide a floor toy to each animal.
Research design is as shown in Table 15:
Table 15 experimental design
-=inapplicable.
# dosage level represents in a free form.
About for animal overnight fasting 16 hours fed immediately by a before each dosage after 6hr time point.
Administration first day is appointed as the 1st day.Administration natural law is subsequently the 6th, 9 and 13 day.At the 1st, 9 and 13 day, the capsule that all animal oral administrations are prepared or tablet.At the 6th day, to the TA-6 of all animal single intravenous dose 0.5mL/kg.The actual volume of each TA-6 of administration with the nearest ABW of each animal for benchmark.Test sample 1 to 6 illustrates in table 16.
The specification of table 16 test sample
Pre-test whose body weight of each administration in period and administration sky before administration.During studying, do not observe the relevant clinical sign for the treatment of and during studying, do not observe any animal and have the body weight change or body weight increase that treatment is relevant.
To collect blood sample to serum separator tube for the treatment of being the serum at following time point at the 1st, 6,9,13 day from all animals: 2 minutes (only i.v.), 5 minutes (only i.v.) before administration, after administration, 10 minutes (only i.v.), 15 minutes, 30 minutes, 1,2,4,6,8 and 24 hour.Urine sample is collected in the jar wet ice or ice bag with following interval from all animals: (to spend the night about 15 hours) before administration, after administration 0 to 4,4 to 8,8 to 12 hours at the 1st, 6,9,13 day.Sample is collected according to table 17 and table 18:
Table 17PK sample collection planning chart
X=collects sample
A collects sample before administration.
Table 18 A urine sample collection device planning chart
X=collects sample
A spent the night before each administration (about 15 hours) collects blank diaper.
Blood sample being placed under room temperature at least 30 minutes but making it solidify in no more than 1 hour, under about 2700rpm, frozen centrifugation (about 4 DEG C) continues 10 minutes subsequently.To be placed on dry ice, until be transferred to (setting remains on-80 DEG C) in refrigerator in from the serum transfers of each sample separation to polypropylene tube.Urine sample to be stored in refrigerator (setting remains on-80 DEG C) until analyze.
The analytical method verified is used (to measure the checking of the sialic method of free solubility in dog serum and urine with liquid chromatography-tandem mass spectrometry (LC-MS/MS)-PN 102653; The sialic long-term matrix stability of the free solubility evaluated in dog serum and urine with liquid chromatography-tandem mass spectrometry (LC-MS/MS)-PN 102654) measure the drug level in serum and urine by LC MS/MS.Described method has the range of linearity of 10 ~ 1000 μ g/mL and lower limit of quantitation is 10 μ g/mL.
Use from AB Sciex's collect data.Use Watson tMlaboratory Information Management System (LIMS) and Microsoft Excel carry out statistical analysis (comprising regression analysis) and descriptive statistic (comprising arithmetic mean of instantaneous value and standard deviation, accuracy and precision).
Use pharmacokinetic parameter estimated by pharmacokinetics software (version 5.2.1, Pharsight Corp., Mountain View, California, USA).The non-compartment model method consistent with intravenous or oral administration route is used to carry out parameter estimation.All parameters produce by the sialic acid concentration in individual serum.Use the standard sample time estimation parameter relative to each dosed administration.Only mean concentration derives from 3 animal/group/time points in the case of intravenous administration.Actual time point is within the aspects of specifying.The serum concentration that before using administration, time point obtains is as the concentration of oral administration time zero.Use based on the most realistic body weight of each animal the actual dose level of the SA total test sample 1 to 5 of its administration.
The linear trapezoid method with linear interpolation is used to calculate the area under curve (AUC) of the individual serum-concentration relative time of sialic acid.At least final three concentration values observed are used to determine that the end of each bulk concentration versus time plot eliminates phase.The log-linear regression of non-weighting concentration data is used to measure the slope that end eliminates phase.If determine that coefficient is less than 0.800, or be greater than 20% of the gross area when AUC is extrapolated to infinity, or can not determine that end eliminates phase, so just do not report that end eliminates relevant parameter.The parameter of observing or describing in computer chart 19.
Comprise the concentration lower than LLOQ all data from serum (except lower than zero those) be all applied to pharmacokinetic analyses.
The parameter that table 19 is estimated from sialic acid serum-concentration
Use excel 2007 calculates the sialic acid concentration of urine.Use comprise concentration lower than LLOQ all data from urine (except lower than zero those).
Total increase that after the data of urine sample calculate administration before using administration, in 12 hr urine, sialic acid is drained.Estimate the sialic acid urine drains (form with the percentage ratio of dosage) under each administrations.According to this hypothesis of dosage that the excretion of drug amount reflection in urine after oral administration absorbs, based on the sialic bioavailability of excretion numerical value percentage test after IV and oral administration.
The parameter of observing or describing in computer chart 20.
The parameter that table 20 is estimated from the sialic acid concentration of urine
The relevant clinical sign for the treatment of is not observed after oral or intravenous administration sialic acid during studying.During studying, notice number of animals 201 and 203 skin rubefaction, this is considered to accidental.
During studying, do not observe any animal has the body weight that treatment is relevant to change or body weight increase.Any weight differences or body weight increase may change with the biology estimated relation.
Individual sialic acid concentration after IV or oral administration in beasle dog serum is shown relative to the time in Fig. 8 A-8H.
TA-1
Except number of animals 103 (it is a little more than zero but lower than 20% of LLOQ), before the administration of five in six animals, the background Sialic Acid Level of sample is lower than zero.
With the TA-1 of 3250mg SA/ animal oral administration in the capsule of preparation, the peak concentration then observed is the scope of 12.6-40.8 μ g/mL.Except number of animals 103 (0.5 hour), within 2 hours, observe T upon administration max.All six animals upon administration 24 hours sialic acid concentration reduce to the level lower than zero.The number of animals 201 upon administration concentration (22.0989 μ g/mL) of 24 hours is considered to abnormal, and got rid of from analysis, because it is the value of > LLOQ, but be next the sample of three < LLOQ, its three measurable concentration then in sampling sequence.
At the end of the sampling period, it is obvious that sialic acid concentration reduces, but only to calculate the terminal elimination half-life (scope at 1.39-1.49 hour) of number of animals 103,201 and 203.
Based on the value of the individual AUC (0-t) after IV and oral administration, the bioavailability of the TA-1 of estimation 2.73% to 6.76% scope.
Before all administrations, urine sample has the sialic acid can measuring concentration, and the data of each individuality are different, and it is in the scope of 8.16-25.1 μ g/mL.Except number of animals 202 (after administration 0-4 hour), in the sample of 4-8 hr collections upon administration, observe the excretion of maximum sialic acid.The sialic acid total amount of draining in urine equals the 0.43-3.56% of the SA dosage contained in TA-1.
Based on the TA-1 of the individual urine percentage ratio excretion value estimation after IV and oral administration bioavailability 1.29% to 39.1% scope.
TA-2
Except number of animals 101 (but it is a little more than zero lower than 20% of LLOQ), before the administration of number of animals 102 and 103, the background Sialic Acid Level of sample is lower than zero.
With the TA-2 of 3250mg SA/ animal oral administration in the tablet of preparation, then within 2.00 to 4.00 hours, observe T upon administration max, the scope of peak concentration is 7.98-13.7 μ g/mL.For the animal of all administrations, sialic acid concentration is usually at T max24 little levels be reduced to constantly lower than zero upon administration afterwards.In number of animals 103, the sialic elimination half-life of estimation is 1.28 hours.For number of animals 101 and 102, the half-life can not be estimated, because measurable data deficiencies is to determine that end eliminates phase.
Based on the value of the individual AUC (0-t) after IV and oral administration, the oral administration biaavailability of the TA-2 of estimation 1.64% to 3.25% scope.
Before all administrations, urine sample has the sialic acid concentration measured of the scope of 13.5-34.8 μ g/mL.For all animals, the sample observing 4-8 hr collections upon administration has maximum sialic acid to drain.Sialic total increase of draining in urine after administration equals the 1.08-3.20% of the SA dosage contained in TA-2.
Based on urine percentage ratio excretion value individual after IV and oral administration, the bioavailability of the TA-2 of estimation number of animals 102 and 103 is respectively 2.53% and 3.73%.The bioavailability of number of animals 101 is 97.4%, and it is more obvious than other two animals higher, and this is because the percentage ratio excretion value of its IV dosage is low.
TA-3
Before the administration of all three animals, the background Sialic Acid Level of sample is lower than zero.
With 3250mg SA/ animal oral administration preparation tablet in TA-3 after, within 2.00 to 4.00 hours, observe T upon administration max, the scope of peak concentration is 6.52-17.0 μ g/mL.The sialic acid concentration of all three animals is usually at T max24 little levels be reduced to constantly lower than zero upon administration afterwards.But, because measurable data deficiencies is to determine end and eliminate mutually or AUC is extrapolated to that infinity is greater than the gross area 20%, so can not estimate the half-life of three animals.
Based on the value of the individual AUC (0-t) after IV and oral administration, the oral administration biaavailability of the TA-3 of estimation 1.46% to 4.14% scope.
