JP6697539B2 - Colchicine sustained-release preparation and method of using the same - Google Patents

Description

[Related application]
This application claims the benefit of US Provisional Application No. 61 / 812,514, filed April 16, 2013, and European Patent Application No. 13194505.7, filed November 26, 2013. There, and are hereby incorporated by reference in their entirety.

Colchicine, chemical name (-)-N-[(7S, 12aS) -1
, 2,3,10-Tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo [
a] Heptalen-7-yl] -acetamide is a product of dog saffron (Colchicum a).
alkaloids found in extracts of plants such as utumale) and fox lily (Gloriosa superba). Colchicine is an inhibitor of microtubule formation (mi) used in the treatment of anti-inflammatory treatments, conditions that can be alleviated or prevented.
It is a crotubule-disrupting agent).

Colchicine is well recognized as an effective therapeutic agent in acute redness of gouty arthritis, familial Mediterranean fever (FMF), and Behcet's disease. Colchicine has also been used to treat many inflammatory disorders susceptible to fibrosis. In recent years, it has been proposed that colchicine is effective in the treatment of cardiovascular disease.

In particular, colchicine has been identified in the 2004 European Guidelines for the management of pericardial disease as
It has been proposed as a first-line drug (class I indication) for recurrent pericarditis and a class IIa drug for acute pericarditis (Maisch et al., Guideli).
nes on the Diagnostic and Management of P
ericial Diseases, Eur Heart J. , 2004, 25
, 916-928).

Imazio et al. (Circulation, 2005, 112 (13), 2012-2.
016) is acute pericarditis (idiopathic, viral, postpericardiotomy syndrome, and connective tissue disease)
No prospective treatment of 120 first-patients who were randomly assigned to existing treatment with aspirin or existing treatment + colchicine (1.0 to 2.0 mg on the first day and 0.5 to 1.0 mg / day for the next 3 months) Randomized open label design test (prospective, random
It was shown that colchicine was effective in the treatment and prevention of recurrent pericarditis in an ized, open-label designed study. The primary endpoint was the recurrence rate, which was significantly reduced from 32.3% to 10.7% at 18 months in the colchicine group (p = 0.004).

In addition, the same group showed that colchicine may be effective even after failure to manage acute pericarditis with existing treatments (Imazio at al., Arch.
InternMed, 2005, 165 (17), 1987-91). In a prospective, randomized, open-label design, 84 patients with continued treatment for first episode of recurrent pericarditis were treated with aspirin alone or with existing treatment plus colchicine (1.0-2.0 mg on the first day, They were then randomly assigned to either treatment at 0.5-1.0 mg / day for 6 months. The primary endpoint was recurrence rate, which was significantly decreased in the colchicine group (actual statistical rate at 18 months was 50.6% with the existing treatment, whereas 24. It was 0%).

Colchicine has also been shown to be effective in the secondary prevention of recurrent pericarditis (Imazi
o et al. , Ann. Intern. Med. , 2011, 155 (7), 409
-14). Colchicine has also been proposed to suppress post-pericardiotomy syndrome reactions manifested as pericarditis (Imatio et al., Am. Heart J., 2).
011, 162 (3), 527-532; Meurin and Tabet, Arch.
． Cardiovasc. Dis. , 2011, 104 (8-9), 425-427).

Post-pericardiotomy syndrome (P)
Colchicine (1.5 mg / day) reserve compared to placebo for 163 patients undergoing cardiac surgery with colchicine for the treatment of PS), starting on the third day after surgery First in a traditional, open-label, randomized trial (Finkelst
ein et al. , Herz, 2002 27, 791-194).

Colchicine's efficacy for the prevention of PPS has also been demonstrated in a multicenter, double-blind, randomized trial (mu).
litcentre, double-blind, randomized trial
) Is also shown. On the 3rd day after the operation, 360 patients (mean age: 65.7 ± 12.3)
Age (66% male), 180 cases in each treatment group, placebo group and colchicine group (
For patients weighing 70 kg or more, 1.0 mg twice daily on the first day and then 0.5 mg twice daily.
Routinely assigned to either one-month maintenance dose, body weight <70 kg or half dose for patients not tolerated at maximum dose) (Imazio et al., European).
Heart Journal, 2010, 31, 2749-2754).

In another study, the efficacy of colchicine has been shown for cardiovascular disease. Prospective randomized observer blinded assessment item design (prospective, randomized,
In this clinical trial with observer-blinded endpoint design, aspirin and / or clopidogrel (93%) and statin (95%)
%) Of 532 patients with stable coronary artery disease were randomly assigned to receive colchicine 0.5 mg / day or colchicine non-administration, and a median follow-up study for 3 years was performed (N
idorf et al. , JACC, 2013, 61 (4), 404-410). This study included colchicine 0.5 given in addition to statins and other standard second-line prophylaxis.
It has been shown that mg / day appears to be effective in preventing cardiovascular events in patients with stable coronary artery disease.

The recommended dose of colchicine (COLCRYS®) for the treatment of gout is 1.
Single dose of 8 mg / day or divided doses within 1 hour. For adult gout patients, treatment is begun with a dose of 1.2 mg at the first onset of symptoms and then 0.6 hours later.
administer mg. (Physician's Desk Reference, 68th
ed. , (2014)).

COLRYS® is an immediate release formulation. Adverse effects associated with the administration of COLRYS® include, but are not limited to, nausea, vomiting, abdominal pain, diarrhea, hair loss,
Includes weakness, irritability, severe anemia, leukopenia, and thrombocytopenia (Physicia
n's Desk Reference, 68th ed. , (2014)).

The present invention addresses these and other needs by providing improved formulations of colchicine that are characterized by sustained release of the active ingredient. The present invention additionally provides an effective once-daily dosage form of colchicine or a salt thereof, which complies with patient compliance.
Compliance can be improved and some of the side effects of colchicine can be suppressed compared to current or high dose daily immediate release colchicine formulations.

According to an embodiment of the invention exemplified herein, a sustained release of colchicine as an active ingredient comprising colchicine or a pharmaceutically acceptable salt thereof, a retarder and at least one pharmaceutically acceptable excipient. A sustained release formulation is provided.

According to an aspect of the invention illustrated herein, a method for treating and / or preventing cardiovascular disease in a subject, comprising administering to the subject a therapeutically effective amount of a sustained release formulation of colchicine. A method is provided.

According to an aspect of the invention illustrated herein, a method for treating and / or preventing an inflammatory disease in a subject comprising administering to the subject a therapeutically effective amount of a sustained release formulation of colchicine. A method is provided.

According to an aspect of the invention illustrated herein, (A) 0.25 to 0.75% by weight of the total composition.
Forming a granulating agent by dissolving colchicine in step (B), and adding a filler and a binder in step A to wet granules (wet granules).
granulation), (C) drying the wet granules of step B, and (D) blending the granules dried in step C with retarders, fillers, lubricants, and lubricants. , (E) compressing the final granules obtained in step D into tablets, a process for preparing colchicine sustained release tablets is provided.

In accordance with an aspect of the invention illustrated herein, a shaped article comprising colchicine and excipients combined in a matrix, which is characterized by a sustained slow and relatively constant, gradual release of colchicine upon administration. And a compressed sustained release therapeutic composition, wherein the excipient comprises hypromellose, the total amount of the excipient being effective to bind colchicine in the sustained release solid matrix, said molding and compression Sustained release therapeutic compositions are provided that are greater than 99% by weight of the formulated composition.

According to aspects of the invention illustrated herein, a sufficient amount of colchicine to comprise about 0.25 to about 0.75% of the total composition is wet granulated with an excipient.
g) A molded and compressed colchicine sustained release tablet produced by
The excipient comprises about 10 to about 80% of the total composition of lactose monohydrate.
nohydrate, from about 5 to about 50% of the total composition of pregelatinized starch (prege
latinized starch), about 1 to about 30% of the total composition of hypromellose (
Hypromellose) 6 mPa ^* s, purified water, (purified water, (
q. s. )), Colchicine comprising about 5 to about 40% of total composition, Retalac, about 0.5 to about 5% of total composition, talc, about 0.5 to about 5% of total composition of stearic acid. Sustained-release tablets are provided.

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the United States Patent and Trademark Office upon request and payment of the necessary fee.

3 shows the dissolution profiles of colchicine sustained release formulations containing 10%, 15% and 20% of exemplary retardant, respectively. Figure 3 shows the dissolution profile of a colchicine sustained release formulation containing 30% of an exemplary retarder and tablet hardnesses of 50N and 130N, respectively. Figure 3 shows the dissolution profile of colchicine sustained release formulations according to Figures 1 and 2. 3 shows the dissolution profile of a colchicine sustained release formulation containing 0% exemplary retarder.

I. Definitions For the purposes of the present invention, the term "colchicine" includes colchicine or any pharmaceutically acceptable salt thereof.

“Pharmaceutically acceptable” means generally safe, non-toxic, not biologically or otherwise unsuitable, and acceptable in veterinary and human pharmaceutical applications. Including that.

"Pharmaceutically acceptable salt" includes derivatives of colchicine, wherein colchicine is
It refers to pharmaceutically acceptable solvates that are modified by making acid or base addition salts thereof, and further include hydrates and co-crystals of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, organic acid addition salts of basic residues such as minerals or amines; organic addition salts of alkaline or acidic residues; and the like; and
Included are combinations that include one or more of the above salts. Pharmaceutically acceptable salts include the non-toxic salts of colchicine and quaternary ammonium salts. For example, non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitrogen; other acceptable inorganic salts include sodium salts, potassium salts, cesium. Metal salts such as salts; alkaline earth metal salts such as calcium salts, magnesium salts, combinations including one or more of the above salts. Pharmaceutically acceptable organic salts include acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, Glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-
Organic acids such as acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC- (CH2) n-COOH (n is 0 to 4); triethylamine salt, pyridine salt , Organic amine salts such as picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt; amino acid salts such as alginate, asparaginate and glutamate; and the above salts A combination comprising one or more of the following; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'dibenzylethylenediamine salt; alginate salt, asparagine salt Acid salts, amino acid salts such as glutamate; as well as; salts prepared from combinations comprising one or more of the above salts. All forms of such derivatives of colchicine are contemplated herein, including all crystalline, amorphous and polymorphic forms. Specific colchicine salts include colchicine hydrochloride, colchicine dihydrochloride, and co-crystals, hydrates or solvates thereof.

