CN107708681A - Preparation containing diacerein and the method using its reduction uric acid blood level - Google Patents
Preparation containing diacerein and the method using its reduction uric acid blood level Download PDFInfo
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- CN107708681A CN107708681A CN201580081063.7A CN201580081063A CN107708681A CN 107708681 A CN107708681 A CN 107708681A CN 201580081063 A CN201580081063 A CN 201580081063A CN 107708681 A CN107708681 A CN 107708681A
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- Prior art keywords
- rhein
- compound
- release layer
- preparation
- diacerein
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- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 title claims abstract description 42
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229940005267 urate oxidase Drugs 0.000 description 1
- 108010078530 urate transporter Proteins 0.000 description 1
- 230000003424 uricosuric effect Effects 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Abstract
There is provided herein a kind of controlled release preparation containing diacerein or its analog.Being also provided herein reduces the method for uric acid blood level using said preparation.In one embodiment, the invention provides a kind of controlled release preparation comprising release layer and slow release layer, its adverse side effect mitigates and/or bioavilability is higher.
Description
The cross reference of related application
It is inapplicable.
Technical field
The present invention relates to a kind of diacerein preparation, more particularly to a kind of side that uric acid blood level is reduced using said preparation
Method.
Background technology
In chemistry, Rhein is 9,10- dihydro -4,5- dihydroxy -9,10- dioxo -2- anthracene carboxylic acids, has formula (I)
One of structure, its prodrug diacerein be 4, double (acetoxyl group) 9,10- dihydro -4,5- dihydroxy -9, the 10- dioxos of 5- -
2- anthroic acids, there is the structure of formula (II).Diacerein is fully converted to Rhein before system circulation is reached, and in vivo
Its physiological function is played in the form of Rhein.
Formula (I)
Formula (II)
Diacerein is widely used a kind of antiinflammatory in osteoarthritis is treated, and it has been shown to suppress leucocyte
Interleukin -1 (IL-1) signal transduction.At present, diacerein capsule has 50mg specification and in country variant with extensive stock name
Claim sale, including Art Deng.Such as United States Patent (USP) No.8, disclosed in 536,152, diacerein may be used also
For use as the auxiliary treatment of type ii diabetes.Although diacerein can orally administer, it can not be fully absorbed by alimentary canal,
And the oral administration biaavailability of diacerein is about 40% to 60% according to estimates.The endless hypersorption of diacerein may cause
Adverse side effect such as diarrhoea or soft stool.The unabsorbed diacerein of in vitro and in vivo studies have shown that is metabolized as greatly in colon
Yellow acid, then its cause aperient effects.Therefore, this area still needs the adverse side effect compared with existing commercial formulation and mitigated
And/or the diacerein preparation that bioavilability is higher.
Such as United States Patent (USP) No.8, disclosed in 865,689, it is found that diacerein can effectively reduce blood uric acid levels,
Available for treatment hyperuricemia or the metabolic disorder related to hyperuricemia.However, so far, not yet develop special
Reduce the diacerein preparation of blood uric acid levels.
In view of the demand, has the diacerein preparation and its that improve property in treatment disease the invention provides a kind of
Purposes in disease, the disease include but is not limited to hyperuricemia, the metabolic disorder related to hyperuricemia, osteoarthritis
And diabetes B.
The content of the invention
In one embodiment, the invention provides a kind of controlled release preparation, its adverse side effect mitigates and/or biology profit
Expenditure is higher, and it includes release layer and slow release layer.
In another embodiment, the invention provides a kind of method for reducing subject's uric acid blood level, it is wrapped
Above-mentioned controlled release preparation is applied containing its subject to needs.
In another embodiment, the invention provides a kind of method for reducing subject's uric acid blood level, it is wrapped
Containing to need its subject apply the compound containing therapeutically effective amount preparation, the compound be selected from by diacerein,
The group that Rhein, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt are formed, wherein when applying institute to the subject
When stating preparation, the preparation provides at least one following pharmacokinetic parameter：(i) the maximal plasma concentration C of RheinmaxIt is high
In 5.0 μ g/ml；(ii) area AUC under the Cot curve of Rhein0-tOr AUC0-∞Higher than 35.0 μ ghr/ml；(iii)
Under the conditions of on the feed rear T is orally administered to subjectmaxIt is about 3 to 4.5 hours；And (iv) Rhein plasma concentration is higher than 2.8
μ g/ml continue at least 4 hours.
In another embodiment, the invention provides a kind of method for reducing subject's uric acid blood level, it is wrapped
Containing to needing its subject to apply the preparation containing at least about 75mg compounds, the compound is selected from by diacerein, greatly
The group that yellow acid, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt are formed.
In order to which those skilled in the art are best understood by the feature of invention claimed, in the following paragraphs with reference to attached
Figure to implement the detailed technology of the present invention and preferred embodiment to being described.