Notice that the sialic acid concentration of urine sample before all administrations is a little more than LLOQ, it is in the scope of 10.1-11.2 μ g/mL.For number of animals 102 and 103, the sample observation of 4-8 hr collections is drained to maximum sialic acid upon administration, and drains to maximum sialic acid for the sample observation of number of animals 101 8-12 hr collections upon administration.Sialic total increase of draining in urine after administration equals the 0.94-2.99% of the SA dosage contained in TA-3.
Based on the value of urine percentage ratio excretion individual after IV and oral administration, the bioavailability of the TA-3 of estimation number of animals 102 and 103 is respectively 3.49% and 1.51%.The bioavailability of number of animals 101 is 85.0%, and it is more obvious than other two animals higher, and this is because the percentage ratio excretion value of its IV dosage is low.
TA-4
In the animal treated with TA-4, time upon administration more than 30 minutes, there is no measurable sialic acid.
With 5000mg SA/ animal oral administration preparation tablet in TA-4 after, except a dog (number of animals 201), most of sialic acid concentration lower than LLOQ, wherein upon administration 4 and 6 hour concentrations a little more than LLOQ.Within after administration 2.00 to 4.00 hours, observe T max, peak concentration is in the scope of 8.97-15.7 μ g/mL.For the animal of all administrations, sialic acid concentration is usually at T max24 little levels be reduced to constantly lower than zero upon administration afterwards.Because measurable data deficiencies is to determine that end eliminates phase, so can not estimate the half-life.
Based on the value of the individual AUC (0-t) after IV and oral administration, the oral administration biaavailability of the TA-4 of estimation 1.57% to 2.09% scope.
Before all administrations, urine sample has the sialic acid concentration measured of the scope at 6.4-42.6 μ g/mL.For number of animals 201 and 203, the sample observation of 8-12 hr collections is drained to maximum sialic acid upon administration, and drains to maximum sialic acid for the sample observation of number of animals 202 at 0-4 hr collections.Sialic total increase of draining in urine after administration equals the 0.54-1.93% of the SA dosage contained in TA-4.
Bioavailability based on the TA-4 of the number of animals 202 and 203 of the individual urine percentage ratio excretion numerical estimation after IV and oral administration is 1.42% and 2.55%.Because during Data correction, after administration, sialic acid excretion quality is set to zero, so can not estimate the bioavailability of number of animals 101 before by administration.
TA-5
Before all animals administers after sample and administration the background Sialic Acid Level of 15 minutes all lower than zero.
After the TA-5 of 5000mg SA/ animal oral administration in the tablet of preparation, except number of animals 201 (its upon administration 4 and 6 hours a little more than LLOQ), most of sialic acid concentration is lower than LLOQ.Within after administration 4.00 to 6.00 hours, observe T max, peak concentration is in the scope of 7.79-15.3 μ g/mL.The sialic acid concentration of all three animals is reduced to the level lower than zero usually upon administration for 24 hours.But, because measurable data deficiencies is to determine that end eliminates phase, so can not estimate the half-life of three animals.
Based on the value of the individual AUC (0-t) after IV and oral administration, the oral administration biaavailability of the TA-5 of estimation 1.47% to 1.96% scope.
Before all administrations, the sialic acid concentration of urine sample is in the scope of 2.27-23.6 μ g/mL.For number of animals 202 and 203, the sample observation of 4-8 hr collections is drained to maximum sialic acid upon administration, and drains to maximum sialic acid for the sample observation of number of animals 201 0-4 hr collections upon administration.Sialic total increase of draining in urine after administration equals the 0.02-1.70% of the SA dosage contained in TA-5.
Based on the value of the individual urine percentage ratio excretion after IV and oral administration, the TA-5 oral administration biaavailability of the number of animals 202 and 203 of estimation is 0.52% and 2.24% respectively.Because during Data correction, after administration, sialic acid excretion is set to zero, so can not estimate the bioavailability of number of animals 101 before by administration.
TA-6
Except a dog (but number of animals 102, it is a little more than zero lower than 20% of LLOQ), before the administration of most animals, the sialic acid serum levels of sample is lower than zero.
For all six animals, intravenous administration 25mg/kg TA-6, then sialic acid concentration upon administration the time point of 4 hours be reduced to the level lower than LLOQ fast, and subsequently upon administration the time point of 8 hours be reduced to the level lower than zero.Except number of animals 203 concentration that display in 6 hours is much higher upon administration compared with time point above, the concentration in animal declines usually.Sialic acid half-life of eliminating in dog was the scope of 0.56 to 1.40 hour.
Sialic acid concentration in urine between each animal is different.It should be noted, for number of animals 201, low than before administration of the Sialic Acid Level in the urine of collecting after administration, detects that after three administrations in sample concentration two are lower than zero.
IV administration causes the dosage of five animals urine excretion 72.4-87.7% in six animals.Dog (number of animals 101) display only drains 1.1% of application dosage.
The individual urine percentage ratio excretion of TA-6 is used to the data of oral liquid to regulate amount, thus calculates the sialic mark (Fu, %) absorbed.From the data reported herein, when compared with other animal in identical group, observe number of animals 101 and there is urine drains after much lower administration after IV administration, this value causing significantly higher bioavailability is estimated for its oral dose
In a word, after oral administration TA-1 to TA-5, in serum, test is to low Sialic Acid Level, and wherein major part is lower than quantitative limit.Within after administration 0.5 to 6 hour, observe the scope of peak concentration at 6.52-40.8 μ g/mL.The sialic acid elimination half-life calculated based on the serum concentration data of the intravenous dosages from TA-6 is 0.56 to 1.40 hour.Based on individual AUC (0-t) the value estimation bioavailability after IV and oral administration.Table 21 to table 23 provides sialic pharmacokinetic parameter in the serum of estimation.
Sialic pharmacokinetic parameter in the serum that table 21 is estimated
-=inapplicable.
Before all administrations, urine sample all has measurable sialic acid concentration, and corrects total increase of 12 hours sialic acid urine drains after administration with this.Compared with serum, the most of concentration detected in urine sample exceedes quantitative limit.Estimate the sialic acid urine drains (form with the percentage ratio of dosage) under each administrations.According to this hypothesis of dosage that the excretion of drug amount reflection in urine after oral administration absorbs, based on the sialic bioavailability of excretion value percentage test after IV and oral administration.Table 24 to table 26 provides the sialic urine drains parameter of estimation.
The sialic urine drains parameter that table 24 is estimated
-=inapplicable.
In a word, in this study, based on serum and the urine concentration data estimation sialic pharmacokinetics in beasle dog after single oral or intravenous administration in different preparation.
Embodiment 6
About the dog pharmacokinetics research of sialic acid slow release (SA-ER)
General introduction: the cross-over study design in normal dogs obtains dog pharmacokinetics (PK) to evaluate absorption and the pharmacokinetics of the SA-ER tablet of three kinds of different single doses.When every day be administered three times lasting seven days time evaluate the accumulated dose effect of SA-ER.
Test sample
-325mg SA-ER tablet (as example in above-described embodiment)
-gavage: be dissolved in the sialic acid powder (API) in saline with 325mg/mL
Design:
-in N=5 dog, carry out four continuous print doses research (having cleaning in 1 week); 5,10 then 15
-carrying out an independent repeated doses research: 1625mg/ dosage (=5) TID (every 8 hours), continues in 7 days (4875mg/ dog/sky)
Fasting before-administration, feed in about 4 hours after administration
-survey weekly body weight (BW)
-carry out PK sampling in administration sky and collect urine (collecting/dog in 0-24 hour)
Result:
Fig. 9-12 shows the data in graph form of result
In dog, SA-ER obtains rational steady state blood level
Although disproportionate with dosage level, serum levels show dose dependency difference
Repeat administration shows some accumulations and maintains significant paddy SA level, but does not have high peak
API gavage better (has higher C with being absorbed than SA-ER max), may be based on the absorption of stomach due to early stage
Target is wide, smooth absorption curve, does not have peak
Total silicic acid in urine shows that 2 dosage levels flatly absorb
In a word, dog PK data display repeat administration every day 3 times, although remove fast, about 10 times that paddy SA level is free sialic acid background level are maintained
Embodiment 7
The pharmacokinetics of sialic acid slow release (SA-ER) tablet of single and repeated doses is evaluated in the patient suffering from Hereditary inclusion body myopathy (HIBM)
Carry out this research to be determined at the pharmacokinetics of sialic acid slow release (SA-ER) after single and repeat administration.More particularly, following research evaluation in the patient suffering from Hereditary inclusion body myopathy (HIBM) under fasting and fed conditions with the single dose of four (4) individual dosage levels, then with pharmacokinetics (PK) parameter of the SA-ER of 7 days repeated doses of three (3) individual dosage levels.
master-plan and control method
This is the research of (open-label) of the non-blind of SA-ER in the patient suffering from HIBM, single dose (inpatient) and repeated doses (inpatient and out-patient).Research oral administration is respectively containing the sialic slow releasing tablet of 325mg (as example in above-described embodiment).With the timetable administration repeated doses of every day three times (TID).