“Pharmacokinetic parameters” refers to plasma concentration (plasma concentration).
) (C), Cmax, Cn, C24, Tmax, and AUC, such as acti.
ve agent) (or metabolite or surrogate marker of active agent) over time. "Cmax" is the plasma concentration of active agent measured at the highest or peak concentration. "Cmin" is the plasma concentration of the active agent measured at the minimum concentration. "Cn" is the plasma concentration of the active agent measured approximately n hours after administration. "C24
Is the plasma concentration of the active agent measured about 24 hours after administration. The term "Tmax" refers to the time at which the measured plasma concentration of the active agent is highest after administration of the active agent. "
"AUC" is the area under the curve of a graph of measured plasma concentration of active agent versus time measured from one time point to another. For example, AUC0-t is the area under the curve of plasma concentration over time from time 0 to time t, where t is the final time point corresponding to the measurable plasma concentration of the individual formulation. be able to. AUC0-∞ or AUC0-INF is the area under the calculated curve of plasma concentration over time from time 0 to time infinity. In steady state testing, AUC
0- [tau] is the area under the curve of plasma concentration over the dosing interval (ie, time 0 to time [tau] (tau), where tau is the length of the dosing interval). Other pharmacokinetic parameters were calculated as parameters Ke or Kel, terminal elimination rate constants calculated from semi-log plots of plasma concentration versus time curves; t1 / 2 terminal elimination half-life, 0.693 / Kel. CL / F is the apparent systemic clearance (apparent tot) after administration.
albody clearance), calculated as total dose / total AUC∞; and Varea / F represents the apparent total volume of distribution after administration, total dose / (total AUC∞ × K).
el) is calculated.

"Efficacy" means the ability of an active agent administered to a patient to exert a therapeutic effect in that patient.

"Bioavailability" refers to the extent or rate at which an active agent is absorbed by a biological system, or becomes available at the site of physiological activity. For active agents that are intended to be absorbed into the bloodstream, the bioavailability data for a given formulation provide an estimate of the relative percentage of a administered dose absorbed into the systemic circulation. obtain. "Bioavailability" can be characterized by one or more pharmacokinetic parameters.

"Dosage form" means a unit of administration of the active agent. Examples of dosage forms are tablets, capsules,
It includes injections, suspensions, solutions, emulsions, creams, ointments, suppositories, inhalation dosage forms, transdermal dosage forms and the like.

  "Immediate release formulation" refers to a formulation that releases about 80% or more of the drug within about 30 minutes.

For purposes of this application, an activator (“enhancer”) is defined as any non-pharmaceutical active ingredient that improves the therapeutic potential of the formulation.

"Sustained release" is defined herein as the sustained release of the drug over a prolonged period of time.

"Extended time" is a continuous time of greater than about 1 hour, greater than about 4 hours, greater than about 8 hours, greater than about 12 hours, greater than about 16 hours, or greater than about 24 hours. Means

As used herein, unless otherwise indicated, "rate of release" or "release rate" or "dissolution rate" refers to the amount of drug released from a dosage form per unit time, eg, hourly. Refers to the milligram of drug released (mg / hr) or the percentage of the total dose of drug released per hour. The drug release rate of a dosage form is typically as the in vivo rate of drug release, i.e., the amount of drug released from the dosage form per unit time measured in a suitable body fluid under appropriate conditions. To be measured. The release rate is determined herein by placing the dosage form to be tested in the culture medium in a suitable dissolution bath. Aliquots of culture fluid, taken at preset intervals, are then injected into a chromatography system fitted with a suitable detector to quantify the amount of drug released during the test interval.

  Side effects are defined herein as secondary and usually adverse effects of the drug.

"Treating" or "treatment" or "to treat" or "alleviating"
Or terms such as “to alleviate” 1) therapeutic treatment to cure, delay, alleviate symptoms, reverse and / or arrest progression of the diagnosed condition or disorder; and 2) Prophylactic or preventive to prevent and / or delay the onset of the targeted pathological condition or disorder.
native) refers to both treatments. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; those in which the disorder is to be prevented. Beneficial or desired clinical results include, but are not limited to, detectable or undetectable symptom relief, diminished severity of disease, stable (ie, non-exacerbating) condition of disease, disease state. Delay or slowing of progression progression
g), recovery or alleviation of the condition, and remission (whether partial or total remission). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder; those in which the condition or disorder is to be prevented.

"Subject" or "individual" or "animal" or "patient" or "mammal" means any subject for which diagnosis, prognosis, or therapy is desired, particularly a mammalian subject. Mammalian subjects include humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, dairy cows,
This includes domestic animals such as bears, livestock, zoo animals, sports animals and pets.
The meanings of the terms "eukaryote", "animal", "mammal" and the like are well known in the art, eg Wehner und Gehring.
(1995; Thieme Verlag). It is also envisaged in the present invention that animals should be treated as being of economic, agricultural or scientific significance. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Non-limiting examples of agronomically important animals are sheep, cows and pigs,
On the other hand, for example, cats and dogs can be considered as economically important animals. In one embodiment, the subject / patient is a mammal; in another embodiment, the subject / patient is a human or non-human mammal (eg, guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, Monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, or pig); and most preferably, the subject / patient is a human.

II. Colchicine The colchicine used according to the invention is described in detail below. Colchicine (Che
The chemical structure of mID2010) is as follows:

The chemical name for colchicine is N [5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy 9-oxobenzo [a] heptalen-7-yl], (S) -acetamide (
N [5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy 9-oxob
enzo [a] heptalen-7-yl], (s) -acetamide) and has a molecular formula of C ₂₂ H ₂₅ NO ₆ ; CAS number: 64-86-8.

Colchicine is a long-standing anti-inflammatory drug in human medicine used as a symptomatic treatment for inflammatory diseases, most notably gout. It is a natural product that can be extracted from two plants of the lily family, dog saffron and fox lily. Colchicine is a tricyclic alkaloid and has a molecular weight of 399.437. The active ingredient colchicine and its tablet formulations are listed in various pharmacopoeias in Japan and abroad, such as the United States Pharmacopeia (USP).

The positive effects of its botanical sources in the treatment of rheumatism and swelling were first described in Egypt in about 1500 BC. Its use in gout was first described approximately 1500 years ago (Graham and Roberts, 195).
3, Ann Rheum Dis 12 (1): 16-9). Today, the therapeutic value of colchicine is well established in several inflammatory diseases and is approved by the FDA for the prevention and treatment of acute gout flare and familial Mediterranean fever (FMF). Other important established ones are off label use, but above all are Behcet's disease and recurrent pericarditis. For all known indications, generally colchicine 0.5-0.6 m
Orally administered as a solid tablet at strengths of g / tablet (eg European and US respectively). Although the mechanism of colchicine's pharmacotherapeutic action in various disorders is not completely understood, the drug preferentially accumulates in leukocytes, especially neutrophils, which is important for its therapeutic effect. It has been known. The three major interactions of colchicine containing specific proteins are their pharmacokinetics: tubulin, cytochrome P4503A4.
(CYP3A4), P-glycoprotein (P-glycoprotein) is regulated. The maximal therapeutic effect of the drug is related to its ability to bind to β-tubulin and is therefore envisioned to inhibit microtubule self-assembly and polymerization. The availability of tubulin is crucial for some cellular functions such as mitosis. Therefore, colchicine effectively functions as "mitotic toxicity" or "spindle toxicity". By inhibiting microtubule self-assembly, colchicine is involved in many cellular functions involved in immune responses such as regulation of chemokine and prostanoid production and inhibition of neutrophil and endothelial cell adhesion molecules. have a finger in the pie. Finally, it (it)
Is neutrophil degranulation, chemotaxis (c
Hemotaxis and phagocytosis, thus reducing the onset and amplification of inflammation. Colchicine is also used for urate crystal deposition (uric).
It suppresses acid crystal deposition, a process important for the origin of gout, which is enhanced by low pH in tissues, probably by suppressing glucose oxidation and subsequent lactate depletion in leukocytes (Imazio, Bru.
cato et al. 2009, Eur Heart J, 30 (5): 532-9;
Cocco, Chu et al. 2010, Eur J Intern Med, 21
(6): 503-8; Stanton, Germanert et al. 2011, Med
Res Rev, 31 (3): 443-81). In the management of pericarditis, colchicine exerts its therapeutic effect by suppressing acute pericardial inflammation. However, the exact cellular and molecular mechanism of action of how colchicine relieves pain and inflammation and prevents recurrence in acute pericarditis is not well understood.

Colchicine in the present invention can be used for the prevention and / or treatment of cardiovascular diseases and / or inflammatory diseases.

III. Sustained Release Formulation The present invention additionally provides a sustained release colchicine formulation for the treatment or prevention of cardiovascular disease and / or inflammatory disorders in a subject, wherein colchicine is at a predetermined or desired level. It is released from the formulation at a sustained rate along the release profile. Such a release is
This is accomplished by incorporating into the formulation an extended release component and an optional immediate release component. The colchicine preparation of the present invention comprises tablets, pills (pi)
ll), capsules, caplets, troches, sachets, cachets (c)
It may be formulated in a dosage form selected from achet, pouch, sprinkle, or any other form suitable for oral administration.

According to the invention, the colchicines described herein (ie, especially in the form of (pharmaceutical) compositions) are administered in the form of sustained release preparations. Other expressions such as “sustained release”, “controlled release”, “modified release” or “delayed release” “preparation” or “formulation” are understood herein to have the same meaning as “sustained release preparation”. To be done. Such preparations, in principle,
As long as sustained release is ensured, it can be in any form recognizable to those skilled in the art, oral (solid, semi-solid, liquid), transdermal (transdermal patch), sublingual, parenteral Na (injection), for eye drops (
(Including eye drops, gels or ointments) or pharmaceutical forms for rectal (suppository) administration.

According to the invention, a sustained release preparation is provided.
is applied to the drug substant over a sustained period of time after application to the patient.
ace, drug substance) for which a constant drug release profile is achieved. Such continuous time may range from 10, 20, 30, 40, 50 or 60 minutes to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1
It may be between 5, 16, 17, 18, 19, 20, 20, 22, 23 or 24 hours. Sustained release can also be after about 10, 20, 30, 40, 50 or 60 minutes, and about 2
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1.
After 8, 19, 20, 21, 22, 23 or 24 hours, 50, 55, 60, 65, 70
, 75, 80, 85, 90, 95 or more than 99% of colchicine released (f
undefined). As used herein, sustained release also refers to uptake, where some colchicine cannot be absorbed at all by the patient.
It may be defined as making colchicine available to a patient. Various sustained release dosage forms are disclosed herein to achieve delivery and / or sustained release of colchicine in the liver and / or both the small and large intestines, only the small intestine, or only the large intestine. Can be easily designed by those skilled in the art.

In some embodiments, the sustained release preparation may be pH independent. This allows
It enables such preparations to dissolve in almost any environment. In other embodiments, the sustained release preparation may be pH dependent. This allows for release at a more or less predictable site within the lower intestinal tract, which is distal to the site that would otherwise have been achieved without modification of the delayed release. Methods for delayed release are, for example, coatings. The optional coating should be applied in a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluid at a pH of less than about 5, but at a pH of about 5 or greater. Any anionic polymer that exhibits a pH-dependent dissolution profile is
It is envisioned that in practice of the invention it may be used as an enteric coating to achieve delivery to the lower intestinal tract. The mixture compatible with the polymer may be used to provide a coating for delayed or sustained release of the active ingredient, some of their properties including, but not limited to: purified lac. Shellac, also known as "refined p", obtained from resin secretion of insects
products). The coating dissolves in media with a pH above 7.