Brief description of the drawings
Fig. 1 shows the controlled release preparation A and F of present invention stripping curve, according to American Pharmacopeia (USP) apparatus II (paddle method)
Measured at 37 DEG C in 900ml pH 6.8PBS with 50rpm；
Fig. 2 is the statistics block diagram for showing the suppression that the Rhein of various dose absorbs to uric acid；
Fig. 3 shows that subject receives mean plasma concentration-time song of Rhein after different diacerein preparation processing
Line；And
Fig. 4 is the statistics block diagram for showing the serum uric acid concentration with different diacerein preparations before and after the processing.
Embodiment
Term " quick-release " used herein or " IR " refer to medicine (for example, diacerein) to be released in a manner of conventional or be non-modified
Put.
It is interior in a manner of different from quick-release in a period of time that term " controlled release " or " CR " and " sustained release " or " ER " refer to medicine
Set rate gradually discharges.
Term " therapeutically effective amount " used herein refers to the amount for the one or more symptoms for relaxing or mitigating disease.
Term " C used hereinmax" refer to the maximal plasma concentration observed, with the flat of the maximum blood plasma concentration of individual
Mean value computation.
Term " mean plasma concentration " finger counting art average blood plasma concentration used herein.
Term " T used hereinmax" refer to for each individual for participating in bioavailability study, it was observed that peak (most
The time of blood plasma drug concentration greatly).
Term " AUC used herein0-∞" or " AUCinf" refer to plasma/serum/blood concentration versus time curve extrapolation to infinite
Area under big averaged curve.It is calculated as the TG-AUC that plasma concentration v. time curve is extrapolated to infinity from time zero
Arithmetic mean of instantaneous value, it is for each individual calculating for participating in bioavailability study.
Term " AUC used herein0-t" refer to plasma/serum/blood concentration versus time curve from time zero to time as t's
TG-AUC, there is the last sampling time point of measurable concentration wherein " t " is single preparation.
Term " diacerein or its analog " used herein refer to diacerein, Rhein, single acetyl Rhein or its
Pharmaceutically acceptable salt or prodrug.
In addition to this otherwise noted, the term " a (an) ", " the " that are used in this specification (particularly claims)
Etc. being understood to include singulative and plural form.
As described above, in order to improve the adverse side effect of diacerein and/or bioavilability, the invention provides one kind
Controlled release preparation, it includes release layer and slow release layer.
In one embodiment, release layer include the compound of therapeutically effective amount, filler, adhesive, disintegrant and
Lubricant, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt
The group that (hereinafter referred to as " diacerein or its analog ") is formed；And slow release layer includes the diacerein or its class of therapeutically effective amount
Like thing, controlled release polymer, filler and lubricant；And in the diacerein or its analog wherein in release layer and slow release layer
Diacerein or the weight ratio of its analog be about 2:1 to about 1:9.
In one embodiment, preparation also includes face coat.
Preferably, the present invention preparation in, the gross weight based on release layer, release layer include by weight about 5% to
About 60%, the diacerein of preferably from about 5% to about 50% or its analog；By weight about 30% to about 95%, preferably from about
The filler of 40% to about 85%；By weight about 0.1% to about 20%, the adhesive of preferably from about 1% to about 10%；By weight
Meter about 0.1% to about 20%, the disintegrant of preferably from about 1% to about 10%；By weight about 0.01% to about 5%, preferably from about
The lubricant of 0.1% to about 2.5%；And the gross weight based on slow release layer, slow release layer include by weight about 5% to about
60%, the diacerein of preferably from about 5% to about 50% or its analog；By weight about 1% to about 60%, preferably from about 10% to
About 50% controlled release polymer；By weight about 1% to about 70%, the filler of preferably from about 10% to about 55%；By weight
Meter about 0.01% to about 5%, the lubricant of preferably from about 0.1% to about 2.5%.
The example of filler includes but is not limited to lactose monohydrate, anhydrous lactitol sugar and starch.Preferably, filler is breast
Sugared monohydrate.
The example of adhesive includes but is not limited to polyvinylpyrrolidone, starch, gelatin, tragacanth, methylcellulose, hydroxyl
Third methylcellulose and hydroxypropylcellulose.Preferably, adhesive is polyvinylpyrrolidone.
Suitable disintegrant includes but is not limited to sodium carboxymethylcellulose, L- hydroxypropylcelluloses, crosslinked polyethylene pyrrolidines
Ketone, cornstarch, sodium starch glycolate, starch, Ac-Di-Sol and alginic acid or its sodium salt.Preferably, it is disintegrated
Agent is Ac-Di-Sol.
Suitable lubricant includes but is not limited to light anhydrous silicic acid, talcum, stearic acid and its zinc, magnesium or calcium salt and poly- second
Glycol.Preferably, lubricant is magnesium stearate.