After all screening sequences (studying the-28 to-3 days) complete, each patient enters research unit, and prove research qualified through one section 3 days single dose (fasting) period (research sky 0-3), then through the individual washout periods of outpatient service in 2 days (research sky 4-5), receive again and carry out 2 days single dose (feed) periods (research sky 6-8), 5 days outpatient service individual weight multiple drug treatments period (research sky 9-12), receive again and carry out last 2 days repeat administrations (research sky 13-14), then next day, (research sky 15) was got rid of from research unit.Each individuality receives follow-up phone call after final the eliminating about 1 week.Research sky may depend on and be recruited and the dosage level stage in yes or no continuous print nature sky.
study individual recruitment and be dispensed to treatment group
Before carrying out the relevant screening sequence of any research, each possible individuality provides Informed Consent Form.Informed consent is with written, signature and note dated informed consent form form and carry out record.Researcher by interview possible individuality and by carry out by scheme screening assessment measure possible individuality to research fitness.The possible individuality filtering out enough numbers is individual to recruit in about 24 researchs in about two (2) individual research places.Leave after acceptance test medicine or substituted depending on each situation by the patient removed from research.
At research the 0th day report, distribute unique patient code continuously by each patient qualified for this research.Identified case report form (CRF) data of described patient by this patient code in whole research.
the research persistent period
Each patient can participate in this research and continue about 4-8 week, and it comprises the treatment phase of 14 days of 7 the spend the night stops of needs in hospital unit or 1 phase unit.
After all screening sequences complete each individuality enter research unit (research sky-28 to-3) and prove research qualified through one section 3 days single dose (fasting) period (studying sky 0-3), then through the individual washout periods of outpatient service in 2 days (research sky 4-5), receive again and carry out 2 days single dose (feed) periods (research sky 6-8), 5 days outpatient service individual weight multiple drug treatments period (research sky 9-12), receive again and carry out last 2 days repeat administrations (research sky 13-14), then next day, (research sky 15) was got rid of from research unit.Each individuality receives follow-up phone call after final the eliminating about 1 week.Research sky may depend on and be recruited and the dosage level stage in yes or no continuous print nature sky.In this research, each individuality estimates that the persistent period was about 4 to 8 weeks.
patient selects and restriction
Comprise standard
Following all standards must be met for the individuality participating in this research qualified.
1. the age is necessary for 18-70 year.
2. after the essence explaining this research, and be ready before any research relative program and Informed Consent Form that is written, signature can be provided.
3. must there is the diagnosis of the record of Hereditary inclusion body myopathy (HIBM), be confirmed by gene test, owing to proving that the gene mutation of coding GNE/MNK enzyme is also referred to as having Rimmed vacuoles distal myopathy (DMRV) or Nonaka myopathy.
4. be ready and all research steps can be obeyed, be included in hospital unit or 1 the phase unit stop of repeatedly spending the night.
5. must be ready to use acceptable contraceptive device (i.e. pair Barrier method) in during participating in research and after the final dose accepting last SA-ER 30 days of the individuality that enlivens of property.
6. must conceived test be feminine gender when having the women of reproductive potential to screen, and be ready to carry out other pregnancy test during studying.Do not think that having the women of reproductive potential to comprise enters at least 2 years menopause, or at least 1 year before screening carries out bilateral salpingo ligation, or carry out those women of total hysterectomy.
Exclusion standard
The individuality meeting any following exclusion standard is underproof for this research of participation.
1. or suckling conceived when screening, or the random time plan pregnancy (self or spouse) during studying.
2. use any test product or test armarium in 30 days before screening, or before the research evaluation completing all arrangements, need any test with medicament.
3. absorb ManNAc, sialic acid or relevant metabolite in screening in first 30 days, or provide the sialic acid donor of this substrate with the form of chemicals or nutritional supplement.If used ManNAc or other substrate more than 30 days before screening, the time of use, the compound of use and dosage and dosage regimen should be recorded in the history of patient.If patient carries out substrate alternative medicine in the past, then, before this patient of recruitment, researcher must consider the aliasing effect that this therapy is possible.
4. exist serious in the patient's condition that is fierceness, with researcher viewpoint, prove to need surgical operation immediately or other treatment.
5. exist or in history to SA or its excipient allergy, judged by researcher, individuality is placed in the risk of the untoward reaction of increase.
6. exist and the Study of Interference can participate in or affect complication or the patient's condition of safety, as dysphagia.
7. exist or have any patient's condition in history, with the viewpoint of researcher, individuality being placed in the excessive risk that poor treatment compliance maybe can not complete research.
8. 3 times of the horizontal > upper limits of normal (ULN) of serum transaminase (ALT, AST, GGT), or serum creatinine > 2.0mg/dL.
The Drug therapy of forbidding
If patient uses any test product or test armarium in screening in first 30 days, or they needed any test with medicament before the research evaluation completing all arrangements, then they can not be recruited.In first 30 days of screening and absorb N-acetyl-D-MANNOSE amine (ManNAc), sialic acid or relevant metabolite in whole research, or the sialic acid donor of this substrate is provided to forbid with the form of chemicals or nutritional supplement.If used ManNAc or other substrate more than 30 days before screening, then the time of use, the compound of use and dosage and dosage regimen are recorded in the history of patient.If patient carries out substrate alternative medicine in the past, then, before this patient of recruitment, researcher considers the aliasing effect that this therapy is possible.
Within first 4 days, within the 15th day, get permission to leave (discharge) from research unit to research from screening, patient does not allow use ethanol, medicated cigarette or anyly comprise the product of nicotine, any food or beverage comprising caffeine, or grapefruit or any product comprising grapefruit.
The Drug therapy allowed
Except the medicine clearly forbidden, patient can accept concurrent medication on request.If patient uses any medicine except SA-ER, patient will record the reason of date and time, medicine name and the use medicine using medicine in drug administration diary.
Any concurrent medication or other treatment is recorded, together with dosage and treatment persistent period in the medical records and CRF of patient.
clinical trial supply and management
Preparation, Package and label
The sialic acid slow releasing tablet (SA-ER tablet) used in this study is the white, ellipse, the film coating tablet that comprise the sialic acid active component of 325mg as example in above-described embodiment, and weight is approximately 780mg (43% activating agent).Described tablet is used for oral administration and researches and develops to make active component (SA) sustained release up to 24 hours.The all excipient (non-activity) comprised in tablet formulation meet USP or USP NF outline specification, and are commonly considered as safe (GRAS).The product being derived from animal is not used when preparing described tablet.Carry out drug products (tablet form) according to Good Manufacturing Practice and Quality Control of Drug (GMP) rule to prepare, pack and label.
SA-ER 325mg tablet is bottled and labelled.Each bottle label, tablet quantity in the qualification of displaying scheme numbering on described label, city title, country and sponsor's postcode, content and what bright (" sialic acid slow releasing tablet, 325mg "), bottle, lot number, condition of storage and statement (" noting: new drug-by federal (US) legal restrictions is for research uses ").
Drugs administration
In the single dose phase, the SA-ER tablet of the individual dosage level of the oral acceptance of patient four (4), and in three (3) individual dosage levels is accepted in the repeated doses phase.During repeat administration, every TDD is divided into 3 dosage in the morning, at dusk and h.d. (qHS) give (see below).Not administration placebo or expression activitiy agent, and based on non-blind administration drugs.
24 patients be recruited respectively are continuously allocated to specific dosage level, and the single dose accepting twice same dose level exposes (fasting and feed).Low dosage quota (filled) was from generation to generation made before distribution higher dosage from generation to generation (cohort).Then patient is dispensed to acceptance repeated doses scheme.Lower repeated doses quota was from generation to generation made before carrying out higher repeated doses level.Dosage level is as follows.
Single dose:
650mg(n＝6)
1,950mg(n＝6)
2,925mg(n＝6)
4,875mg(n＝6)
Multiple dosing:
650mg TID (1,950mg/ days; N=8)
975mg TID (2,925mg/ days; N=8)
1,625mg TID (4,875mg/ days; N=8)
When patient is restricted to hospital or 1 phase unit, by the drugs of Field Force's administration single dose.For repeat administration scheme, distribute the drugs of supply in 7 days with the dosage level of order-assigned to each patient, together with Drug Accountability daily record (drug accountability diary).
Patient's use water is instructed to take SA-ER, according to following timetable every day three times: morning (7:00AM-9:00AM), at dusk (5:00PM-7:00PM) and h.d. (qHS; 10:00PM-12:00AM).For forgetting that the probability of taking medicine is prepared, after instructing patient at the appointed time 6 hours at the most, but at least before taking with post dose, within 2 hours, take the dosage missed.Patient does not take doubling dosage.Require that patient intactly swallows the tablet of institute's administration, and do not crush or chew them.
As shown in research approach (Figure 13), sequentially study dosage level, proceed to higher exposure level from lower exposure level.Under each single dose level, it is stage that recruitment adds, make the dosage level accepting current research first week no more than two patient of this dosage level, suppose do not have significant adverse events to occur two patients at first after accepting the dosage studied, all the other 4 patients of this dosage level are in next week or be shortly after that treated.Once all 6 patients have accepted the single dose of given dose level, then start the repeat administration to expose (being divided into TID dosage) this every day.