In some embodiments, sustained release preparations may be affected by the presence of alcohol in the body. The presence of alcohol in the patient's body can enhance dissolution of the composition and cause immediate release of the full dose. This effect is known as "dose dumping" and depends on the alcohol solubility of the substance. For example, in the case of sustained-release preparations containing high doses, which assume a slow release over 24 hours, this effect may have safety concerns and may even be life-threatening.

In order to achieve a constant or sustained release rate, a time-release hydrophilic matrix (t
Sustained-release preparations may be prepared using im release hydrophilic matrices). Their time-release hydrophilic matrices are known in the pharmaceutical arts. For example, one such hydrophilic matrix is hydroxypropyl methylcellulose (HPMC) or hypromellose. The hydrophilic matrix provides the initial release of the formulation at the first stage, mainly caused by the rapid swelling of the surface of the matrix tablet, combined with the erosion process, and distributed near the surface of the tablet. Results in immediate release of the drug substance. In certain embodiments, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15 of the drug substance.
%, Or about 10%, may be released immediately, depending on the release profile desired. In some embodiments, at least about 20% of the drug substance can be released immediately. In another embodiment, at least about 20% of the drug substance may be released within the first about 30 minutes. As used herein, the term "about" or "approximately" means the stated value (eg, 50%, 45).
%, 40%, etc.), and in the case of a range of values, it means a difference of 10% from both the lower and upper limits of the range. For example, "about 50%" refers to a range between 45% and 55%. Upon initial swelling of the tablet surface, gel formation of the hydrophilic matrix begins. This gelation prevents immediate dissolution and disintegration of the tablet core, which causes the major portion of the drug substance to slowly dissolve in the gel structure over time, in solution according to the rules of Fick's law. To be able to spread to. This diffusion itself can be caused in the formulation approach by the concentration of hypromellose and the viscosity of the gel formed, well defined from the molecular weight of hypromellose. Therefore, the drug release profile can be modified with different viscosity grades of hypromellose or mixtures thereof. All corresponding formulation and process parameters that achieve the expected release profile are known and can be adjusted using practical development techniques such as formulation screening, statistical clinical trial design.

In certain embodiments, substances involved in the sustained release of controlled release formulations can be further mixed with a binder. Binders are added during formulation to increase the mechanical strength of the granules and tablets. Binders can be prepared in different ways: (1) wet agglomerat
(2) during wet granulation, as a dry powder that is mixed with other ingredients prior to ionization), agglomerates called solution binders.
It can be added to the formulation as a solution used as on liquid) and (3) as a dry powder mixed with other ingredients before compression. In this form, the binder is called a dry binder. Solution binders are a common method of incorporating binders into granules. In certain embodiments, the binder used in the formulation is in the form of a dry powder binder. Non-limiting examples of binders useful in the core include hydrogenated vegetable oils, castor oil, paraffins, higher fatty alcohols, higher fatty acids, long chain fatty acids, fatty acid esters, fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, carbonized Included are wax-like materials such as hydrogen, normal wax, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers with a hydrocarbon backbone, and mixtures thereof. Specific examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (
HPC)), polyvinyl alcohol and mixtures thereof. In certain embodiments, the binder is HPMC. In another embodiment, the binder is hypromellose 6 mPa ^*.
s. In certain embodiments, the binder may be present in an amount of about 1% to about 30% by weight of the formulation.

In another embodiment of the invention, the sustained release formulation may include a disintegrant. Disintegrants are agents used in the pharmaceutical preparation of tablets, which disintegrate and release their medicinal substances on contact with water. In certain embodiments, the disintegrant may be water soluble to support disintegration of the tablet in the stomach. Non-limiting examples of disintegrants used in the formulation include sucrose, lactose,
In particular lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, DVB methacrylate, cross-linked PVP, microcrystalline cellulose, polacryllin potassium, sodium starch glycolate, starch, Includes pregelatinized starch and mixtures thereof. In at least one embodiment, the disintegrant is microcrystalline cellulose (eg, Avicel P
H101), cross-linked polyvinylpyrrolidone (for example, KOLIDON (registered trademark) CL)
, Cross-linked sodium carboxymethyl cellulose (eg, AC-DI-SOL ™)
, Starch or starch derivatives such as sodium starch glycolate (eg E
XPLOTAB®) or in combination with starch (eg PRIMOJEL
™), AMBERLITE ™ IRP 88, and other swellable ion exchange resins,
Formaldehyde casein (eg ESMA SPRENG ™), and mixtures thereof.

In another embodiment of the invention, the sustained release formulation may include fillers or fillers. Filler refers to an inert substance used as a filler to produce the desired bulk, flow and compression properties in the preparation of tablets. Non-limiting examples of fillers for use in the formulation are sucrose, lactose, especially lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, DVB methacrylate, Includes cross-linked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and mixtures thereof. In certain embodiments, lactose monohydrate is included as a filler in an amount of about 10% to about 80%, preferably about 59% by weight of the tablet. In certain embodiments, pregelatinized starch is included as a filler in an amount of about 5% to about 50% by weight of the tablet, preferably about 7.5%.

In another embodiment, the sustained release formulation of the present invention may include a release retarding agent to maintain a constant release rate of the drug. Examples of release-retarding agents include, but are not limited to, cellulose ethers, cellulose esters, acrylic acid copolymers, waxes, gums, glycerin fatty acid esters and sucrose fatty acid esters. In one embodiment, the retarder is RETALAC.
® (Meggle), a spray agglomerated blend of 50 parts lactose monohydrate and 50 parts hypromellose.
As used herein, hypromellose has a viscosity of 6 mPa ^{* s-} 100,000 mPas.
^It may be in the range of ^* s. In one embodiment, the hypromellose used has a viscosity of 4
000 Pa ^* s. The release rate of the drug may be altered by adjusting the amount of retarder in the composition. In one embodiment, the delay agent of the formulation of the present invention is adjusted in such a manner that it releases colchicine in a sustained and constant manner and about 80% of the active ingredient is released in vitro at a given time. It For purposes of illustration, and not for the purpose of limiting the scope of the invention, the time does not exceed 24 hours, 16 hours, depending on the desired properties of the final product.
No more than 12 hours, no more than 8 hours, no more than 6 hours, no more than 4 hours, 3.5
It may be a time not exceeding the time, or not exceeding 1.5 hours. It is understood that the release rate can vary based on whether the experiment is performed in vitro or in vivo. Thus, if the desired release rate is between about 1.5 and about 3.5 hours in vitro, or between about 1.5 and about 6 hours in vitro, the release rate under in vivo conditions is , May actually differ depending on the experimental conditions. In certain embodiments, the sustained release formulations of the present invention provide a sustained and constant release of colchicine such that about 80% of the active ingredient is released in vitro between about 1.5 hours and about 3.5 hours. discharge.

In another embodiment, the sustained release formulation of the present invention may include a glidant.
Lubricants can be used before or during tabletting to improve powder flow properties and prevent set. Suitable lubricants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, tricalcium phosphate and the like. In one embodiment, about 0.0 of tablets.
Talc may be included as a lubricant in an amount from 5% to about 5% by weight, preferably about 1% by weight.

In another embodiment, the sustained release formulation of the present invention may include a lubricant. Lubricants can be added to the pharmaceutical formulation to reduce friction that occurs between the solids during tablet manufacture and the die wall. High friction during tableting can lead to inadequate tablet quality (tablet capping or even fragmentation during ejection and vertical scratches on the edges of the tablet). It can cause a range of problems, including even discontinuing production. Accordingly, lubricants are added to certain tablet formulations of the present invention, including certain embodiments of the formulations described herein. Non-limiting examples of lubricants useful in the core include glyceryl behenate, stearic acid, hydrogenated vegetable oil, (hydrogenated cottonseed oil (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM) and hydrogen. Soybean oil and castor wax (S
TEROTEX (registered trademark) K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, preferably 1450, preferably 4000 or more), magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymer (for example, Union Carbide). , Inc., Danbury, Conn
． Under the registered trademark CARBOWAX®), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate,
Includes DL-leucine, colloidal silica, mixtures thereof and others known in the art. In one embodiment, stearic acid comprises from about 0.05% to about 5% by weight of the tablet.
, Preferably in an amount of about 1% by weight, included as a lubricant.

Sweeteners that may also be used in the taste masking coating of certain embodiments of the matrix dosage form include glucose (corn syrup), glucose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin, and sodium. Various salts of saccharin such as salts; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; stevia rebaudiana (stevioside); sucrose such as chloro derivatives or sucralose; and sugar alcohols such as sorbitol, mannitol, xylitol. . Furthermore, as expected, hydrogenated starch hydrolyzate (hydrogenated starch h) is used.
artificial sweeteners such as hydrate and 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazine-4-1-2,2-dioxide, especially potassium salts (acesulfame-K), and Including their sodium and calcium salts. The sweeteners can be used alone or in any combination thereof.

The controlled release formulations of the present invention can further include one or more pharmaceutically acceptable excipients. Granulation aids or agents, colorants, fragrances, pH adjusting agents, anti-adhesive agents, lubricants and similar excipients conventionally used in pharmaceutical compositions may be included. In one embodiment,
Colored excipients may be advantageous to add as they produce a visual change that avoids misuse. Coloring excipients can color liquids or particles simultaneously, or one independently of the other. Among the suitable coloring excipients are the following: indigotine, cochineal carminic acid,
Yellow Orange S, Arla Red AC, Iron Oxide, Curcumin, Riboflamine, Tartrazine, Quinoline Yellow, Azorubine, Amaranth, Carmine, Erythrosin, Red 2
G, Patented Blue V, Glittering Blue FCF, Chlorophyll, Copper Complex of Chlorophyll, Green S, Caramel, Glittering Black BN, Carbo Medicinal Vegetabilis, Brown FK and HT, Carotenoid, Anato Extract, Paprika Extract , Lycopene, rutin, canthaxanthin, beetroot red, anthocyanin, calcium carbonate, titanium dioxide, aluminium, silver, gold or resole rubin BK or any other coloring excipient suitable for oral administration.

In some embodiments, the sustained release formulation may be coated. The coating may provide various functions. In some embodiments, coatings can be used, for example, to achieve delayed release, acid resistance, targeted release in the lower GI tract, and to avoid a bad taste spread to the mouth. In some embodiments, coatings may be used to protect the API / tablet from light and provide good mechanical resistance. Of course, it should be understood that the coating may serve other functions and one of ordinary skill in the art would know the purpose of tablet coating.

The pharmaceutical composition and / or solid carrier particles can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compression coatings, fast disintegrating coatings or enzyme degradable coatings. Multiple coatings may be applied to obtain the desired performance. In addition, one or more of the active agents may be immediate release, pulsatile release, controlled release, sustained release, delayed release, targeted release, synchronized release.
release, or targeted delayed release
as)). In practice, the formulation will include typical pharmaceutically active substances (eg,
Pseudoephedrin and vitamins (eg vitamin C), minerals (Ca, Mg, Zn, K) or other supplements (eg St. John's Wort, echinacea).
e), amino acids). For controlled release / absorption, solid carriers can be made from coats of various ingredient types and levels or thicknesses with or without the active ingredient. A wide variety of such solid carriers can be blended in dosage forms to achieve the desired performance. Solutions are oral, nasal, buccal, intraocular, urethral, transmucosal,
It can be delivered and adapted for vaginal, topical or rectal delivery, but mainly oral delivery is used.