Controlled release polymer available for the present invention can be, for example, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl fiber
Element, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthans (xanthan gum), guar gum, locust bean gum, poly- acetic acid
Vinyl acetate, polyvinyl alcohol carboxy vinyl polymer, polyvinyl alcohol, glucan, scleroglucan, mannosan, xanthans
(xanthans), alginic acid and its derivative, polyanhydride, polyaminoacid, carboxymethyl cellulose, Ac-Di-Sol, poly-
Vinylpyrrolidone, PVPP, carboxymethylamide, methacrylic acid potassium/divinyl benzene copolymer, starch
And its derivative, beta-schardinger dextrin, straight or branched dextrin derivative, ethyl cellulose, methylcellulose, methacrylic acid copolymer
Thing and cellulose derivative.Preferably, controlled release polymer is hydroxypropyl methyl cellulose (HPMC).
Because the present invention preparation alleviate adverse side effect, its can deliver the diacerein of higher doses without
Increase side effect as suffered from diarrhoea.Specifically, with business diacerein medicine (for example,50mg Q.D or B.I.D, often
Day totally 50 or 100mg) compared to higher dosage can be applied to patient, can contain at least about 75mg, preferably from about 75 to
200mg, more preferably from about 75 to 100mg diacerein or its analog, thus improve the therapeutic effect of single dose.
On the other hand, inventors herein have recognized that, the preparation ratio containing at least about 75mg diacereins
(quick releasing formulation containing 50mg diacereins) more effectively reduces uric acid blood level.Therefore, preparation of the invention includes excellent
Select at least about 75mg, more preferably from about 75 to 200mg, most preferably from about 75 to 100mg diacerein or its analog.
Dissolution inspection in, when according to American Pharmacopeia (USP) apparatus II (paddle method) at 37 DEG C in 900ml pH
When being measured in 6.8PBS with 50rpm, by weight, the dissolution rate in vitro of controlled release preparation is to discharge about 30% to about after 1 hour
45%, the diacerein of preferably from about 35% to about 40%；The diacerein of about 50% to about 60% is discharged after 4 hours；After 8 hours
Release about 60% to about 75%, the diacerein of preferably from about 65% to about 75% and after 16 hours release no less than about 80%
Diacerein.
In one embodiment, when being applied to subject, controlled release preparation of the invention can provide it is at least one with
Lower pharmacokinetic parameter：(i) the maximal plasma concentration C of RheinmaxHigher than 5.0 μ g/ml；(ii) concentration-time of Rhein
TG-AUC AUC0-tOr AUC0-∞Higher than 35.0 μ ghr/ml；(iii) on the feed under the conditions of subject is orally administered after
TmaxIt is about 3 to 4.5 hours；And (iv) Rhein plasma concentration continues at least 4 hours higher than 2.8 μ g/ml.With conventional immediate release
Preparation is compared, and the preparation for showing above-mentioned pharmacokinetic parameter shows that adverse side effect mitigates, food effect mitigates, biology
Availability is higher and/or the effect of reduction blood uric acid levels is more preferable.
Preferably, the preparation is the controlled release preparation (taken once a day) once a day.
Because the preparation of the present invention has above-mentioned advantage, therefore works as and be used to treat the therapeutically effective all diseases of diacerein
When be beneficial.These diseases include but is not limited to hyperuricemia, the metabolic disorder related to hyperuricemia, osteoarthritis
And diabetes B.The metabolic disorder related to hyperuricemia includes but is not limited to acute gout, chronic gout, gouty and closed
Save inflammation, gout breaking-out, uric acid kidney stones, gouty nephropathy, angiocardiopathy (such as hypertension and atherosclerosis), obesity
Disease, chronic kidney disease and insulin resistant.
The preparation can be used for the inflammatory reaction for reducing the urarthritis as caused by hyperuricemia and gout breaking-out；
And/or dissolving kidney stone；And/or reduce the arthritic recurrence rate of the acute inflammatory as caused by hyperuricemia；And/or slow down
The progress of subject's urate nephropathy.
In one embodiment, the preparation can also include one or more additional therapeutic agents, for example, antiinflammatory or
Uric acid depressant, to strengthen the therapeutic effect of diacerein.The example of antiinflammatory includes but is not limited to NSAIDs
(NSAID), corticosteroid and colchicin.The example of uric acid depressant include but is not limited to xanthine oxidase inhibitor,
Uricosuric drug, urate oxidase, urine alkali alkaline agent and fenofibrate.
Present invention also offers a kind of method for reducing subject's uric acid blood level, and it is included to its subject of needs
Using the preparation containing diacerein or its analog.
The preparation that can be used in the method can have as above to the present invention preparation defined in structure, composition and its
Its property.Alternatively, there can be different structure and compositions suitable for the preparation of this method, subject is applied to as long as working as
When, they can provide at least one following pharmacokinetic parameter：(i) the maximal plasma concentration C of RheinmaxHigher than 5.0 μ
g/ml；(ii) area AUC under the Cot curve of Rhein0-tOr AUC0-∞Higher than 35.0 μ ghr/ml；(iii) on the feed
Under the conditions of to subject orally administer rear TmaxIt is about 3 to 4.5 hours；And (iv) Rhein plasma concentration is higher than 2.8 μ g/ml
Continue at least 4 hours.