As implied above, in this research, maximum every daily dose of SA-ER is 4,875mg, with the form administration of 1,625mgTID.The maximum persistent period of institute's drugs administration, be then single dose be cleaning phase of 2 days, and then second single dose (if be suitable for, not having cleaning subsequently) is then the TID administration phase of 7 days.Depend on that recruitment adds and the dosage level stage, research sky can be or can not be continuous print.
Monitoring compliance
During single dose, patient be limited in hospital or 1 the phase unit, in this time, distribution drugs, and taking under the supervision of personnel at the scene.For repeat administration scheme, distribute the drugs of supply in 7 days to each patient with the dosage level of order-assigned, and require the self administration of its drugs of holding the record in Drug Accountability daily record.When checking this daily record in research when within the 13rd day, patient returns research unit, and collected by Field Force before research is got permission to leave on the 15th day.Field Force holds the record to all medicines being distributed to each patient.
Blind if (blinding) program
This is non-blind research.When patient research the 0th day in hospital or 1 phase unit report time, it is sequentially dispensed to the SA-ER dosage group of non-blind.
search procedure and assessment
Program Type and order
The overall procedure of described research illustrates in fig. 13.
Screening assessment
Before the research the 0th day receiving research unit, about 3 to 5 days (allowing 28 days at the most) screens possible research participant.Screening sequence comprise obtain medical history, carry out health and neurologic examination, acquisition Clinical Laboratory test sample (test of hematochemistry, hematology, urinalysis, infective virus [hepatitis A, B and C and human immunodeficiency virus] disease and urine pregnancy tests [only women]), and record vital sign (after the 5min that sits quietly, comprise heart rate, blood pressure, respiratory frequency and temperature), height and body weight and early stage Drug therapy.
After the result of assessment screening and assessment, meet and to comprise with exclusion standard and the patient that there is not the reason of other any eliminating is considered to for recruiting into research is qualified.
Screen unsuccessfully
Individuality if possible provides the Informed Consent Form of having signed, but does not meet and comprise and exclusion standard, or is considered to be not suitable for participating in test due to other any reason, and he or she is considered to screen unsuccessfully, and is not required or allows to participate in further research.In the CRF of possible individuality, record the eliminating reason of possible individuality and make the date and time of the decision getting rid of described individuality.
The single dose phase (the 0th day to the 7th day)
The reception of first single dose and administration (fasting)
The patient meeting screening criteria the research dusk of the 0th day enter hospital unit or 1 the phase unit.Upgrade medical history and check the lasting compliance to Engage of standard.Carry out health and neurologic examination, comprise body weight, and repeat all screening Clinical Laboratorys test.In addition, obtain blood sample and be used for the analysis of summation free sialic acid.Record vital sign and concurrent medication.
Research the 0th day, by patient's order-assigned to dosage group, starting with lowest dose level, is then the later step being assigned to higher dosage.It is stage that recruitment adds, make the dosage level accepting current research first week no more than two patient of this dosage level, suppose do not have significant adverse events to occur two patients at first after accepting the dosage studied, all the other 4 patients of this dosage level are in next week or be shortly after that treated.
Untoward reaction (AE) (by follow-up screening) is monitored continuously by the spontaneous report when adverse events occurs in whole research.Drug Accountability is recorded after each distribution drugs.
Research the 1st day, (nominal) time point 0,4,8,12,16,20 and 24 hr collections blood sample on paper to measure the baseline 24 hours of free SA, the serum levels of time match, and set up the day-night cycle of SA level.The blood collecting time that record is actual, and its predetermined acquisition time ± 30 minutes within (except 0 time time point).From first day 10:00PM (evening before administration) until research second day 10:00AM (the administration same day), patient is not per os acceptance except required water.
Research the 2nd day, at initial single dose and the 240mL water of about 8:00AM administration institute drugs, and before administration within 30 minutes and following nominal time point collect the blood sample being used for PK and measuring: after administration 10,20 and 30 minutes and 1,2,4,8,12,16,20 and 24 hour.The blood collecting time that record is actual, and its 10,20,30 minutes and 1 hours point ± 5 minutes within, 2 hours points ± 15 minutes within, and all the other all time points ± 30 minutes within.Before administration within 30 minutes and administration after 6,12 and 24 hour record vital signs (sitting quietly).Record AE and any concurrent medication.
Research the 3rd day, 0 time, (identical with during research the 2nd day 24) obtained the sample being used for summation free sialic acid.Record vital sign, AE and any concurrent medication.After enforcement all research program of the 3rd day, research the 3rd day morning patient from hospital unit or 1 the phase unit get permission to leave.
The administration (feed) of second single dose
The research dusk patient of the 6th day return hospital unit or 1 the phase unit.At this moment, they accept health/neurologic examination (comprising body weight), and if be applicable to (only women), carry out urine pregnancy test.Record vital sign (sitting quietly), concurrent medication and AE.
Research the 7th day, at about 8:00AM, within edible full fat/proteins after the meal 30 minutes, second single dose of administration institute drugs (dosage identical with research the 2nd day) and 240mL water.Before administration within 30 minutes and following nominal time point collect the blood sample being used for PK and measuring: after administration 10,20 and 30 minutes and 1,2,4,8,12,16,20 and 24 hour.The blood collecting time that record is actual, and its 10,20,30 minutes and 1 hours point ± 5 within, 2 hours points ± 15 minutes within, all the other all time points ± 30 minutes within.Before administration within 30 minutes and administration after 6,12 and 24 hour record vital signs (sitting quietly).Record AE and any concurrent medication.
The repeated doses phase (studying the 8th day to research the 14th day)
Research the 8th day, 0 time (identical with during research the 7th day 24), obtain the sample being used for summation free sialic acid.Record vital sign, AE and any concurrent medication.Patient is sequentially dispensed to repeated doses scheme (as described above).Give patient enough supplies of the institute's drugs for TID administration in 7 days, and comprehensively administration illustrates (comprising drug administration daily record), or arrange individual date after a while return hospital or 1 the phase unit carry out drugs distribution and make a house call.Individual before getting permission to leave hospital or 1 the phase unit take the predose of its repeated doses drugs.
Depend on that recruitment adds and the dosage level stage, research sky yes or no continuous print.Therefore, research the 8th day most of individuality under the drugs not accepting 7 days repeat administrations from hospital or 1 the phase unit get permission to leave.For these patients, in order to distribute the object of the drugs of TID administration in 7 days, other research is needed separately to make a house call.This make a house call from hospital or 1 the phase unit arrange before getting permission to leave.This make a house call occur in research the 8th day from hospital or 1 the phase unit get permission to leave after 1 week 4 weeks at the most.In order to the object studied, this is made a house call and is considered to restarting of these individual researchs the 8th day.
Make a house call period in the distribution of this drugs, record AE and concurrent medication.Give patient enough supplies of the institute's drugs for TID administration in 7 days, and comprehensively administration illustrates (comprising drug administration daily record).In hospital or after 1 phase, their predose of repeated doses drugs was taken by unit, patient gets permission to leave.
The research dusk patient of the 13rd day return hospital unit or 1 the phase unit.Now, they accept health/neurologic examination (comprising body weight).Record vital sign (sitting quietly), concurrent medication and AE.The drugs tablet of remainder is counted.In research unit, patient continues repetition TID administration.
Research the 14th day, before the administration in morning (at about 8:00AM) of drugs within 30 minutes (when 0) and afterwards time point 4,8,12,16,20 and 24 hr collections be on paper used for the blood sample that PK measures, to check the steady-state level of free sialic acid.The blood collecting time that record is actual, and its acquisition time arranged ± 30 minutes within (except 0 time time point).Record is the vital sign (sitting quietly) of 6,12 and 24 hours within 30 minutes and after morning dose before administration.Record AE and any concurrent medication.
Get permission to leave research (studying the 15th day)
Research the 15th day, 0 time (identical with during research the 14th day 24), obtain the sample being used for summation free sialic acid.Record vital sign, AE and any concurrent medication.Obtain any remaining drugs from patient, and do not take other dosage.Unless there are any residual safety problem, after carrying out all research the 15th day program, after deliberation person judge, then patient from hospital unit or 1 the phase unit get permission to leave.
In the end think that patient completes research; Complete research to get permission to leave program for the 15th day.
Vital sign
Vital sign (after sitting for 5 minutes, record, comprises heart rate, blood pressure, respiratory frequency and body temperature) is assessed when screening and in the every day of three inpatient study periods (studying 0-3,6-8 and 13-15 days).Research the 2nd, 7 and 14 days, (before the research predose of the 14th day) and 6,12 and 24 hour record vital signs afterwards within 30 minutes before administration.Screen time and research the 0th, 6 and 13 day measure body weight.
Concurrent medication is monitored
When using concurrent medication, record their use.
Pharmacokinetic Assessments
The free sialic steady-state level of solubility in serum is included in after repeat administration to the evaluation of the pharmacokinetics of SA-ER.
Research the 1st day, time point 0,4,8,12,16,20 and 24 hr collections blood sample on paper to measure the baseline 24 hours of free sialic acid (SA), the serum levels of time match, and set up the day-night cycle of SA level.The blood collecting time that record is actual, and its predetermined acquisition time ± 30 minutes within (except 0 time time point).