When formulated with microparticles or nanoparticles, the drug release profile can be easily tailored by adding coatings, such as hard or soft gelatin coatings, starch coatings, resin or polymer coatings and / or cellulose coatings. .. Such dosage forms include, but are not limited to, microparticles or nanoparticles (such as in microcapsules or nanocapsules) using, for example, occlusive coatings, enteric coatings, sustained release coatings, or targeted delayed release coatings. May be further coated. As used herein, the term "enteric coating" refers to a mixture of pharmaceutically acceptable excipients applied to, combined with, admixed with, or added to a carrier or composition. .. The coating may be applied to the compressed, shaped, extruded active substance and may also comprise gelatine of the carrier or composition and / or pellets, beads, granules or particles. The coating can be applied through aqueous dispersion or after dissolution in a suitable solvent. The carrier may be wholly or partially biodegradable or non-biodegradable.

In some embodiments, polymethacrylic acid acrylic polymers can be used as coating polymers. In at least one embodiment, the coating is Rohm Ph
Acrylic resin paints used in the form of an aqueous dispersion, such as those marketed by ARMA under the trade name EUDRAGIT® or BASF under the trade name KOLLICOAT®. In a more preferred embodiment, EUDRAGIT® E100, a chaotic copolymer based on dimethylaminoethyl methacrylate and a neutral methacrylic acid ester, having an average molecular weight of about 150,000 is used as the coating polymer. . The different coating polymers of certain embodiments can be blended together in any desired ratio to ultimately obtain a coating with the desired drug dissolution profile. The coating method is a pan-type coating device (pan).
coater or fluid bed coating
can be sprayed with a solution of the polymer on the tablet. The solvent can be organic or aqueous, depending on the nature of the polymer used. In a preferred embodiment, the solvent is alcohol. Coating methods are well known in the art.

The composition of the invention is also an enteral coated delayed release oral dosage form, i.e. an oral dosage form of a pharmaceutical composition described herein using an enteric coating which results in release in the lower gastrointestinal tract. It can be formulated. Enteric-coated dosage forms generally comprise microparticles, microgranules, micropellets or microbeads of the active ingredient and / or other compositional ingredients themselves coated or uncoated. Enteric-coated oral dosage forms are also capsules (coated or uncoated) containing pellets, beads or granules of the solid carrier or composition themselves coated or uncoated. You may.

The carriers used with the present invention include permeable and semipermeable matrices or polymers which control the release characteristics of the formulation. Such polymers are described, for example, in cellulose acylate, acetic acid, and US Pat. No. 4,285,987, which is incorporated herein by reference. And other semipermeable polymers, such as those described in US Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,3. Coprecipitates of polycations and polyanions as disclosed in US Pat. No. 546,142, the relevant portions of which are incorporated herein by reference.
cation) forming a selectively permeable polymer.

Other carriers for use with the present invention include, for example, but not limited to starch, modified starches, and starch derivatives, gums such as, but not limited to, xanthan gum, alginic acid, other alginates, benitonite, vegum, agar, guar gum, locust bean gum. , Gum arabic, quinspsillium, flax seed, okra gum, arabinogratin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, cross-linked polyvinylpyrrolidone, ion exchange resin, potassium polymethacrylate, carrageenan (and Derivatives), karaya gum, biosynthetic gum and the like.
Other useful polymers are polycarbonate (straight carbonic polyester); microporous materials (bisphenol, microporous poly (vinyl chloride), microporous polyamide, microporous modacrylic copolymer, microporous styrene-acrylic). And their copolymers); porous polysulfones, halogenated poly (vinylidene) s, polychloroethers, acetal polymers, polyesters prepared by esterification of dicarboxylic acids or anhydrides with alkylene polyols,
Poly (alkylene sulfide), phenols, polyester, asymmetric porous polymer (a
Symmetric porous polymer, crosslinked olefin polymer, hydrophilic microporous homopolymer, low bulk density copolymer or interpolymer
polymer), and other similar materials, poly (urethane), cross-linked chain extension (cross-
Linked chain-extended poly (urethane), poly (imide), poly (benzimidazole), collodion, regenerated protein, semi-solid crosslinked poly (vinylpyrrolidone).

The choice of additional additives and their levels, as well as the primary coating material (s), has the following properties: pH level at the target site, desirability of making the tablet pH dependent or pH independent, alcohol. Solubility in the stomach, resistance to gastric dissolution and disintegration; impermeability to gastric juice and drugs / carriers / enzymes while in the stomach; ability to rapidly dissolve or disintegrate at the target intestinal site; in storage Physical and chemical stability; non-toxic; easy to apply as a coating (substrate affinity)
ly)); as well as economic feasibility.

In addition to the above, without limiting the scope of the invention, various formulations illustrating the invention are described below. Controlled release tablets or capsules and the like contain colchicine as a core coated with an immediate release layer. Controlled release bilayer tablets or capsules and the like include a sustained release layer and an immediate release layer. A three or more layer controlled release tablet comprises (i) a layer of one or more substances that control the sustained release, and (ii) one or more immediate release layers.

According to one embodiment of the present invention, the composition comprising colchicine controls the release of colchicine, so that at least one of the sparingly soluble intermediate layers has a release-releasing intermediate layer.
It is further coated with a slowing intermediate layer).

Traditionally, colchicine immediate release dosage forms (primarily tablets, as well as injectable or oral solutions) have been used in the treatment of gout or FMF. All globally approved colchicine containing pharmaceuticals are approved only for gout and / or FMF and are immediate release tablets.
Colchicine can be used to prevent certain other inflammatory diseases such as pericarditis, PPS, and more recently, stable coronary heart disease patients. The difference between treatment and prevention for colchicine is
In treatment, overt disease and / or ongoing inflammation is treated. Therefore, high levels of colchicine are required and are usually associated with undesirable side effects, most notably gastrointestinal i.
nsult). In prophylaxis, colchicine does not need to suppress ongoing inflammation, but rather the rapid onset of inflammation. Therefore, perhaps smaller amounts and stable levels of colchicine are needed and beneficial. As described in the present invention, this is accomplished by administering colchicine, which is formulated as a sustained release preparation, as described above.

In the treatment of acute inflammatory diseases such as FMF or gout, high doses and high serum levels are necessary and desirable to suppress inflammation. Therefore, fast release
release) and a rather short plasma level half-life.
Conventional tablets which are ma half-life) are preferred. However, in the case of cardiovascular disease prevention, low levels may be sufficient to inhibit the activity of neutrophils. Sustained release system (s
The used release system promotes more stable levels of colchicine and reduces the frequency of adverse events.

The advantages of colchicine administered as a sustained release include, for example, the smoothing of the plasma level curve (fl
Attending (relatively lower but broader peak levels) is to suppress the occurrence of serious adverse events associated with colchicine toxicity, even in the presence of potential drug interactions. Most of the toxicity associated with colchicine is one of the elimination pathways (liver and kidney)
One or both is due to the fact that it reduces its activity due to other drugs or due to disease (eg renal failure). In the case of slow and sustained drug absorption (sustained release), the body
It takes more time to excrete colchicine from the system. In this case, colchicine levels are unlikely to reach toxic levels if there is an impaired excretion (due to drug interactions or disease). In addition, administration of colchicine as sustained release is resistant to overdose release,
Therefore, the dissolution of the composition is not significantly affected by alcohol.

Moreover, sustained release extends the time that colchicine is present in blood at therapeutic levels. This results in a more effective inhibition of disease progression and therefore
Improve clinical outcome.

Furthermore, for prophylactic use as described herein, colchicine does not penetrate deeply into tissues (such as gout) and may have activity directly on the blood system (in blood vessels), If
Colchicine acts on plaques and especially on inflammatory blood cells (neutrophils). This means that smaller amounts of total colchicine and lower serum levels can be treated, for example to treat acute gout flare. For example, immediate release and elevated levels of colchicine, such as to treat acute gout flare, may be avoided. Thus, lower levels of colchicine, eg, a sustained release formulation of about 0.1 to about 0.75 mg as described above (or less frequent administration) may achieve desired clinical outcomes. Can be enough to do.

Under normal conditions, most colchicine is absorbed from the small intestine and most passes through the liver (some are also excreted in the urine via the kidneys). There, colchicine is metabolized, but much of the colchicine passes through the liver unmetabolized. This means that colchicine passes through the liver into the bile where it is excreted in the large intestine (colon). There, colchicine can be reabsorbed into the body again, resulting in a unique second peak (accounting for about 50% of all colchicine absorbed, which is thought to be the cause of digestive problems such as diarrhea). ing). When colchicine is formulated as a sustained release preparation as described above, the slow release of colchicine results in slow reabsorption. This results in a more complete metabolism of colchicine in the liver (because less colchicine is present at some point in time) and therefore less recycling of unmetabolized colchicine. as a result,
This suppresses the occurrence of digestive problems. Colchicine administered as a sustained release according to the present invention also has other known side effects associated with colchicine treatment / administration (those skilled in the art are well aware of side effects that may occur during colchicine administration or colchicine treatment). ing)
Can be beneficial to. Therefore, administration of colchicine as sustained release as described above provides improved safety and safety benefits.

IV. Method of Preparing Sustained Release Formulation The present invention additionally provides a method of preparing a formulation of colchicine comprising a sustained release component and an optional immediate release component, wherein the colchicine has a defined and desired release profile. And is released from the formulation at a sustained rate.

In one embodiment, the colchicine composition according to the invention is in the form of tablets. The term "tablet" as used herein means a compressed pharmaceutical dosage form of any shape or size. The tablets described herein may be obtained from a composition containing colchicine and a pharmaceutically acceptable excipient. Any of the colchicine compositions may be in any other dosage form known in the art, in particular in any oral dosage form such as a capsule.

In a first aspect of the invention there is provided a controlled release formulation for use in oral dosage forms. The formulation comprises a mixture containing hypromellose as a hydrophilic matrix, which is effective in providing controlled release of the active pharmaceutical ingredient.

Matrix systems are well known in the art. In a typical matrix system, the drug is evenly dispersed in the polymer with conventional excipients. This mixture is typically compressed under pressure to produce tablets. The API is released from the tablet by diffusion and erosion. Matrix systems are incorporated herein by reference in their both contents: (i) Handbook of Pharmaceuticals.
Controlled Release Technology, Ed. D. L. Wis
e, Marcel Dekker, Inc. New York, N.N. Y. (2000) and (ii) Treatise on Controlled Drug Delivery.
ry, Fundamentals, Optimization, Application
s, Ed. A. Kydonieus, Marcel Dekker, Inc. New Y
ork, N.N. Y. (1992).