In another embodiment, the preparation used in this method contains at least about 75mg, and preferably from about 75 to 200mg,
More preferably from about 75 to 100mg diacerein or its analog.
Hereinafter, the present invention will be further illustrated with reference to following examples.However, these embodiments are merely to illustrate mesh
, rather than limitation the scope of the present invention.
The preparation of the controlled release preparation of [preparation embodiment] containing diacerein
Ten kinds of Dospans containing 75 or 100mg diacereins are prepared according to table 1 (a) and 1 (b).The tablet of preparation is used
In following In vivo study.
Table 1 (a) .75mg diacereins
Table 1 (b) .100mg diacereins
The dissolution test of [embodiment 1] diacerein controlled release preparation
In the present embodiment, dissolution test is carried out according to USP apparatus IIs (paddle method).Using pH 6.8PBS solution as molten
Go out medium.Sample at appropriate time intervals and pass through high pressure liquid chromatography (HPLC) and analyze diacerein content.
Table 2 summarizes the initial data of the tablet A and F of present invention dissolution test, and Fig. 1 shows stripping curve.
Table 2
The uric acid intake experiment that [embodiment 2] human URAT 1 relies on
Uric acid is mainly eliminated by urine drains, and the lithate of up to 90% filtering is gradually resorbed.Lithate is arranged
Letting out rate and reducing is considered as increasing serum uric acid, causes hyperuricemia.URAT1 (urate transporter 1, SLC22A12 genes) is
It is responsible for the major transporter of lithate reabsorption, it is considered to be the main mechanism of regulation blood uric acid salt level.
URAT1 and uric acid salt level have genetic correlation, and suppress URAT1 and may reduce serum uric acid.
In our current research, establish a kind of in-vitro method and mediated to study hURAT1 in the HEK293T cells of transient transfection
Uric acid [8-14C] intake, HEK293T cells are a kind of human embryo kidney 293 cells containing URAT1 transport proteins.
After the HEK293T cell incubations 24 hours to 72 hours of transfection, it is re-seeded into microwell plate.Cell is spread
At least 12 hours after plate, nutrient solution is removed, cleans cell, 5 to 10 points are then incubated in HBSS buffer solutions of the 100 μ l without Cl
Clock.Remove buffer solution, and into cell per hole add 50 μ l with or without Rhein (under four kinds of dosage, 30,10,3.3
With 1.1 μM) containing 50 μM of uric acid [8-14C] (0.13 μ Ci/ holes) without Cl HBSS buffer solutions, 37 DEG C are incubated 5 minutes.Incubating
At the end of educating, stopping uric acid [8-14C] intake.By cell washing three times, 50 μ l 100mM NaOH are added per hole to dissolve cell,
Then it is stirred at 600 rpm at least 20 minutes.Cell lysate is collected, 200 μ l UltimaGold TM are added per hole
XR scintillation solutions, and mixture is stirred at 600 rpm 10 minutes.Finally, microwell plate is counted.As a result it is shown in Fig. 2.
Fig. 2 is shown, is suppressed to 49.4% ± 22.2% to uric acid intake when rheum officinale acid concentration is 3.3 and 10 μM, concentration
For 30 μM when be 79.3% ± 1.5%.The IC of Rhein in URAT1 suppression50For 10 μM, about 2.8 μ g/ml.Maintain blood plasma
Rheum officinale acid concentration may occur to reduce the effect of uric acid more than 2.8 μ g/ml.
This studies have shown that diacerein or its analog can reduce serum uric acid by suppressing URAT1, therefore can be used for controlling
Treat hyperuricemia and the metabolic disorder related to hyperuricemia.
[embodiment 3] pharmacokinetic
Under the conditions of on the feed, carried out in healthy male and female volunteers diacerein quick releasing formulation (
50mg capsules) and I phases of diacerein controlled release preparation of three kinds of various doses of the present invention, random, open, single dose, 4-
Processing, 4- sequences, 4- cycles, crossover pharmacokinetic research.
Method：In healthy male and female volunteers, carry out by orally administering50mg and three
The 4 of the controlled release preparation (75,100 and 200mg) of kind various dose, which intersect, compares pharmacokinetic.Have the removing phase of 7 days with
Separate treatment cycle.
Subject：Meet the whole selection standards of this research and do not meet the healthy volunteer of this research culling level.
Program：The diacerein with different preparations and dosage administration is compared in a random basis, the removing during week
Phase is 7 days.Subject is randomized to either in a treatment sequence as shown in table 3 below.Research is started with screening access.Only close
Lattice subject take part in research.
Table 3. studies sequence
● processing A：1×50mg capsules；
● processing B：1 × 75mg tablets；
● processing C：1 × 100mg tablets；
● processing D：2 × 100mg tablets (200mg).