Research the 2nd and 7 days, before administration drugs within 30 minutes and within 10,20 and 30 minutes and 1,2,4,8,12,16,20 and 24 hour, get blood at nominal time point afterwards and analyze for PK.The blood collecting time that record is actual, and its 10,20 and 30 minutes and 1 hours point ± 5 minutes within, 2 hours points ± 15 minutes within, and all the other all time points ± 30 minutes within.
Research the 14th day, before the administration in morning (at about 8:00AM) of drugs within 30 minutes (when 0) and afterwards time point 4,8,12,16,20 and 24 hr collections be on paper used for the blood sample that PK measures, to check the steady-state level of SA.The blood collecting time that record is actual, and its acquisition time in reality ± 30 minutes within (except 0 time time point).
The cumulative volume of the blood collected
In order to all arrangements research assessment collected by the cumulative volume of blood be about 219mL.
the consideration of statistics and the analysis of plan
Sample size is evaluated
Estimate that the single dose phase is often organized sample size that 6 and repeat administration phase often organize 8 and provides enough information to meet the target of this research.Sample estimates amount is carried out by the number of patients needed for assessment PK parameter evaluation.According to the PK research before in history in rare disease, it is enough for determining that each dosage group 6 to 8 patients measure for PK, particularly under slow release characteristic slowly.Sample size is each dosage group 6 to 8 patients, and believes that dosage-levels of drugs relation that 24 patients show altogether is enough to plan the dosage level for research in the future.
Pharmacokinetic analyses
Free sialic acid and metabolite thereof use specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method to carry out quantitatively.Measure the serum-concentration of free sialic acid, result data is listed and tabulates.
the responsibility of clinical trial supply
Store and process
Clinical trial supply be stored in control room temperature, cover high light and leave the place of the safety on ground.
At each drug metabolism sampling time point, get 3.5mL blood and put into serum separator tube, and rotate 20 minutes with 2000RPM (or equal conversion) at 4 DEG C.Separation of serum transfer is two equal aliquots, and be stored in-70 DEG C of refrigerators vertically before analysis.
Result-pharmacokinetic data
It is the PK data of single dose administration acquisition under the fasting of 650mg (Figure 14), 1,950mg (Figure 15), 2,925mg (Figure 16) and 4,825mg (Figure 17) that Figure 14-17 shows for people's patient dose.Figure 18 display is for people patient's repeated doses (650mgx3; 1,950mg) administration obtain PK data.Figure 19 shows different repeated doses (975mgx3; 2,925mg) administration obtain PK data.Observed horizontal exceeding normal patient level, and its with start in HIBM disease to occur before observe during one's childhood be on close level.This shows that this level is clinical relevant.In addition, the data of Figure 18 and 19 show to achieve fabulous homeostatic control level (not having substantial peak or paddy), and sufficiently high concentration is the twice of normal value all day and whole night continuously at which level.
Embodiment 8
1 phase clinical ER/SA research: interim (interim) safety research
Carry out the 1 phase research that title is " safety of sialic acid slow release (SA-ER) tablet in the patient suffering from Hereditary inclusion body myopathy (HIBM) of assessment single and repeated doses and the 1 phase research of pharmacokinetics ".Safety in HIBM patient of described research assessment single dose and 7 days repeat administration SA-ER and pharmacokinetics (PK).In HIBM patient, carry out this research because compared with normal healthy volunteer, the sialic acid deficiency state in HIBM patient fundamentally can change the metabolism of active component.Original scheme comprises and uses 325mg tablet format (see table 8, containing the hypromellose) dosage of 4875mg/ days at the most, is revised as to comprise using the 500mg tablet format other generation of 6000mg/ days subsequently.500mg tablet and 325mg tablet are same recipe, and researching and developing it is conveniently to the SA-ER of patient's administration more high dose.
The objectives of this research are as follows:
Evaluate on the feed with the safety of days single dose of 650mg, 1950mg, 2925mg, 4875mg and 6000mg/ under fasting.
Evaluate that repeat administration dosage is 1950mg/ days, the safety of the SA-ER of 2925mg/ days, 4875mg/ days and 6000mg/ days (by its decile and be administered three times every day, continue 7 days).
Measure the PK of SA-ER, it is included in the C of single dose under feed and fasting maxand AUC, and the steady-state level after repeat administration.Also can measure the background baseline SA level in HIBM patient.
It is the optimal choice 2 phases determining dosage.
research design
Recruit 27 HIBM patients altogether in two (2) individual research places, but only have 26 to accept medicine.Accept SA-ER tablet at single dose phase individuality so that in five (5) individual dosage levels is oral, and accept SA-ER tablet in the repeated doses phase so that in four (4) individual dosage levels is oral.The individuality of recruitment is sequentially dispensed to specific dosage level, and accepts two single doses exposure (fasting and fed conditions) with the dosage level distributed.Then specified individual accepts a repeated doses scheme.During repeat administration, every TDD is equally divided into three dosage, and in the morning, at dusk and h.d. (qHS) give.Not administration placebo or expression activitiy agent, and based on non-blind administration drugs.
When individuality is restricted to hospital or 1 phase unit, by the drugs of Field Force's administration single dose.Single dose level is as follows: 650mg (n=6); 1950mg (n=6); 2925mg (n=6); 4875mg (n=4); With 6000mg (n=6).For repeat administration scheme, distribute the drugs of supply in 7 days with the dosage level of order-assigned to each patient, together with Drug Accountability daily record.Multiple dose level is as follows: 650mg TID (1950mg/ days; N=8); 975mg TID (2925mg/ days; N=8); 1625mg TID (4875mg/ days; And 2000mg TID (6000mg/ days n=6); N=6).
As shown in figure 20, dosage level is sequentially, from the lower exposure proceeding to higher level.Under 650mg, 1950mg, 2925mg and 4875mg single dose level, it is stage that recruitment adds, make under same dose level, at least two individual acceptance two single doses (fasting and fed conditions), then all the other four individualities of administration.All the other four individual carrying out depend on the safety features of observation.Once all 6 individualities have accepted the single dose of given dose level, then start the repeat administration to expose (being divided into TID dosage) this every day.Individuality in the generation of 6000mg/ days by recruit treatment and not stage by stage.Comparatively low dosage repeated doses quota was from generation to generation made before carrying out higher repeated doses level.
result of study
Below present the preliminary safety in research and pharmacokinetics result.
preliminary safety results is summed up
recruit
Individual recruitment state and the distribution for the treatment of group is shown in table 28 below and table 29.Altogether screen 37 patients, recruit 27.26 (26) individualities complete administration, one by one body premature termination (before administration), and eight (8) individual individualities recall agreement before by administration.All individualities at least by administration dosage, complete all administrations.
In 650mg, 1950mg, 2925mg and 6000mg single dose generation, every administration from generation to generation 6 patients.In 1950mg/ days and 2925mg/ days multiple dose generations, every administration from generation to generation 8 patients.4875mg has 4 patients in the single dose phase from generation to generation, has 6 patients in the repeated doses stage.6 individualities are always had at 6000mg dosage level (single and duplication stages).The dosage group (individual 101-010B and 102-004B) of two individualities in the 6000mg dosage generation before this research is participated in early days.
8 patients exit research before administration altogether, and these exit is due to following reason: recall agreement (individual reason) for 3,4 are screened unsuccessfully (1 GGT level having a rising, do not make a definite diagnosis HIBM for 1,2 have the concurrent medication forbidden).Body premature termination (namely before initial treatment) one by one.Body is qualified and agrees to one by one, but the non-administration because 6000mg is full from generation to generation.Do not have individual to exit due to adverse events, and do not have individual at initial dose backed off after random.
Table 28 patient enrolment *state & dose distribution
Table 29 patient enrolment * state & dose distribution (Cont ' d)
* be recruited=comprise all patients taking the medicine of at least one dosage.
B=represents that patient participates in twice research with two different dose distribution.
Table 29 patient enrolment and dosage component when recruiting are joined
Table 29 patient enrolment and dosage component when recruiting are joined (Cont ' d)
102-004B Be recruited 6000 6000
102-013 Be recruited 6000 6000
102-014 Be recruited 6000 6000
101-020 Be recruited 6000 6000
101-010B Be recruited 6000 6000
B=represents that patient participates in twice research with two different dose distribution.
adverse events (AE)
death and other significant or serious adverse events (SAE)
Do not report death and other significant or serious adverse events (SAE) in this study.
adverse events (AE)
The summary of all AE is shown in table 30.16 (61.5%) report, 31 adverse events altogether in the individuality of 26 administrations.It is slight or moderate for evaluating all events.Report that three events have unknown result: 1) think and the bronchitis that studied medicine has nothing to do; 2) think equally and the cough (these two events are from identical individual 101-016) that studied medicine has nothing to do; And 3) tip edema (finger swelling) from first 4875mg single dose that day, and its be considered to may relevant with studied medicine (individual 101-017).
The adverse events that rises from all around is had to be rated as moderate: 1) to think wound (the individual 101-001) owing to falling down had nothing to do with studied medicine; 2) fatigue/tired (the individual 101-008) that start after 3 days of 1950mg single dose, it disappeared in 1 day, and its be considered to may be relevant with studied medicine; 3) completing the 2925mg repeated doses phase (after namely research is got permission to leave on the 15th day, and notice during follow-up phone call) after the headache (individual 102-008) that starts that day, it disappeared in 2 days, and its be considered to may be relevant with studied medicine; And 4) before initial drugs 2 days report backache (individual 102-014), it is disappearing on the same day, and its be considered to studied medicine have nothing to do.