When a tablet is exposed to an aqueous medium, such as in the gastrointestinal tract, the tablet surface becomes moist and the polymer begins to partially hydrate, forming a gel layer on the outside. This outer gel layer is completely hydrated and begins to penetrate the aqueous liquid. The water subsequently penetrates towards the core of the tablet, allowing another gel layer to form just below the dissolving outer gel layer. Those continuous concentric gel layers are
Maintains uniform release of API by diffusion from the gel layer and maintains exposure through tablet erosion. In the case of the mixtures according to the invention, hypromellose, when contained in a compressed tablet matrix, provides a hydrophilic, swollen structure which can act as a gel layer. In this way, drug release is controlled.

According to one embodiment, the colchicine formulation of the present invention comprises blending granules provided by either wet granulation or dry granulation of a colchicine composition with an excipient and then compressing the composition into tablets. Can be manufactured by

In one embodiment, wet granulation is used to prepare wet granules containing colchicine. Granulation liquid is used in the wet granulation process. Both aqueous and non-aqueous liquids may be used as the granulating liquid. In one embodiment, the granulation liquid is an aqueous solution, more specifically purified or deionized water. The amount of the granulating liquid used is, for example, the type of the granulating liquid,
It can be determined by a number of factors such as the amount of granulation fluid used, the type of excipient used, the nature of the active agent, and the loading of active agent.

In one embodiment, colchicine particles and suitable excipients are mixed with the granulation liquid for a sufficient period of time to promote good distribution of all starting materials and good content uniformity. Wet granules are generally at temperatures between about 20 ° C and about 35 ° C, or more specifically at room temperature (about 2 ° C).
5 ° C). After the wet granules, the temperature of the granules is increased and the granules are dried to obtain dry granules. In certain embodiments, the drying step may be performed for a sufficiently long period of time until the desired residual water content is achieved. In certain embodiments, the drying step comprises about 12-4 at about 45 ° C.
It can be 8 hours. The total time to carry out the granulation process can be determined by various factors including, but not limited to, the solvent used, batch size, equipment used, etc.

Any device for contacting the granulation fluid with colchicine and excipients may be used, so long as a uniform distribution of the granulation fluid is achieved. For example, a small amount of production can be achieved by mixing and moistening colchicine and excipients in a mortar or stainless steel bowl, while a large amount is V- equipped with a booster bar. Blenders, planetary mixers, rotary granulators, high shear granulators, and fluid bed granulators may also be used. In one embodiment, the granulator is a high shear granulator.

In one embodiment, a method of making a colchicine composition comprises wet granulating colchicine with a pharmaceutically acceptable excipient and a granulating liquid to obtain wet granules, and the granules in the next step. Mixing with a second excipient to obtain a colchicine composition. In one embodiment, pharmaceutically acceptable excipients include binders and fillers. In certain embodiments, the binder may be hypromellose. In some embodiments, the filler can be lactose monohydrate and pregelatinized starch. In another embodiment, purified water is used as the granulation liquid. In some embodiments, the second excipient mixed with the granules can be a filler. In certain embodiments, the filler may be lactose monohydrate. The colchicine composition contains from about 0.1% to about 10%, or more specifically from about 0.25% to about 0.75%, colchicine by weight of the total weight of the colchicine composition. be able to.

In certain embodiments, a method of making a composition comprises wet granulating colchicine with a pharmaceutically acceptable excipient to obtain wet granules, and mixing the granules with a filler to form a colchicine composition. Including getting. In some embodiments, the method further comprises drying the mixture. In another embodiment, the wet granules are dried to obtain dry granules, which are then mixed with a binder, a filler, or both to obtain a composition. In another embodiment, the dried granules can be milled to obtain milled granules, which can then be mixed with a binder, a filler, or both. The method can further include mixing the colchicine composition with a lubricant, a lubricant, or both to obtain a blend, or compressing the blend to obtain tablets. In one embodiment, the lubricant may be talc. In another embodiment, the lubricant may be stearic acid. The method can further include coating the tablet.

In another embodiment, a method of making a colchicine tablet is wet granulating colchicine with a pharmaceutically acceptable excipient to obtain wet granules; drying the wet granules to obtain dry granules; Milling the dry granules to obtain milled granules; mixing the milled granules with a filler to obtain a composition; blending the composition with a lubricant, a lubricant, or both to obtain a blend;
And compressing the blend to obtain a colchicine tablet of the invention.

In some embodiments, the wet granules are dried to obtain dry granules, which are then mixed with a second excipient, eg, a filler. The wet granules can be dried by any suitable means to remove the granulation fluid and form a dry granule containing colchicine and a pharmaceutically acceptable excipient. The drying conditions and duration depend on factors such as the liquid used and the weight of the granular particles. Examples of suitable drying methods include, but are not limited to, tray drying, draft drying, microwave drying, vacuum drying, and fluid bed drying.

After drying, the dried granules may be mixed directly with excipients such as fillers, binders, or lubricants for further processing. Alternatively, the dry granules may optionally be subjected to additional processing steps prior to mixing with the excipients. For example, the dry granules may be sized to reduce the particle size prior to mixing with the excipients. Exemplary operations for applying sizing include milling and sieving. Any suitable device for reducing particle size may be used in the present invention.

Suitable excipients are extragranular to form the colchicine composition.
normally) and may be mixed with the granules. As used herein,
The term "extragranular" or "extragranular" refers to a reference sample, such as a suitable excipient,
It means that, after wet granulation, it was added as a dry component or was added. In one embodiment, fillers, binders, lubricants and lubricants are extragranularly added to the granules and mixed to form a blend. The blend may be encapsulated directly in a capsule shell, such as a hard gelatin shell, to form a capsule formulation. Alternatively, the blend may be compressed into tablets. In some embodiments, the granules are dry granules or ground dry granules.

Mixing may occur for a time sufficient to make a homogeneous mixture or blend.
Mixing can be accomplished by blending, stiffing, shaking, tumbling, rolling, or any other method to obtain a uniform blend. In some embodiments, the ingredients to be mixed are combined in a suitable device under low shear conditions, such as a V-blender, a double cone blender or any other device capable of functioning under low shear conditions. ..

The homogeneous mixture or blend is then compressed using any method suitable in the industry. The mechanical force determines the physical properties of the tablet, especially the resulting crush strength of the tablet. Mechanical strength interacts with the initial swelling of the tablet and the rate of dilution of the tablet core. This effect is well known in the art and can be regulated and controlled during the product life cycle. For the colchicine sustained release formulations of the present invention, the compressive strength used may range from about 30N to about 130N. In one embodiment, the compressive strength may be about 100N. In another embodiment, the compressive strength is about 100N.
It may be ± 15N.

Colchicine tablets prepared from the above method have good friability.
And exhibits acceptable physical properties, including hardness. According to EP and USP guidelines, the colchicine tablets disclosed herein have a friability ranging from about 0% to less than about 1%.

Colchicine tablets can be coated. Coating tablets
This may be done by any known process. The coating for the colchicine tablets disclosed herein can be any suitable coating, such as, for example, a functional or non-functional coating, or multiple functional or non-functional coatings. A coating that modifies the release profile of all formulations by "functional coating",
For example, meant to include a sustained release coating. By "non-functional coating",
Non-functional coatings, such as cosmetic coatings (cosmeti)
c coating). Non-functional coatings may affect release of the active agent to some extent by initial dissolution of the coating, hydration reaction, perforation, etc., but are not considered a significant departure from the uncoated composition. May not be done.

In one embodiment, the colchicine composition comprises colchicine, binders, fillers, retarders, lubricants and lubricants. In certain embodiments, the colchicine composition comprises about 0.25 to about 0.75.
colchicine; about 10 to about 80 mg lactose monohydrate; about 5 to about 50 mg pregelatinized starch; about 1 to about 30 mg hypromellose 6 mPa ^* s; about 5 to about 40 mg Retalac (lactose monohydrate). And hypromellose 4000 mPa ^* s 50/50
% Compound); about 0.5 to about 5 mg talc; and about 0.5 to about 5 mg stearic acid 50. In one embodiment, the colchicine composition comprises about 0.5 mg colchicine; about 59 mg lactose monohydrate; about 7.5 mg pregelatinized starch; about 1 mg hypromellose 6 mPa ^* s; about 30 mg Retalac. Hydrate and Hypromellose 4000 mPa ^* s 50/50 wt% compound); about 1 mg talc; and about 1
It contains 50 mg of stearic acid. The colchicine dosage form has a total weight of about 100 mg. The colchicine composition can be in the form of tablets.

V. Therapeutic method using sustained-release colchicine The present invention further provides a method for treating or preventing cardiovascular disease and / or inflammatory disorder in a subject, which comprises administering a therapeutically effective amount of the colchicine formulation of the present invention to the subject. And colchicine is released from the formulation at a sustained rate along a predetermined or desired release profile. The method of the present invention provides a novel design of a colchicine formulation containing a sustained release component and an optional immediate release component to selectively tailor the pharmacokinetics of the administered formulation, depending on the nature and need of the patient's condition. It is flexible and can be selectively modified during the preparation process as described above so that both components are compatible with a given release profile.

In one embodiment, the treatment comprises application or administration to the patient of a colchicine formulation as described herein, wherein the patient has or develops cardiovascular disease and / or inflammatory disorder. There is a risk. In another embodiment, treatment is also intended to include application or administration to the patient of a pharmaceutical composition comprising a colchicine formulation, wherein the patient develops cardiovascular disease and / or inflammatory disorder. Or at risk of developing it.

As used herein, the term “cardiovascular disease” refers to any disease involving the heart and / or vascular system (including all blood vessels, arteries, capillaries and veins). This is an International Statistic created by the World Health Organization.
al Classification of Diseases and Relate
d Health Problems 10th Revision (ICD-10) V
All diseases listed in Chapter 9 “Cardiovascular Diseases (I00-I99)” of version for 2010 (International Statistical Classification of Diseases and Related Insurance Problems, 10th Revised Edition (ICD-10) 2010). including.

More specifically, all diseases of this ICD-10 include a) inflammation of any part of the heart or blood vessels and b) ischemia / atherosclerosis / thickening of any blood vessel of the circulatory system. Classify as.

Colchicine, as described herein, is available in ICD-10 Section 100-I
For use in the treatment and / or prevention of any inflammatory disorder involving heart tissue selected from 99. More specifically, they include acute and recurrent pericarditis, as well as post-operative complications related to pericardial inflammation (post-open heart syndrome, post-pericardiotomy syndrome, pericardial effusion). Other inflammatory heart diseases treated are myocarditis, endocarditis and any form of atrial fibrillation.

The mechanism of action proposed in this indication is the inhibition of plaque instability by neutrophil inhibition. In stable coronary artery disease, fatty substances accumulate in blood vessels and form stable plaques.
This plaque can be vulnerable to attack by neutrophils. This can cause plaque instability, resulting in plaque rupture and clinical events. Therefore, colchicine as described herein, ischemia / atherosclerosis and vascularization of blood vessels (arteries, capillaries and veins) due to plaque formation with risk of clinical events due to plaque instability and And / or for use in the treatment and / or prevention of any disease of the cardiovascular system associated with thickening. Claimed are all diseases classified in ICD-10 Section I00-I99 that meet any of those requirements. Examples are stable coronary artery disease, cardiovascular atherosclerosis and peripheral vascular atherosclerosis, abdominal aortic aneurysm (AAA) and carotid and iliac femoral / renal atheroma (eg I.
25, I70).