Comparison between different preparations and dosage is based on the comparison in subject rather than the comparison between subject.According to estimates 7
It removing phase is enough to avoid the Carryover effect formerly handled.
The statistical method of effect/Pharmacokinetic Evaluation：Protocol is met by non-chamber method measure and calculating
The AUC of Rhein in the blood plasma of (PP) crowd of analysis0-t、AUC0-∞、CmaxAnd Tmax.To AUC0-t、AUC0-∞、CmaxAnd TmaxUse
Variance analysis (ANOVA).T is analyzed using additional non-parametric test (Wilcoxon inspections)max。
Safety evaluation is carried out to all subjects that application of agent quantifier elimination medicine at least once.Researcher obtains
And have recorded all adverse events (AE) observed of on CRF or voluntary report, including its intensity and with research product
Relationship assessment.For all AE, researcher pursue and obtain be enough to determine AE results and its whether meet any seriousness
The information of standard.All AE must be tracked until solving or stably in the acceptable level of researcher.
Pharmacokinetic results are shown in table 4 and 5 and Fig. 3.Subject (n=23) is screened, 16 tested
Person enters group at random.There is the whole research (4 cycles) that 13 subjects complete the pharmacokinetics for assessing PP crowd.
The data obtained from these subjects are only reported in following table.
The Rhein pharmacokinetic parameter of table 4.PP crowd
* data are shown (SD) with average value
The Rhein ratio of table 5.PP crowd
Safe result is shown in Table 6.Important adverse events, death or serious adverse events are not reported.During research, most
The adverse events often reported are diarrhoea, next to that Nausea and vomiting, fash, the increase of blood cretinephosphokinase, contact dermatitis, low
Blood pressure and drowsiness.Diarrhoea event is almost identical between 50mg capsules and 75mg and 100mg tablets.It was reported that all bad things
The intensity of part is slight and finally give solution.In a word, 50mgCapsule and 75,100 and 200mg tablet make
With safety.
The adverse events of table 6. summarize (pressing event)
The above results show that controlled release preparation of the invention shows the C of RheinmaxHigher than 5.0 μ g/ml, Rhein
AUC0-tOr AUC0-∞Higher than 35.0 μ ghr/ml and TmaxIt is about 3 to 4.5 hours.In addition, the preparation of the present invention provides rheum officinale
Sour haemoconcentration continues at least 4 hours (processing B higher than 2.8 μ g/ml (the treatment valid density in embodiment 2)：4.2 hour；Place
Manage C：7 hours；Handle D：12.7 hours), and, dose normalized AUC and C higher than business quick releasing formulation bioavilabilitymax
It is worth high by about 10%.It has been found that AUC and CmaxValue increase generally directly proportional to the increase of diacerein dosage.
75mg and 100mg controlled release preparation has a tolerance similar to 50mg quick releasing formulation, and 200mg dosage then with compared with
High intestines and stomach AE incidences are related.Therefore, withPreparation is compared, preparation of the invention 75mg and 100mg compared with
Improved security is shown under high dose intensity, and accordingly provides the adverse side effect of mitigation.This allows to often
Day is once treated with 75 or 100mg higher dosage to patient, without increasing side effect.
Under the conditions of on the feed, the present invention tablet group in, average blood Rhein reach peak concentration for administration after about
3.62 to 4.16 hours,Capsules group is 5.00 hours.Have confirmed, single oral is applied in healthy volunteer
After 50mg, the empty stomach T of diacereinmaxFor 2.4 hours, with it is postprandial increase to 5.2 hours (Petitjean et al.,
Clinical Pharmacokinetics,November 1998,Volume 35,Issue 5,pp 347-359).The present invention
Preparation on the feed under the conditions of faster absorbed and withCapsule is compared and shows less food effect.
[embodiment 4] serum uric acid is studied
Under the conditions of on the feed, carried out in healthy volunteer diacerein quick releasing formulation (50mg capsules)
The serum uric acid in research with the diacerein controlled release preparation of three kinds of various doses of the present invention reduces evaluation.
It is right for treatment of purpose (ITT) crowd in the pharmacokinetic of embodiment 350mg and
The tablet (75,100 and 200mg) of three kinds of various doses of the present invention is to the shadow of the serum uric acid of healthy volunteer under fed condition
Sound has carried out subsequent analysis.15 subjects are analyzed altogether.Serum uric acid is dense before and after the processing with paired t-test com-parison and analysis
Degree.
As a result it is shown in Fig. 4.Through handle A (Serum uric acid concentration after 50mg) does not have significance difference with before processing
It is different.However, serum uric acid concentration reduces than before processing after handling B.Identical result is also showed that in processing C and processing D.
The difference that this serum uric acid reduces be probably due to Rhein be maintained above 2.8 μ g/ml effective haemoconcentration it is lasting when
Between caused by.As shown in figure 3, processing A Rhein blood concentration, which reaches, continues the extremely short time higher than 2.8 μ g/ml, deficiency
To play uric acid reducing effect.