All 31 adverse events of current report, 16 is what possible be correlated with, and 2 in 16 events are moderate and disappear (as described above), and remaining 14 event is slight, and all disappear except together.What do not disappear has unknown result together.Be assessed as 14 slight adverse events to have:
Five gastrointestinal tract (GI) diseases, wherein three occur in the patient (individual 101-003) of a 1950mg dosage, and seem not to be treat (emergent) that cause, " food stagnates (heavy in stomach) in stomach " is slight together, and occur in the first day (individual 101-008) of 7 days administration phases of 1950mg dosage, and " xerostomia " occurs in 7 days treatment phases (individual 102-005) of 1950mg continual cure together;
Fatigue slight is together reported, its disappeared in one day (individual 101-003) under 1950mg dosage;
The event of unable/malaise together occurs at the first day of 2925mg dosage, and it is slight, and disappear when continual cure (individual 102-002);
In body one by one, (individual 101-013) is in each backache and the leg pain event together that occur on the same day, and starts between its single dose phase to 1 all treatment phase under 2925mg dosage level;
In the drowsiness together event (individual 102-004) of the 1st day of 7 days administration phases of 1950mg dosage;
In the event of throat pain together (individual 101-008) of second day of 7 days treatment phases of 1950mg dosage level;
Each mild headache event together in 2 individualities, it disappeared in one day, and reported at the first day of 7 days administration phases of 4875mg dosage (individual 101-012) and 6000mg dosage (individual 102-004B);
The swelling of finger together (tip edema) event under 4875mg single dose level, it is slight, and has unknown result (individual 101-017).
Modal adverse events is GI disease.3 patients report, six GI events altogether, and in 6 events 4 are from the patient of under 1950mg dosage (individual 101-003).Think that these three of rising from all around in event in individual 101-003 may be correlated with, and they occur in 7 days treatment phases before and treatment time same time.But the time seems not to be reflected as treatment and causes event, and does not have GI event in the highest 6000mg dosage group.The pattern of disorder of gastrointestinal tract is not had to show the effect for the treatment of or dosage is relevant.The sialic amount of picked-up is far below the amount produced needed for osmotic diarrhea (fecal incontinence namely observed under the highest 2000mg/kg dosage level in the chronic toxicity research of dog), but based on these results, this effect is uncorrelated with clinical research.
In general disease, 4 individualities altogether occur tired, unable or point swelling.Event duration one day or two days, and it disappears (the individual 102-002 under 2925mg dosage) when continuing research or when treating.The substantive myasthenia that these individualities suffer from and fatigue are the common symptons of HIBM patient.Do not observe tired pattern and be indicated as the problem for the treatment of and causing.Tired event is not had in the maximum dose level group of 6000mg.
The summary of all adverse events of table 30
In a word, the adverse events observed so far is inapparent, does not show dose relationship and does not show the untoward reaction pattern of any rational safety effects under any dosage level.The scope of the adverse events observed and type are common, and not for showing that SA-ER has dose-dependant pattern that is that any medicine of any recognizable untoward reaction is correlated with or incoherent event in these 26 individualities.
clinical assessment
medication history
The comprehensive medication history obtained when screening.This history is checked during the qualification that each possible individuality of mensuration adds for recruitment.
Generally speaking, individually prove to have serious (profound) amyotrophy of expectation and weak.Observe multiple other for the representational patient's condition of this age group (29 to 61 years old) patient.
physical examination
Screening and carrying out complete health and neurologic examination in research when within the 0th, 6 and 13 days, each patient is in hospital or 1 phase unit report.Neurologic examination comprises the assessment to cognition, cranial nerve, motor function, coordination and gait, reflection and sensory function.
Unexpected discovery is not had when baseline.It is serious weak that individual general display lower limb and upper limb affects arriving of the moderate of gait and muscular strength.The indication that the weak or muscular strength do not increased in this study is lost.
vital sign
Do not observe significant discovery.Generally speaking, when baseline and during research systolic pressure and diastolic pressure in low normal range.Other vital signs all are inapparent.Not significant is obvious extremely, by not changing when treating.
clinical Laboratory is assessed
The Clinical Laboratory assessment carried out in this experiment is listed at table 31.
The Clinical Laboratory test list that table 31 carries out
Abbreviation: SGOT, serum glutamic oxalacetic transaminase; SGPT, serum glutamic pyruvic transminase
Often observe several slight Clinical Laboratorys when screening abnormal, but obviously do not treat the exception caused.Observe following common exception:
Generally speaking, it is discovery known in HIBM patient that the creatine kinase observed raises, and expects.These abnormal level range from mild are higher than about 2-3 times of normal range to normal range, and it exists when baseline.Not with the pattern for the treatment of change.
Low kreatinin is observed in Most patients.When baseline, kreatinin normally normal level about 1/2, and not with treatment change.This discovery is most possibly due to the low muscle quantities of HIBM patient, and it causes the total amount of kreatinin to reduce.
Observe urine uric acid level low in these individualities when screening, and it is not with treatment change.Low urine uric acid level may upgrade relevant with purine degradation with low muscle quantities (as kreatinin) and a small amount of adenosine-5 '-triphosphate (ATP).Do not show that SA-ER does not cause disadvantageous secondary nucleotide metabolism to upgrade with treatment change.In other words, sialic acid needs to add cytidine triphosphate (CTP) (CTP) and becomes cmp sialic acid carrier.If CTP is excessively consumed, this will cause needing ATP degraded increase to carry out equilibrative nucleoside acid concentration, and can generate by purine degradation the uric acid increased.Do not occur based on this degradation pathway of these results.
When baseline, alkali phosphatase is low in many individualities, and this is not with treatment change.This result can reflect in HIBM patient that lacking body movement and less bone upgrades.
When baseline, lipase and LDH marginally raise in some individualities.Also notice MIN low hemoglobin and/or hematocrit, numeration of leukocyte change, appropriateness or the transaminase level on border.Do not observe and the relation for the treatment of.
safety Conclusions
In a word, based on AE characteristic, there is not SAE and treat in any parameter (AE, physical examination, vital sign and Clinical Laboratory assessment) upper nothing the change caused, the medicine studied is well-tolerated in this group HIBM patient.So far the adverse events characteristic observed is inapparent, does not show dose relationship and does not show the untoward reaction pattern showing to have any significant safety effects.Do not observe possible problem (such as due to the diarrhoea of sialic acid load), and not for the dose-dependence of GI symptom.In 2 patients, observe fatigue, but disappear.Consider universality tired and weak in this crowd, lack dose-dependant change and disappeared by treatment in 1 case, fatigue seems not to be treat the phenomenon caused.
Based on the safety evaluation so far in the research of this 1 phase, there is no security concern for continuing to for 2 phases.
preliminary pharmacokinetic result is summed up
recruit
Obtain from 26 individual data (fasting and fed conditions) under (being divided into every day three times (tid)) 5 single dose levels and under 4 of lasting 7 days.The recruitment of patient in different generations is shown in table 32.
pK data collection
Each individuality in generation is carried out free sialic acid (SA) assessment of baseline time series by the program, administration SA-ER, and collects PK as follows and carry out SA assessment:
1st day: 24 hours monitor SA levels as baseline to set up the day-night cycle of free sialic acid level.
2nd day: the SA level of the monitoring in PK and 24 hour after the dosage of administration fasting
7th day: the SA level of the monitoring in PK and 24 hour after the dosage of administration feed
14th day: the 7th day 24 hours period monitoring SA level of separating the SA-ER administration of administration in every day for three times.During the 7th day, under monitoring individuality, administration SA-ER helps the stable state SA level setting up chronic administration.
the analysis of the SA (fasting and fed conditions) of single dose free SA level afterwards
Free sialic acid (SA) level is measured by using the algoscopy (lower limit of quantitation (LLOQ) is 0.05 microgram/ml) of Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS) methodological empirical tests.The SA-ER (fasting and fed conditions) that single dose summed up to each generation afterwards with free SA data during baseline, and it to be illustrated in figure 21.
Average SA baseline values for all individualities affected by HIBM be recruited is 0.143 (SD0.0094) mcg/ml, and significantly lower than normal individual, (sample obtains beyond the program for it; N=47, the range of age 18-78 year, and use the algoscopy of identical empirical tests to test) average SA (0.203 (SD 0.047) mcg/ml).For the SA level of the group of individual (not shown) independent arbitrarily or individuality, baseline SA level does not disclose any significant day-night change, and smooth baseline curve has the standard deviation (Figure 21) of quite little (fairly tight).
The PK curve of Figure 21 shows described medicine and is absorbed with the form of dose dependent substantially, the dosage increased causes the increase of the size and shape of curve, except 6000mg dosage (using 500mg tablet), its curve has lower peak level than 4875mg dosage level (using 325mg tablet).The display of PK curve is for most of dosage level, and the SA persistent levels 8-12 hour of increase, 6000mg dosage realizes the persistent levels 12-16 hour increased.Generally speaking, fasted treatment starts to absorb early than fed treatment, and takes food curve and continue longer than the fasted treatment curve reduced more fast.