In the present invention, an acute cardiovascular event in a patient with stable coronary artery disease is preferably a cardiovascular event in a patient with stable coronary artery disease. In the present invention, the terms "stable coronary artery disease" and stable coronary heart disease have the same meaning and are used interchangeably. Both terms include the condition stable coronary artery disease (SCAD). The term “stable” in the terms “stable cardiovascular disease”, “stable coronary artery disease” or “stable coronary artery disease” means in the absence of an acute cardiovascular event,
Defined as any condition of diagnosed cardiovascular disease. Thus, for example, stable coronary artery disease defines various graded aspects of coronary artery disease except in situations where coronary thrombosis is predominant in clinical presentation (acute coronary syndrome).

Colchicine in the present invention can be used for the prevention and / or treatment of cardiovascular diseases. Cardiovascular diseases include, but are not limited to, for example, Robbins and
Cotran, Pathological Basis of Disease, Eight
th Edition, including Saunders Elsevier heart disease. Cardiovascular disease refers to a group of diseases of the circulatory system, including the heart, blood vessels and lymph vessels. In particular, cardiovascular disease may include atherosclerosis, vascular disease associated with plaque formation or disposition. The most common cardiovascular diseases are coronary heart disease and stroke. Non-limiting examples of cardiovascular diseases that can be prevented or treated by the method of the present invention include coronary heart disease (a disease of blood vessels supplying blood to the heart muscle), cerebrovascular disease (a disease of blood vessels supplying blood to the brain), peripheral. Arterial disease (a disease of blood vessels that supply blood to the arms and legs), rheumatic heart disease (damage to myocardium and heart valves by rheumatic fever caused by streptococcus), congenital heart disease (heart present at birth) Structural dysplasia), deep vein thrombosis and pulmonary embolism (thrombus in the leg veins that can travel to the heart and lungs), hyperlipidemia (excessive levels of blood fat such as LDL), hypertension , Coronary artery disease, atherosclerosis, ischemic disease, abdominal aortic aneurysm, carotid and iliac femoral / renal atheroma, heart failure, cardiac dysrhythmia, arteriosclerosis, heart attack and stroke. Heart attacks and strokes are usually acute events, primarily caused by obstructions that prevent blood from flowing to the heart or brain. The most common reason for this is the accumulation of fatty deposits on the lining of blood vessels that supply blood to the heart or brain. Stroke can also be caused by bleeding or blood clots from blood vessels in the brain.

In particular, in the present invention, colchicine undergoes acute pericarditis, recurrent pericarditis, recurrent pericarditis in patients with a history of pericarditis, postpericardiotomy syndrome (PPS), cardiac surgery. PPS in patients and stable cardiovascular events in patients with stable coronary (cardiac) disease, which may be acute cardiovascular events.

Pericarditis is an inflammatory disease involving the pericardium, which is a thin, double-walled, fibrous sac (sac) that surrounds the heart. Due to inflammation, it causes pericardial irritation and swelling.
). This causes the sac to rub against the heart, causing chest pain, the most common symptom of pericarditis. Very rare on a population basis, pericarditis is the most common form of inflammatory disorder of the heart. Pericarditis is uneven in its cause, clinical findings and duration of symptoms. It can occur as a single clinical problem or as a symptom of systemic disease. In most cases (90%), pericarditis is due to an idiopathic (spontaneous, unexplained) cause, but can also be secondary to systemic infection, acute myocardial infarction or autoimmune disease. Postpericardiotomy syndrome (PPS) occurs days to weeks after surgery,
It can be an annoying complication after heart surgery. The estimated incidence of the syndrome ranges from 10 to 40% of patients undergoing cardiac surgery and is relatively widespread (Prince and Cunhe.
, 1997, Heart Lung, 26: 165).

Non-limiting examples of (acute) cardiovascular events are atherosclerotic wall injury, acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardiogenic ischemic stroke. Further such events are eg Rob
bins and Cotran, Pathological Basis of Dise
, Ease Edition, Saunders Elsevier.

In certain embodiments, the colchicine formulations of the invention can be used to treat inflammatory diseases other than those mentioned above. In certain embodiments, inflammatory diseases include, but are not limited to, gout, familial Mediterranean fever, Behcet's disease, age-related macular degeneration and Alzheimer's disease.

Patients / subjects suffering from the diseases mentioned above and / or suitable for treatment with colchicine according to the invention can be diagnosed by conventional and / or usual procedures. Those skilled in the art are well aware of them. Diagnosis can also be made, for example, by Robbins and Cotran,
Pathological Basis of Disease, Eighth Edit
on, Saunders Elsevier.

In certain embodiments, the colchicine formulations described herein are useful in the treatment of various cardiovascular diseases and / or inflammatory disorders. In some embodiments, treating cardiovascular disease and / or inflammatory disorder comprises curing, ameliorating, ameliorating, reducing the severity of, or shortening the disease, disorder or condition, or parameters or symptoms thereof. Is intended. In certain embodiments of the invention, the term "disorder", "disease" or "condition" should be understood as a cardiovascular disease and / or inflammatory disorder as described above. In the present invention,
"Amelioration" refers to, without limitation, any observable beneficial effect.

According to the present invention, the colchicine formulations herein can be used to promote a positive therapeutic response for cardiovascular disease and / or inflammatory disorders. A "positive therapeutic response" for a cardiovascular disease and / or inflammatory disorder is, for example, delaying the onset of clinical symptoms of a disease or condition, reducing the severity of some or all of the clinical symptoms of a disease or condition, disease or Includes a gradual progression of the condition, an improvement in the subject's overall health or well-being, or an improvement in the disease that may be evidenced by other parameters specific to the individual disease that are well known in the art. Is intended.

In another embodiment, the colchicine formulations described herein are associated with various cardiovascular diseases and / or
It is also useful for preventing inflammatory disorders. In the present invention, the term "prevention" is well known in the art. For example, in particular, patients / subjects suspected of being prone to the disorder or disease manifested herein may benefit from prophylaxis of the disorder or disease. The subject / patient has a susceptibility to the disorder or disease.
y) or a predisposition, for example, but not limited to, an inherited predisposition. Such a predisposition is
For example, genetic markers or phenotypic indicators
) Can be identified by standard assays. Understand that the disorder or disease that is to be prevented by the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (eg, the patient / subject does not show any clinical or pathological symptoms). It should be. Thus, the term "prevention" refers to any clinical and / or
Alternatively, the use of a compound of the invention prior to or before the pathological condition is diagnosed or identified by the attending physician. Prophylaxis is not limited to the following and may be predisposed to developing a disease or condition in a patient and / or subject who has not yet experienced or exhibited symptoms of the disease. Including avoidance (prophylactic treatment).

Colchicine according to the present invention may also be used in combination with conventional therapy for any of the diseases disclosed herein. Such conventional therapies are well known in the art and the skilled artisan is aware of any such therapy. The colchicines described herein may also be used in combination with colchicine compatible statins. In general, non-limiting examples of statins are atorvastatin (Lipitor®, Torvast®), fluvastatin (Lescol®), lovastatin (Mevaco).
r (registered trademark), Altocor (registered trademark), Altoprev (registered trademark), pitavastatin (Livalo (registered trademark), Pitava (registered trademark)), pravastatin (Pravachol (registered trademark), Selektine (registered trademark), Liposta)
t), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®). In connection with the present invention,
Colchicine compatible statins are used. Preferably, in the present invention, the combination of the composition of the present invention and a colchicine-compatible statin is achieved in the context of stable coronary heart disease. Such statins preferably interfere with or to the extent that metabolism and / or clearance due to the nature of their mechanism of action does not interfere with, or only to a low extent, the mechanism of action, metabolism and / or clearance of colchicine, and thus A statin that, when used in combination, reduces the risk, severity and / or incidence of drug-related adverse drug events.

In certain embodiments, the use of colchicine is in a defined (in the same pharmaceutical preparation) or undefined (different pharmaceutical preparation) combination. “Predetermined combination” should be understood as meaning a combination in which the active ingredients are combined at a predetermined dose in the same vehicle (single formulation) which delivers the active ingredients together to the application site. .. A given combination can mean, for example, a single tablet, solution, cream, capsule, gel, ointment, salve, patch, suppository or transdermal delivery system. As used herein, an "undefined combination" refers to a vehicle having two or more active ingredients / components (eg, tablets, solutions, creams, capsules, gels, ointments, salves, It should be understood as meaning that it is in a patch, suppository or transdermal delivery system.Each vehicle may contain any desired pharmaceutical composition or active ingredient, eg, as described herein. Preferred non-predefined combinations of, wherein one vehicle contains colchicine, as described herein, and another vehicle contains a colchicine-compatible statin, as described herein. Examples of colchicine described herein in a defined or undefined combination (s) are one or more colchicine suitability selected from the group consisting of atorvastatin, rosuvastatin, simvastatin and pravastatin. Colchicine in combination with a statin is included, in particular colchicine as described herein in a defined or undefined combination is to be understood as meaning colchicine in combination with atorvastatin. In particular, colchicine as described herein in a defined or undefined combination should be understood to mean colchicine in combination with rosuvastatin. Colchicine as described herein in a non-defined combination is to be understood as meaning colchicine in combination with simvastatin, specifically as defined herein in a defined or undefined combination. Colchicine should be understood as meaning colchicine in combination with pravastatin.

In some embodiments, the colchicines described herein can be used in combination with another agent such as statins and ezetimibe / simvastatin. Colchicine described herein,
For example, other drugs used in medicine and known to those skilled in the art (eg, antibiotics, N
You may use together with SAID (non-steroidal anti-inflammatory drug) and corticosteroid drug.

VI. Methods of Administration Methods of preparing the colchicine formulations of the present invention and administering them to a subject in need thereof are well known to, or easily identified by, those of skill in the art. The route of administration of the colchicine formulation can be, for example, oral, parenteral, by inhalation or topically. The term parenteral as used herein refers to, for example, intravenous, intraarterial, intraperitoneal,
Includes intramuscular, subcutaneous, rectal, or vaginal administration.

Colchicine, when used as a composition in the present invention, may include one or more pharmaceutically acceptable carriers and thus may be prepared in the form of a topical formulation for administration of colchicine. Good. Pharmaceutically acceptable carriers include saline and sterile water (ste.
ile water), Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and a mixture of one or more thereof, and if necessary, an antioxidant, a buffer, a bacteriostatic agent. Agent (bacteriostatic age)
nt) and the like. Furthermore, when the composition according to the invention is prepared in the form of a topical formulation, for example an ointment, lotion, cream, gel, skin emulsion, skin suspension, patch or spray, a diluent, dispersant, Surfactants, binders and lubricants may be added.