The controlled release preparation of the invention that the research discloses the various dose higher than 75mg significantly reduces serum uric acid.
It is disclosed above to be related to its detailed technology contents and inventive features.Based on described disclosure of the invention and build
View, those skilled in the art can carry out various modifications and replacement without departing from its feature.
Claims (20)
1. a kind of method for reducing subject's uric acid blood level, its include to need its subject apply comprising release layer and
The controlled release preparation of slow release layer.
2. according to the method for claim 1, wherein the release layer includes the compound of therapeutically effective amount, filler, viscous
Mixture, disintegrant and lubricant, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmacy
The group that upper acceptable salt is formed；And the slow release layer include the compound of therapeutically effective amount, controlled release polymer, filler and
Lubricant, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt
The group of composition；And the weight ratio of the compound wherein in release layer and the compound in slow release layer is about 2:1 to
About 1:9.
3. according to the method for claim 1, wherein the gross weight based on release layer, release layer include by weight about 5%
To about 60% compound, the compound is selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmaceutically
The group that acceptable salt is formed；The filler of by weight about 30% to about 95%；By weight about 0.1% to about 20% it is viscous
Mixture；The disintegrant of by weight about 0.1% to about 20%；The lubricant of by weight about 0.01% to about 5%；And base
In the gross weight of slow release layer, slow release layer includes the compound of by weight about 5% to about 60%, and the compound is selected from by double vinegar
The group that Rui Yin, Rhein, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt are formed；By weight about 1% to about
60% controlled release polymer；The filler of by weight about 1% to about 70%；The profit of by weight about 0.01% to about 5%
Lubrication prescription.
4. according to the method for claim 1, wherein the controlled release polymer be selected from by hydroxypropyl methyl cellulose (HPMC),
Hydroxypropylcellulose, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthans (xanthan gum), guar gum, locust bean
Glue, polyvinyl acetate, polyvinyl alcohol carboxy vinyl polymer, polyvinyl alcohol, glucan, scleroglucan, mannosan, xanthan
Glue (xanthans), alginic acid and its derivative, polyanhydride, polyaminoacid, carboxymethyl cellulose, Ac-Di-Sol,
Polyvinylpyrrolidone, PVPP, carboxymethylamide, methacrylic acid potassium/divinyl benzene copolymer, shallow lake
Powder and its derivative, beta-schardinger dextrin, the dextrin derivative with straight or branched, ethyl cellulose, methylcellulose, methyl-prop
The group that olefin(e) acid copolymer, cellulose derivative and its any combination are formed.
5. according to the method for claim 1, wherein the preparation includes at least about 75mg diacerein.
6. according to the method for claim 1, when applying the preparation to the subject, it can provide at least one
Following pharmacokinetic parameter：(i) the maximal plasma concentration C of RheinmaxHigher than 5.0 μ g/ml；(ii) during the concentration of Rhein
Area AUC under half interval contour0-tOr AUC0-∞Higher than 35.0 μ ghr/ml；(iii) on the feed under the conditions of orally administered to subject after
TmaxIt is about 3 to 4.5 hours；And (iv) Rhein plasma concentration continues at least 4 hours higher than 2.8 μ g/ml.
7. according to the method for claim 1, wherein the preparation is controlled release preparation once a day.
8. according to the method for claim 1, wherein the subject has selected from by hyperuricemia and hyperuricemia
The disease or illness for the group that related metabolic disorder, osteoarthritis and diabetes B is formed.
9. a kind of method for reducing subject's uric acid blood level, it includes effective comprising treatment to needing its subject to apply
The preparation of the compound of amount, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmaceutically
The group that acceptable salt is formed, wherein when applying the preparation to the subject, the preparation provides at least one following
Pharmacokinetic parameter：(i) the maximal plasma concentration C of RheinmaxHigher than 5.0 μ g/ml；(ii) concentration-time of Rhein is bent
Area AUC under line0-tOr AUC0-∞Higher than 35.0 μ ghr/ml；(iii) on the feed under the conditions of rear T is orally administered to subjectmax
It is about 3 to 4.5 hours；And (iv) Rhein plasma concentration continues at least 4 hours higher than 2.8 μ g/ml.
10. according to the method for claim 9, wherein the preparation is controlled release preparation and comprising release layer and slow release layer.
11. according to the method for claim 9, wherein the release layer includes the compound of therapeutically effective amount, filler, viscous
Mixture, disintegrant and lubricant, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmacy
The group that upper acceptable salt is formed；And the slow release layer include the compound of therapeutically effective amount, controlled release polymer, filler and
Lubricant, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt
The group of composition；And the weight ratio of the compound wherein in release layer and the compound in slow release layer is about 2:1 to
About 1:9.