The comparison display food of feed curve (Figure 21) has different impacts to various dose group.650mg and 4875mg dosage group PK curve is on the feed lower, similar under 2925mg dosage group (feed and fasting state), and 1950mg and 6000mg dosage group is on the feed higher.Generally speaking, relative to feed, fasted treatment absorbs and starts comparatively early, and takes food curve and continue longer than the fasted treatment curve reduced more fast.
For most of dosage group, the curve of fasting reaches higher C max, but for 1950mg and 6000mg dosage group, the apparent C of feed and fasting maxsimilar.For the 6000mg dosage with 500mg tablet time variations and to expose curve broadening be obvious especially, the blood level that its performance significantly increases, continues 16-20 hour.
When comparing fasting curve and feed curve (Figure 22 and Figure 23), be below obvious: at below 4875mg, SA level has dose-dependent rising (as expected), and lower than 4875mg/ all over the world, picked-up SA seems not reach capacity.Under higher dosage level, peak dosage level has the diversity of increase, and this represents the interindividual variation of highly significant in SA absorption mode.In 4875mg single dose level (n=4), with normal (0.203mcg/mL) with two other individuality (the individual 101-012:0.79mcg/ml organized; Individual 101-017:0.5mcg/ml) to compare, two in 4 individualities have very high-caliber free SA (individual 101-016:1.36mcg/ml; Individual 101-015:1.18mcg/ml).Original prediction is compared with 4875mg dosage, and 6000mg dosage group has slightly high C max(considering that 6000mg has more the medicine of 20%), but for the PK of single dose, result is in fact lower.Do not determine the reason for it completely, but may be to dissociate SA level (it may make data be inclined to higher average SA level randomly in the group that this is less) due to two height obtained especially in four total individualities in 4875mg single dose group, or compared with 325mg tablet, 500mg tablet has slower and longer absorption curve.
When comparing the PK curve of " feed " state in Figure 23, the difference between 4875mg dosage and 6000mg dosage is much smaller than the difference of fasting state.In addition, the long absorption phase of 6000 dosage with in 4,8 levels almost identical with 12 hours, show relative to other " feed " dosage group, its longer absorption curve.Other dosage group lower shows the remarkable exposure of similar dose-dependent absorption and about 12 hours on the feed.
the analysis of free SA level after 7 days repeat administration SA-ER
One in each individual administration four repeated doses levels (be divided into administration every day 3 times, continue the time of 7 days).In the 7th day (scheme the 14th day) of administration, carry out 24 hours monitoring SA levels and whether realize with assessment stable with continuous print exposure level.Figure 24 shows the PK curve of 24 hours monitoring phases.Show the PK curve (Figure 24 A-24D) of each repeated doses group, then by all curve plottings in one drawing to compare (Figure 24 E).The comparison of average SA level during (Figure 24) last figure shows each dosage group 24 h cycle on the right side of bottom.
Curve (Figure 24 A-24D) is presented at the SA maintenance level realized in 24 h cycle, and its paddy never reaches the average SA concentration (0.143mcg/ml) of baseline.Under the lowest dose level being divided into the 1950mg of three times every day (Figure 24 A) (it is 650mg every day three times, and before the meal early, before dinner and h.d. administration), touch the bottom at 8 hours curves, but again realize metastable level during 24 h cycle.Peak level at 20 hours, and may represent converging of individual PM dosage and h.d. dosage.Consider that muscle has the physiology of anabolism activity at night, SA concentration curve shows enough coverings of crucial night period really.
Under the higher dose levels being divided into 4875mg or 6000mg of three times every day, realize more significant level (Figure 24 C and Figure 24 D) at all time points.Although very different for the single dose PK level of 4875mg and the 6000mg dosage by different tablet size (being respectively 325mg and 500mg tablet), when giving many days by it with the dosage separated, and during 6 of our relatively each group individual 24 hourly average SA levels (Figure 24 F), two dosage are suitable.500mg tablet longer PK open-assembly time may be provided in overlap larger between administration, and thus causes depot levels higher under 6000mg dosage.When compared with untreated HIBM patient baseline, the free SA level of two lower repeated doses groups is about 2 times of baseline, and two dosage levels the highest are about 3 times of baseline SA level.All dosage causes free SA level far above normal free SA serum levels (0.203 (SD 0.047) mcg/ml).
the formal analyses of pharmacokinetic parameter
Use WinNonLin (version 5.3 (PharSight Inc.Mountain View CA, USA)) to carry out PK to analyze with the standard P K parameter assessing single dose data.Considered endogenous SA level, in order to assess administration with the change of SA level absorbed, suitable PK parameter calculates needs deduction baseline SA level.Although do not affect round the clock significantly, the baseline SA level of each individuality is deducted from the corresponding PK level of this time point, to set up " correction " data point.Therefore, no matter when use term " correction ", it means this PK parameter by deduction baseline SA level calculation.For do not have the time point of corresponding baseline values (such as the 2nd day short 30 minutes points of PK, the mean baseline data deducting this individuality with measure than baseline correction SA level have a net increase of length.These data all show in PK table (table 33A is to table 33D), main C max, AUC, T maxand T 1/2value provides as follows.
C maxgenerally speaking, for all dosage levels except 1950mg dosage level, the data (the 2nd day) of fasting show the highest C in data (table 34) display max.The highest C max(0.958mcg/ml) obtain in the 4875mg dosage group (n=4) using 325mg tablet, but in this dosage group, the scope of value is about 3 times (namely from 0.423mcg/ml to 1.36mcg/ml).Using the C obtained under the 6000mg dosage level (n=6) of 500mg tablet maxfor lower 0.520mcg/ml, but have less standard deviation, and the scope of value is 0.335mcg/ml to 0.711mcg/ml.Ironically, in the repeated doses phase, two high dose 4875mg (n=6) have similar C with 6000mg (n=6) maxlevel (being respectively 0.676 and 0.661).
AUC 0-24 hourthe value that data (table 35) display corrects on the the 2nd, 7 and 14 day.Baseline PK value (the 1st day) does not correct, and considers and do not give medicine, and it is incoherent.On the feed, the slower absorption of all curve displays starts and longer exposure curve.Unlike to C maximpact, the impact of food on AUC is complicated, AUC (the 650mg and 4 that the display of some dosage levels is higher in fasted condition, 875mg dosage), AUC (2925mg dosage) similar under fasting with fed condition and AUC (1950mg and 6000mg dosage) higher under taking food.The extension of curve seems by C lower under 8-16 hour period, wider curve caused overlap more possible between dosage to compensate some dosage levels maxthe effect at peak.For 6000mg dosage, compared with 2.856 under fasting, the AUC significantly larger (about+46%) of administration under fed conditions, it is 4.165mcg-hr/ml.Consider that 6000mg dosage uses 500mg tablet for administration, viewed difference may be because larger tablet size is to the delicate effect absorbing dotted line, even if 325mg and 500mg tablet stripping data are in vitro suitable.Tablet larger in vivo may need longer time release.The delayed action SA that this difference combines upper food leaves stomach, and this may strengthen the overall absorption (acid its electric charge of neutralization that passes through should improve sialic absorption) of SA.Therefore all factors are considered and based on data, and not bound by theory, think that larger tablet and food can provide better clean drug absorption.In any case, clearly can be with or without food from result, under all dosage levels, all carry out enough drug absorption.
In addition, at the AUC of the 14th day (or the 7th of repeat administration the day) period 0-24 hourdisplay, when administration is divided into every day 3 times, can realize overall higher AUC level when stable state, this shows there are some saturations on absorbing.Such as, under 6000mg dosage level, the repeated doses AUC of correction 0-24 hourbe 6.740mcg*hr/ml, by comparison, under the single dose of 6000mg, AUC level is 2.856mcg*hr/ml (fasting state) and 4.165mcg*hr/ml (fed conditions).When being given with the repeated doses of separating instead of a single dose by dosage, the AUC of 6000mg dosage group exceeds about 235% and about 160%.The AUC of 4875mg repeated doses group 0-24 hourbe 7.442mcg*hr/ml (standard deviation 2.702), the 6.740mcg*hr/ml (standard deviation 3.487) of itself and 6000mg repeated doses group is suitable.Although the PK difference of 4875mg and 6000mg seems comparatively large after single dose administration, the data of the dosed administration of three times every day (it is more relevant to infective use) are divided into seem similar.Consider that the absorption of SA may be based on the pinocytotic process of active (Oetke C., Hinderlich S., Brossmer R., Reutter W., Pawlita M. and Keppler OT.2001.Evidence for efficient uptake and incorporation of sialic acid by eukaryotic cells.Eur.J.Biochem.268 (16): 4553-4561), the saturated and competition of drug absorption can occur simultaneously.
T maxdata (table 36) display food can have substantial effect to peak level, as medicine T during administration together with food maxmigrate to more late.For 4875mg and 6000mg dosage level, described migration is respectively 2.8 hours (fasting) to 6 hours (feed) and 4.3 hours (fasting) to 9.6 hours (feed).Except minimum 650mg dosage, under other dosage level, observe similar change.The change of peak concentration time and the global shape of curve show that food may be the key factor during SA-ER absorbs.