Non-limiting examples for administration of the compounds and / or compositions according to the invention include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions. Agent, emulsion agent, suspension agent,
Syrup, elixir, reconstitution
) Powders and granules, dispersible powders and granules, medicated gums, chewing t
ablets) and effervescent tablets. The composition according to the invention may be orally (eg solid, semi-solid, liquid), transdermal (eg transdermal patch),
It may be administered in the form of any pharmaceutical for sublingual, parenteral (eg injection), eye drop (eg eye drop, gel or ointment) or rectal (eg suppository) administration. In certain embodiments, the composition is formulated as a tablet, capsule, suppository, transdermal patch or sublingual formulation.

The pharmaceutical composition used in the present invention includes, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, saturated plants. Fatty acid, water, salt such as protamine sulfate, or partial glyceride mixture of electrolyte, disodium hydrogen phosphate,
Potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol And a pharmaceutically acceptable carrier, including wool fat.

Certain pharmaceutical compositions used in the present invention have acceptable dosage forms, such as capsules,
It can be administered orally in tablets, aqueous suspensions or solutions. Certain pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are formulated in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other conventional solubilizers or dispersants. Can be prepared as a solution.

The amount of colchicine formulation combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The composition may be administered as a single dose, multiple doses, or by infusion over an established time period. Dosage may be adjusted to provide the optimum desired response (eg, a therapeutic or prophylactic response).

In some situations, the compositions of this invention may be administered parenterally. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil,
And injectable organic esters such as ethyl oleate. Aqueous carriers include, for example, water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. In the subject invention, pharmaceutically acceptable carriers include, but are not limited to: 0.0
1-0.1 M, preferably 0.05 M phosphate buffer or 0.8% saline. Other common parenteral vehicles include sodium phosphate solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicle (intr
Avenous vehicles include liquid and nutritional supplements, electrolyte supplements such as those based on Ringer's dextrose, and the like. For example, antibacterial agents, antioxidants, chelating agents,
Preservatives and other additives such as and inert gases may also be present.

Parenteral formulations can be a single bolus dose, an infusion or an initial loading bolus dose followed by a maintenance dose. The compositions may be administered at specific, pre-determined or irregular intervals, such as once a day or "on demand."

The composition according to the present invention may be administered in different dose ranges depending on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate and disease severity of the patient. The compounds of the invention as a compound or essentially as a compound in their use as a pharmacophore or as a pharmaceutical composition may be administered to a patient and / or subject at a suitable dose. Usage will be determined by the attending physician and clinical factors. As is well known in the medical arts, the dose to any one patient will be the patient's size, body surface area, age, individual compound administered, sex, time and route of administration, general health status, And depends on many factors, including other drugs administered simultaneously. In general, the regimen for normal administration of pharmaceutical compositions, including those defined herein, should be, for example, in the range below. Progress can be monitored by periodic assessment.

The composition according to the invention may be administered in a single dose or, if desired, 2, 3, 4, 5, 6, 7, 8
, 9 or 10 doses can be administered. The composition is 1, 2, 3, 4 per day
It can be given 5, 6, 7, 8, 9 or 10 times. Preferably, colchicine according to the present invention is administered once daily. More preferably, the colchicine according to the invention is 1 daily
It is administered in a single dose.

The composition according to the invention can be administered regularly over a long period of time. In certain embodiments, the composition can be administered regularly over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. In another embodiment, the composition is 1, 2, 3, 4, 5, 6, 7, 8, 9,
It can be administered regularly over 10, 11, 12 months or longer. In other embodiments, the composition can be administered on a regular basis over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks. As used herein, the term "regularly" refers to the administration at regular times or intervals over a period of time. For example, the composition may be administered to a patient once a day for 3 years. In other embodiments, the composition may be administered to the patient once every other day for 5 years. The frequency of dosing is not limited to many, including, but not limited to, the severity of the disease, the general health of the patient, any additional drugs the patient is taking, and whether the treatment is prophylactic. It should be understood that it may vary based on the factors of. It should be understood that the frequency of dosing can also be adjusted at any time.

The amount / concentration / dose of the composition according to the invention is between 0.1 mg and 5.0 mg
Between g and 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.0 mg, 0.1 m
g-0.75 mg, 0.1 mg-0.5 mg, 0.25 mg-5.0 mg, 0.25 mg
-2.0 mg, 0.25 mg-1.5 mg, 0.25 mg-1.0 mg, 0.25 mg-
It can be 0.75 mg or 0.25 mg to 0.5 mg. In one embodiment,
The composition according to the invention is administered in a daily dose of between about 0.1 mg and about 0.75 mg or between about 0.1 mg and about 0.5 mg of colchicine. In another embodiment, the composition according to the invention is between about 0.25 mg to about 0.75 mg or about 0.25 mg to about 0.5 mg.
Daily dose of colchicine between In one embodiment, the composition according to the invention is administered at a daily dose of colchicine of about 0.5 mg.

In a preferred embodiment, the amount / concentration of colchicine used herein is from the first day onward (
It can be administered at a higher dose (concentration / amount) on the first day of administration as compared to the administration of colchicine at a maintenance dose / maintenance dose). Alternatively, such dose reduction (maintenance dose) may be initiated 2, 3, 4, 5, 6, 7, 8, 9 or 10 days after the first administration with the high dose. If the course of treatment is as described above, a high dose / amount / concentration of colchicine (eg, on the first day of administration) will result in a maintenance dose If lower than the initial dose / amount / concentration (eg, on the first day of administration), it can be any of those mentioned above. Preferably, the compositions of the present invention are administered a dose of colchicine (preferably as a single dose) of between about 1.0 mg and about 2.0 mg on the first day of administration, and a maintenance dose of colchicine from the first day onward is about 1 day. Between 0.5 mg and about 1.0 mg.

Without departing from the scope of the present disclosure, the colchicine formulations of the present invention can be administered to humans or other animals according to the methods of treatment described above in an amount sufficient to produce a therapeutic effect. Colchicine formulations are prepared according to known techniques in conventional dosage forms prepared by combining the colchicine formulations of the present invention with a conventional pharmaceutically acceptable carrier or diluent such human or other animal Can be administered to. It will be appreciated by those skilled in the art that the form and characteristics of the pharmaceutically acceptable carrier or diluent will depend on the amount of active ingredients combined together, the route of administration and other well known variables.

A "therapeutically effective dose or amount" or "effective amount", when administered, results in a positive therapeutic response in the treatment of a patient with the disease to be treated, such as delayed onset of clinical symptoms of the disease or condition, the disease or It is well known in the art that the severity of some or all of the clinical symptoms of a condition is reduced, the disease or condition is slowly progressing, the general health or well-being of the subject is improved, or specific to the particular disease. Other parameters contemplate the amount of colchicine formulation at which improvement in disease may be observed.

The invention also provides the use of a colchicine formulation in the manufacture of a medicament for treating a subject, for treating cardiovascular disease and / or inflammatory disorders, wherein the medicament is at least one other therapy. Used in subjects who have been pre-treated or are being treated at the same time.
"Pretreated" or "pretreatment"
) ”, It is intended that the subject has received one or more therapies prior to being administered a medicament comprising a colchicine formulation. “Pre-treated” or “pre-treatment” means within 2 years, within 18 months, within 1 year, within 6 months before the start of treatment with a drug including a colchicine preparation.
Within 2 months, within 6 weeks, within 1 month, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, or on the previous day To subjects treated with at least one other therapy. By "simultaneous" or "in combination" is intended that the subject is receiving one or more other therapies while simultaneously receiving a medicament comprising a colchicine formulation. It is not necessary that the subject was a pretreatment responder with pretherapy (s) or a concomitant therapy (s). Thus, a subject receiving a drug, including a colchicine formulation, may be pretreated with pretreatment, or, if the pretreatment is composed of multiple therapies, for one or more of the pretreatments. , May have reacted, or may not have reacted.

All references cited above, as well as all references cited herein, are incorporated by reference in their entireties.

Although the present invention has been described and described in detail above, such description and description should be considered as illustrative and exemplary and non-limiting. It will be appreciated that changes and modifications may be made by those skilled in the art without departing from the scope and spirit of the claims below. In particular, the invention covers additional embodiments with any combination of features from the various embodiments described above and below.

The present invention is additionally described by the following illustrative, non-limiting examples that provide a better understanding of the invention, and of the many advantages of the invention. The following examples are included to demonstrate preferred embodiments of the invention. The techniques disclosed in the examples that follow represent techniques used in the present invention that work well in the practice of the invention, and thus can be considered as constituting a preferred form for the practice of the invention. Should be recognized by those skilled in the art. However, one of ordinary skill in the art can make many modifications in the specific embodiments disclosed in light of the present disclosure, and similar or similar results without departing from the spirit and scope of the present invention. You should understand that you can get

[Example 1: Colchicine sustained-release tablet]
This example illustrates a colchicine sustained release tablet. The tablets use the ingredients and concentrations shown in Table 1 below.

Concentrations may be varied to modify particular properties of the formulation, such as the dissolution profile.
Table 2 shows the range of each component.

[Example 2: Method for producing sustained-release tablet of colchicine]
Using the above ingredients, tablets are made according to the following work instructions.

Granulation: Granulation was performed in a Kenwood mixer. First, colchicine and hypromellose 6 MPa ^* s were weighed and individually dissolved in purified water. A solution of hypromellose 6 MPa ^* s was loaded into a mixer containing lactose and mixed for 1.5 minutes and then 3 minutes. The dissolved colchicine was then sprayed with a filler (eg lactose monohydrate) under continuous mixing for 15 minutes. The steps were performed at room temperature. Then, wet granules 1.0 mm
It was passed through a hand sieve. After that, the oven (Haeraeus
) At 45 ° C. for 26 hours to give a residual water content of 0.53% and passed through a 0.8 mm sieve shaker (Erweka AR 400). Density parameters were analyzed (Engelmann). Bulk density 0.53 g / ml, consolidation bulk density 0.67 g / ml, Hausner ratio 1.26, rheology: flow down time 4 seconds; tilt angle 23
． It was 8 °.

Blending: After the granulation process, the granules are filled with fillers (eg lactose monohydrate), retarders (eg Retalac) and other excipients (eg flow enhancers, lubricants and / or lubricants). To facilitate the tablet compression process. For this purpose, the ingredients were manually passed through a 0.8 mm sieve and mixed with the granules in a cube mixer (Erweka) for 10 minutes. In one embodiment, the lubricant used may be talc. In another embodiment, the lubricant used may be stearic acid. The granules are then blended using a suitable mixer.

Tablet compression: Compressive force is required to form tablets. The mechanical force defines the physical properties of the tablet, especially the crushing strength of the resulting tablet. Mechanical strength interacts with the initial swelling of the tablet and the rate of dilution of the tablet core. This effect is well known in the art and can be regulated and controlled during the product life cycle.