12. a kind of method for reducing subject's uric acid blood level, it includes its subject to needs and applied comprising at least about
The preparation of 75mg compounds, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmaceutically
The group that acceptable salt is formed.
13. according to the method for claim 12, wherein when applying the preparation to the subject, it provides at least one
The following pharmacokinetic parameter of kind：(i) the maximal plasma concentration C of RheinmaxHigher than 5.0 μ g/ml；(ii) concentration of Rhein
Area AUC under time graph0-tOr AUC0-∞Higher than 35.0 μ ghr/ml；(iii) on the feed under the conditions of subject is orally administered
T afterwardsmaxIt is about 3 to 4.5 hours；And (iv) Rhein plasma concentration continues at least 4 hours higher than 2.8 μ g/ml.
14. according to the method for claim 12, wherein the preparation is controlled release preparation and comprising release layer and slow release layer.
15. according to the method for claim 12, wherein the release layer include the compound of therapeutically effective amount, filler,
Adhesive, disintegrant and lubricant, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and medicine
The group that acceptable salt is formed on；And compound of the slow release layer comprising therapeutically effective amount, controlled release polymer, filler
And lubricant, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmaceutically acceptable
The group that salt is formed；And the weight ratio of the compound wherein in release layer and the compound in slow release layer is about 2:1
To about 1:9.
16. the controlled release preparation that a kind of adverse side effect mitigates, it includes release layer and slow release layer, is controlled wherein the release layer includes
Compound, filler, adhesive, disintegrant and the lubricant of effective dose are treated, the compound is selected from by diacerein, rheum officinale
The group that acid, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt are formed；And the slow release layer includes therapeutically effective amount
Compound, controlled release polymer, filler and lubricant, the compound be selected from by diacerein, Rhein, single acetyl rheum officinale
The group that acid, its prodrug and pharmaceutically acceptable salt are formed；And in the compound wherein in release layer and slow release layer
The weight ratio of the compound is about 2:1 to about 1:9.
17. preparation according to claim 16, wherein the gross weight based on release layer, release layer includes by weight about
The compound of 5% to about 60%, the compound are selected from by diacerein, Rhein, single acetyl Rhein, its prodrug and pharmacy
The group that upper acceptable salt is formed；The filler of by weight about 30% to about 95%；By weight about 0.1% to about 20%
Adhesive；The disintegrant of by weight about 0.1% to about 20%；The lubricant of by weight about 0.01% to about 5%；And
Gross weight based on slow release layer, slow release layer include the compound of by weight about 5% to about 60%, and the compound is selected from by double
Vinegar is auspicious because of, the group that forms of Rhein, single acetyl Rhein, its prodrug and pharmaceutically acceptable salt；By weight about 1% to about
60% controlled release polymer；The filler of by weight about 1% to about 70%；The profit of by weight about 0.01% to about 5%
Lubrication prescription.
18. preparation according to claim 16, wherein the controlled release polymer is selected from by hydroxypropyl methyl cellulose
(HPMC), hydroxypropylcellulose, sodium alginate, carbomer, sodium carboxymethylcellulose, xanthans (xanthan gum), guar gum,
Locust bean gum, polyvinyl acetate, polyvinyl alcohol carboxy vinyl polymer, polyvinyl alcohol, glucan, scleroglucan, sweet dew gather
Sugar, xanthans (xanthans), alginic acid and its derivative, polyanhydride, polyaminoacid, carboxymethyl cellulose, cross-linked carboxymethyl are fine
It is common to tie up plain sodium, polyvinylpyrrolidone, PVPP, carboxymethylamide, methacrylic acid potassium/divinylbenzene
Polymers, starch and its derivative, beta-schardinger dextrin, dextrin derivative, ethyl cellulose, the Methyl cellulose with straight or branched
The group that element, methacrylic acid copolymer, cellulose derivative and its any combination are formed.
19. preparation according to claim 16, wherein when applying the preparation to the subject, it provides at least one
The following pharmacokinetic parameter of kind：(i) the maximal plasma concentration C of RheinmaxHigher than 5.0 μ g/ml；(ii) concentration of Rhein
Area AUC under time graph0-tOr AUC0-∞Higher than 35.0 μ ghr/ml；(iii) on the feed under the conditions of subject is orally administered
T afterwardsmaxIt is about 3 to 4.5 hours；And (iv) Rhein plasma concentration continues at least 4 hours higher than 2.8 μ g/ml.