At repeat administration period T maxshow peak (namely when dusk dosage and h.d. dosage overlap) between the lights/night.This time is positive with regard to guaranteeing during peak protein synthesis at night with regard to enough Sialic Acid Levels.
T1/2 (the T of SA-ER under three higher dosage 1/2) be similar (about 3 hours), and due to food proper extension (table 37).Under two lowest dose levels, T 1/2seem longer (being 5.6 hours (650mg) and 8.6 hours (1950mg)), but these values as one man do not change with food.Although deduct endogenous SA, T during the PK that may correct at these calculates 1/2the existence impact in the endogenous SA pond (pool) that value is still subject to size closely similar.Consider there is no medicine respectively or there is repeat administration, the T of baseline and repeat administration 1/2be worth nonsensical.
pharmacokinetics conclusion
Data display SA-ER is absorbed and within the time of 8-16 hour, (is depended on dosage level) provide stable with significant levels of drugs, and the degree absorbed at SA has clear and definite interpatient variability.The impact of food on AUC is complicated, but generally speaking, seemed to take food C down maxlower and T maxpostpone.The AUC of the lower 6000mg repeated doses of feed significantly improves.Under higher dosage level, average SA concentration reaches more than the horizontal 2-3 of normal SA level doubly.
Absorption larger under the dosage level that maximum dose level 6000mg/ data all over the world do not show than 4875mg/ sky, this may be due to less 4875mg single dose from generation to generation in the upwards deflection (two wherein in four individualities have very high-caliber free SA) of data.During the single dose administration of 6000mg/ days, compared with the dosage of 4875mg/ days, PK parameter shows lower maximum levels of drugs and longer PK absorption curve.Repeat administration phase (and being service condition more relevant clinically), the dosage of 6000mg/ days shows similar to the dosage of 4875mg/ days.This may be due to 500mg tablet longer PK open-assembly time, and it causes the overlap between administration event (because dosage provides with the form of three times every day), and causes total AUC level higher at this dose.
Consider that the SA level obtained under all dosage is all far above normal range, and PK curve is relatively stable in 24 h cycle, SA-ER tablet as estimate with the form performance effect of slow releasing preparation, and the free SA level that should obtain expectation lacks to correct Sialic Acid Level and improves the sialylation in the muscle of HIBM patient.
Embodiment 9
The dog research of administering drug combinations: rapid release sialic acid is combined with slow release sialic acid (tablet)
Preliminary data display sialic acid quick releasing formulation (SA-API) of dog research absorbs ground better, and earlier obtains higher peak, but removes faster.Therefore, whether the object of the dog research of administering drug combinations surveys directional sustained-release sialic acid (SA-ER) to add rapid release sialic acid free and total SA level can be made to improve.
research 1:
Total SA whether can be made to absorb and average free SA level raising for mensuration adds rapid release sialic acid in SA-ER, carry out two continuous print administration phases.In dog, oral delivery SA-API (TID) continues 4 days, and then administering drug combinations SA-API+SA-ER tablet (TID) continues 4 days.1 phase: continue 4 days in SA-ER tablet: 200mg/kg/ days.2 phases: SA-ER tablet (200mg/kg/ days) adds SA-API (100mg/kg/ days) and continues 4 days.Measure the free sialic acid level in serum.Result shows in fig. 25.
research 2:
Whether stable state can be reached after the longer administration phase for mensuration adds rapid release sialic acid in SA-ER, and make total SA absorb/average free SA level raising, carry out three continuous print administration phases: oral delivery SA-API (TID) continues 4 days, then administering drug combinations SA-API+SA-ER tablet (TID) continues 4 days, and measures the free sialic acid level in serum (dog).1 phase: continue 4 days in SA-ER tablet: 200mg/kg/ days.2 phases: SA-ER tablet (200mg/kg/ days)+SA-API (100mg/kg/ days) continues 4 days.3 phases: SA-ER tablet (200mg/kg/ days)+SA-API (200mg/kg/ days) continues 4 days.The 4th day and the 8th day with measure the free sialic acid level in serum the 12nd day (last day of each administration phase).Result shows in fig. 26.
The area under curve (AUC) of each final point (the 4th day: 0-24hrs):
-TID SA-ER tablet 200mg/kg/ days: 37.8
-TID SA-ER tablet 200mg/kg/ days+SA-API 100mg/kg/ days: 66.4
-TID SA-ER tablet 200mg/kg/ days+SA-API 200mg/kg/ days: 90.4
Conclusion: oral combination SA-ER tablet and SA-API increase total absorption than independent SA-ER tablet.Therefore, more than 50% immediate release forms medicine under, the concentration of the free sialic acid in serum is multiplicable.
The all publications quoted in this manual and patent application are all quoted and are added herein, as being intended to each independent publication or patent application specifically and individually to quote add.
Although having described foregoing invention in greater detail by explanation and embodiment to understand clearly object, it will be apparent for a person skilled in the art that and can carry out some little change and modification.Therefore, description and embodiment should be construed as limiting the scope of the invention.

Claims (23)

1. treatment needs the anacid method of saliva in its individuality, and it comprises oral administration sialic acid or its pharmaceutically acceptable salt, solvate or ester, and wherein said method provides the sialic acid for the treatment of effective dose in the time being greater than about four hours.
2. the process of claim 1 wherein that described sialic acid or its pharmaceutically acceptable salt, solvate or ester are in slow releasing preparation.
3. the process of claim 1 wherein that described sialic acid or its pharmaceutically acceptable salt, solvate or ester are in slow releasing preparation and quick releasing formulation.
4. the process of claim 1 wherein that described sialic acid or its pharmaceutically acceptable salt, solvate or ester are to have the metronomic dosing regimens administration of one or more dosing interval every day.
5. the method for claim 4, wherein said sialic acid or its pharmaceutically acceptable salt, solvate or ester are administered three times every day.
6. the method for claim 5, it provides the sialic acid for the treatment of effective dose in the time being greater than about eight hours.
7. the method for claim 5, it provides the sialic acid for the treatment of effective dose in the time being greater than about 12 hours.
8. the method for claim 5, its average C provided during stable state during described dosing interval minsialic acid is at least about 0.11mcg/ml.
9. the method for claim 5, its sialic mean plasma concentration provided during stable state during described dosing interval is at least about 0.16mcg/ml.
10. the method for claim 5, its sialic mean plasma concentration provided during stable state during described dosing interval is higher at least about 50% than the sialic mean plasma concentration in the described individuality before sialic acid described in administration or its pharmaceutically acceptable salt, solvate or ester.
The method of 11. claim 5, the sialic blood plasma concentration curve during stable state that it provides make the sialic minimum plasma concentration during described dosing interval be maximal plasma concentration during described dosing interval at least about 35%.
The method of 12. claim 5, its on the feed under condition slow releasing preparation described in administration provide the absorption curve of improvement than administration in fasted condition.
The method of 13. claim 12, the average C wherein measured in the fasted state maxhigher than the average C measured under state on the feed max.
The method of 14. claim 12, the average T wherein measured under state on the feed maxhigher than the average T measured in the fasted state max.
The method of 15. claim 5, the sialic acid of wherein administration every day or the total amount of its pharmaceutically acceptable salt, solvate or ester are about 650mg to about 12000mg.
The method of 16. claim 15, the sialic acid of wherein administration every day or the total amount of its pharmaceutically acceptable salt, solvate or ester are about 1950mg to about 12000mg.
17. the process of claim 1 wherein that described sialic acid shortage lacks relevant myopathy to sialic acid.
The method of 18. claim 17, described to lack relevant myopathy to sialic acid be Hereditary inclusion body myopathy (HIBM), Nonaka myopathy and/or have Rimmed vacuoles distal myopathy (DMRV).
The method of 19. claim 2, wherein said slow releasing preparation is solid matrix form.
The method of 20. claim 19, wherein said solid matrix form is compressed tablets.
The method of 21. claim 19, wherein said slow releasing preparation comprises
The sialic acid of about 25% to about 50%w/w or its pharmaceutically acceptable salt, solvate or ester;
One or more water-swellables of about 20% to about 40%w/w, non-TCP friendly flow polymer or one or more hydrogels form polymer;
One or more aniones, pH dependency, the gel formation polymer of about 15% to about 30%w/w; With
One or more hydrocolloid polymer of about 3% to about 8%w/w or one or more cationic polymers.
The method of 22. claim 21, wherein said slow releasing preparation comprises
The sialic acid of about 25% to about 50%w/w or its pharmaceutically acceptable salt, solvate or ester;
The hypromellose of about 20% to about 30%w/w;
The carrageenan of about 3% to about 8%w/w; With
The sodium alginate of about 20% to about 25%w/w.
The method of 23. claim 21, wherein said slow releasing preparation comprises
The sialic acid of about 25% to about 50%w/w or its pharmaceutically acceptable salt, solvate or ester;
At least one in about 20% to the Polyethylene Glycol and poly(ethylene oxide) of about 30%w/w;
The carrageenan of about 3% to about 8%w/w; With
The sodium alginate of about 20% to about 25%w/w.
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