20. preparation according to claim 16, it is controlled release preparation once a day.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2015/026678 WO2016171656A1 (en) | 2015-04-20 | 2015-04-20 | Formulations containing diacerein and methods of lowering blood levels of uric acid using the same |
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| CN107708681A true CN107708681A (en) | 2018-02-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580081063.7A Pending CN107708681A (en) | 2015-04-20 | 2015-04-20 | Preparation containing diacerein and the method using its reduction uric acid blood level |
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| Country | Link |
|---|---|
| EP (1) | EP3285754A4 (en) |
| JP (1) | JP2018513203A (en) |
| KR (1) | KR20180013880A (en) |
| CN (1) | CN107708681A (en) |
| AU (1) | AU2015392441A1 (en) |
| BR (1) | BR112017022509A2 (en) |
| CA (1) | CA2983394A1 (en) |
| CO (1) | CO2017011722A2 (en) |
| IL (1) | IL255073A0 (en) |
| MX (1) | MX2017013489A (en) |
| RU (1) | RU2690372C2 (en) |
| WO (1) | WO2016171656A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100285114A1 (en) * | 2007-09-27 | 2010-11-11 | Rahul Dabre | Pharmaceutical compositions of rhein or diacerein |
| CN103037849A (en) * | 2010-06-22 | 2013-04-10 | 安成国际药业股份有限公司 | Controlled release compositions with reduced food effect |
| CN103429236A (en) * | 2011-03-11 | 2013-12-04 | 安成生物科技股份有限公司 | Methods and compositions for treating hyperuricemia and metabolic disorders associated with hyperuricemia |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06316517A (en) * | 1993-02-22 | 1994-11-15 | Grelan Pharmaceut Co Ltd | Sustained-release preparation |
| EP1795207A1 (en) * | 2004-10-01 | 2007-06-13 | Nippon Zoki Pharmaceutical Co. Ltd. | Solid pharmaceutical preparation |
| EP2167048B1 (en) * | 2007-05-30 | 2016-10-26 | Wockhardt Limited | A novel tablet dosage form |
| EP2520286A1 (en) * | 2007-09-27 | 2012-11-07 | Wockhardt Limited | Pharmaceutical compositions of rhein or diacerein |
| WO2009048940A2 (en) * | 2007-10-08 | 2009-04-16 | Dr. Reddy's Laboratories Ltd. | Diacerein pharmaceutical formulations |
| TWI473610B (en) * | 2008-10-28 | 2015-02-21 | Twi Biotechnology Inc | Pharmaceutical compositions containing diacerein |
| KR101190708B1 (en) * | 2010-03-12 | 2012-10-12 | 주식회사 대웅제약 | Sustained-release pharmaceutical composition comprising mosapride or salt thereof |
| CN103210084B (en) * | 2010-06-16 | 2016-04-20 | 武田制药美国有限公司 | The release dosage form of the new improvement of xanthine oxidoreductase inhibitors or xanthine oxidase inhibitor |
-
2015
- 2015-04-20 RU RU2017140079A patent/RU2690372C2/en active
- 2015-04-20 KR KR1020177032849A patent/KR20180013880A/en unknown
- 2015-04-20 WO PCT/US2015/026678 patent/WO2016171656A1/en active Application Filing
- 2015-04-20 EP EP15890063.9A patent/EP3285754A4/en not_active Withdrawn
- 2015-04-20 MX MX2017013489A patent/MX2017013489A/en unknown
- 2015-04-20 CA CA2983394A patent/CA2983394A1/en not_active Abandoned
- 2015-04-20 BR BR112017022509A patent/BR112017022509A2/en not_active Application Discontinuation
- 2015-04-20 CN CN201580081063.7A patent/CN107708681A/en active Pending
- 2015-04-20 AU AU2015392441A patent/AU2015392441A1/en not_active Abandoned
- 2015-04-20 JP JP2017555702A patent/JP2018513203A/en active Pending
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2017
- 2017-10-16 IL IL255073A patent/IL255073A0/en unknown
- 2017-11-17 CO CONC2017/0011722A patent/CO2017011722A2/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100285114A1 (en) * | 2007-09-27 | 2010-11-11 | Rahul Dabre | Pharmaceutical compositions of rhein or diacerein |
| CN103037849A (en) * | 2010-06-22 | 2013-04-10 | 安成国际药业股份有限公司 | Controlled release compositions with reduced food effect |
| CN103429236A (en) * | 2011-03-11 | 2013-12-04 | 安成生物科技股份有限公司 | Methods and compositions for treating hyperuricemia and metabolic disorders associated with hyperuricemia |
Also Published As
| Publication number | Publication date |
|---|---|
| BR112017022509A2 (en) | 2018-07-17 |
| IL255073A0 (en) | 2017-12-31 |
| RU2017140079A (en) | 2019-05-20 |
| MX2017013489A (en) | 2018-05-22 |
| CO2017011722A2 (en) | 2018-04-19 |
| CA2983394A1 (en) | 2016-10-27 |
| EP3285754A1 (en) | 2018-02-28 |
| AU2015392441A1 (en) | 2017-11-09 |
| RU2017140079A3 (en) | 2019-05-20 |
| EP3285754A4 (en) | 2018-12-19 |
| JP2018513203A (en) | 2018-05-24 |
| WO2016171656A1 (en) | 2016-10-27 |
| KR20180013880A (en) | 2018-02-07 |
| RU2690372C2 (en) | 2019-06-03 |
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