Tableting was performed on a Korsch (EK0) tablet press using a bi-convex round tableting tool with a diameter of 6 mm. Average tablet hardness is about 100N ± 15
It was N. Tablets were measured to have a mass of approximately 100 mg, but friability was not measurable. The breaking strength and hardness were measured using an Erweka Multicheck.
Crushability was measured using an Erweka Friabilator and a Mettler analytical balance. The dimensions were measured using a Mitutoyo caliper.

[Example 3: Measurement of dissolution profile of sustained-release colchicine preparation]
The dissolution of the sustained release formulation of colchicine was measured at various time points. 500 at 37 ° C
It was dissolved in ml of water and stirred continuously for 6 hours. Samples were extracted at several time points,
The kinetics of the dissolution process of the drug substance in the hydrophilic matrix system was investigated. Colchicine content in the samples was analyzed using HPLC analytical methods.

Several batches were tested to determine the optimal dissolution profile of the sustained release formulation. Release can be modified by the concentration of hypromellose or by using different viscous grades of hypromellose (eg, 1000 mPa or 10000 mPa). Hereinafter, in the batches tested, the viscosity grade remained constant, but the concentration of hypromellose 4000 mPa in the tablets was changed.

  Table 3 below outlines the various compositions tested.

The dissolution profiles of various batches are shown in Tables 4-6 and Figures 1-4. Especially batch 1
An overview of the dissolution profiles of ~ 3 is shown in Table 4 and Figure 1. The batch 1 profile shows about 92% release within about 30 minutes, and a constant release thereafter. Complete dissolution was obtained after 2 hours. Batch 2 shows a release of about 83% within about 30 minutes and a constant release thereafter.
Complete dissolution was obtained after 2 hours. Batch 3 shows about 74% release within about 30 minutes and shows constant release thereafter. Complete dissolution was obtained after 2 hours.

A summary of the dissolution profile for Batch 4 is shown in Table 5 and Figure 2. Batch 4A shows a release of about 30% within about 30 minutes and a constant release thereafter. Complete dissolution was reached after 6 hours.
Batch 4B shows a release of about 23% within about 30 minutes and a constant release thereafter. Complete dissolution was reached after 6 hours. In this example, the difference in tablet hardness results in a difference in release rate. FIG. 3 shows the dissolution profile of batches 1-4.

An overview of the dissolution profile for Batch 5 is shown in Table 6 and FIG. Batch 6 corresponds to the immediate release form of the composition. The profile of batch 5 shows 90% release within 5 minutes. Complete dissolution was reached within 2 hours.

As mentioned above, the release profile of the sustained release formulation is similar to that of the retardant (ie, Letala).
By adjusting the amount of c) as well as the tablet hardness, it is possible to tailor the specific or desired targeted release. Release is dependent on a variety of factors, including erosion of the outer layer of colchicine (ie the immediate release portion) and diffusion of the inner layer of colchicine (ie the sustained release portion). Since the percentage of colchicine is low in sustained release formulations and the tablets are small, the balance between erosion and diffusion is very sensitive and needs to be fine-tuned to achieve a very specific dissolution profile.

[Example 4: Measurement of dissolution profile of sustained-release colchicine preparation in ethanol]
The dissolution of colchicine sustained release formulations in ethanol was measured at various time points to assess the potential for overdose or dissolution of the composition in alcohol. The composition was dissolved in 500 ml of three solutions, namely 5%, 20% and 40% ethanol at 37 ° C and continuously stirred for 6 hours. Samples were extracted at several time points to study the kinetics of the drug substance dissolution process within the hydrophilic matrix system. Colchicine content in the samples was analyzed using HPLC analytical methods.

[Example 5: Therapeutic effect of sustained-release colchicine preparation]
About the therapeutic effect of the sustained-release preparation containing colchicine, about 0.5 different immediate-release preparations of colchicine (0.5 mg immediate-release preparation (control product) administered to healthy subjects) (for example, test product) It was evaluated in a clinical trial, a multidose, randomized crossover study that evaluated bioavailability of 1, 2, 3). The main aim of the study is to evaluate the pharmacokinetics (PK) of test and control drugs in blood and in neutrophils or leukocytes.

Study Objective: The primary objective of this study is to compare the pharmacokinetics of colchicine test and control products in healthy human subjects. In particular, the level of colchicine in blood (referred to herein as blood PK), the level of colchicine in neutrophils or white blood cells (referred to herein as neutrophil PK) are evaluated in treatment with control and test products. To do.

The hypothesis of the study is that administration of an equal amount of colchicine in the form of a sustained release tablet results in lower peak levels (Cmax) while maintaining equal absolute bioavailability (area under the curve, AUC). is there. Since it is generally understood that neutrophils, which reconstitute 60-70% of white blood cells, generally play a central role in the inflammatory response, colchicine concentrations in neutrophils were measured, and Colchicine levels are considered to be a major player in some diseases where colchicine is used as a treatment. Therefore, for the purposes of this experiment, either white blood cells or neutrophils can be analyzed. Therefore, as used herein, the term neutrophils, when used, also refers to white blood cells. Colchicine is known to be a major target for colchicine therapy, as it is known to accumulate preferentially in neutrophils and suppress many of the neutrophil's proinflammatory functions. Has been. Therefore, knowing whether similar concentrations of colchicine were reached in isolated neutrophils or leukocytes may provide information about potential bioequivalence and are of special interest. It is a thing. Therefore, blood is drawn at various time points throughout the study to determine blood and neutrophil colchicine levels.

General Study Design: This study is designed as a randomized crossover study. There are 3 groups of patients (n = 3 × at least 8 cases). Group 1 receives treatment with control or study drug for about 8-14 days. Following the washout period, patients will be treated with Study Drug 1 for approximately 8-14 days. Group 2 receives treatment with control drug for the same period. Following the washout period, patients will be treated with Study Drug 2 for the same period. Group 3 receives treatment with control drug for the same period. Following the washout period, patients will be treated with Study Drug 3 for the same period. Study participants will be treated as inpatients for the first 24 hours and as outpatients for the rest. There should be a sufficiently long washout period between the two studies.

Subject participation: There will be 3 groups of patients (n = 3 × at least 8). For each study drug, healthy subjects are randomly assigned to one drug as a first round.
After a sufficient washout period, the same subjects receive the control drug.

Study Duration: Study drug will be administered in a single dose / day for approximately 8-14 consecutive days. The study consists of 24-hour blood PK (high frequency data collection). Neutrophil PK is analyzed at intervals that allow for a definitive determination of colchicine levels later in the experimental period.

  Treatment regimen: The following is an example of what a treatment regimen might look like.

Research procedures and data analysis: Analytical chemistry methods (HPIC) or immunological methods (radioimmunoassay) may be utilized for the evaluation of colchicine and optionally its metabolites.
Collected data will be analyzed by appropriate data management and statistical software.

Target Population: The study population consists of healthy male subjects. For inclusion in this study, patients should be 25-40 years old; weigh 60 kg or more and 120 kg or less; healthy; have no major comorbidities or contraindications competing for colchicine therapy; It indicates consent and needs to be randomly assigned. Criteria for: Ongoing therapy with other anti-inflammatory / immunosuppressive drugs; Treatment with drugs with known drug interactions with colchicine; Renal / liver disorders; Known hypersensitivity to colchicine Patients who do are excluded.

  Treatment plan: The drug is given once daily in the morning.

DATA COLLECTION PLAN: For blood PK, at short intervals over 24 hours from the start of the study (at a time sufficient to establish pharmacokinetic data, eg (pre-application) -1, +0.5 hours,
1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 7 hours, 10 hours, 12 hours,
Blood is collected (15 and 24 hours). Additional time points may be 24 hours and 72 hours after discontinuation of medication at the end of the study to determine drug holidays. PK analysis includes colchicine blood levels. Appropriate techniques for blood isolation and colchicine quantification are applied.

For neutrophil PK, neutrophils are isolated and purified from raw blood at several time points. Neutrophils are collected at the beginning of the study as well as at least once at the end of the study. PK analysis is
Includes colchicine concentration in isolated neutrophils.

Example 6: Therapeutic effect of immediate release formulation in patients with cardiovascular disease
To evaluate the therapeutic efficacy of immediate release formulations in patients with cardiovascular disease, an objective objective was to combine colchicine 0.5 mg / day with standard second-line prophylactic therapy including aspirin and high doses of statins. A prospective, randomized, observer-blinded endpoint study was conducted to determine if it could reduce the risk of cardiovascular events in patients with clinically diagnosed and clinically stable coronary artery disease. This work is described in PCT / AU2013 / 001261, the entire content of which is incorporated herein by reference.

Study Conduct and Design: Heart Research Institute o
The Lo DoDo test was conducted mainly by f Western Australia. The study is based on the Australian Clinical Trial Registry.
al Registry (12610000293066), designed by the Principal Investigator, July 2008, Sir Charles Gardner Hospital, Perth, Western Australia.
ethical approval by the Human Research Ethics Committee of the Tal Perth Western Australia). There were no external sources of funding.

The study was a prospective, randomized, open-label, endpoint design. Eligible and informed patients with confirmed coronary disease who present with routine clinical reviews, colchicine 0.5 mg / day or, without other changes to their medical care They were randomly assigned to receive no colchicine. All outcomes were assessed by treatment assignment by a trained adjudicator blind.

Study size and eligibility: 28 patients randomly assigned to the control group and 250 patients randomly assigned to treatment with colchicine tolerability for at least 4 weeks after the date of randomization It was planned to form a study population that could include 250 cases. The following criteria: 1) Angiographically confirmed diagnosis of coronary artery disease; 2) Age 35 to 85 years; 3) Clinically stable for at least 6 months 4) Colchicine therapy No major comorbidities or contraindications competing against 5)
Adhering to therapy and being considered to be attending for routine cardiology follow-up, and
6) Patients were eligible for enrollment if they met each of the informed consent and their willingness to be randomly assigned to the study. Patients with a history of bypass surgery must be over 10 years old, or have had angiographic evidence of graft failure or stenting after bypass surgery.
Qualified. Prior to randomization, all patients received informed consent.
ed consent) was signed.

Randomization: The order of assignment was computer generated, kept secret from the investigator at all times, and managed by a Research Assistant who had no involvement in the assessment or management of the study patients. When the assistant receives the consent form, the patient's demographic data is entered into the database and the investigator and patient are informed of the treatment groups assigned in writing. Despite choosing to use an effective minimum dose of colchicine, some patients were expected to discontinue therapy early after randomization due to gastrointestinal side effects. To ensure that the required number of patients in the treatment group are actually tolerated by the protocol, the protocol will provide a fresh replacement by the Research Assistant if patients discontinue colchicine due to side effects in the first month. Allowed patients to be assigned to treatment. Patients who were intolerant to therapy continued to be the subject of this study and, in accordance with usual practice,
included in the contention-to-treat analysis.

Intervention: Patients randomly assigned to effective treatment were prescribed 0.5 mg of colchicine daily by a referral cardiologist. The drug was dispensed by a regular pharmacist and, if requested, the patient was reimbursed for their prescription costs. All other treatments continued normally.

Definition of follow-up and clinical outcomes: Patient adherence to treatment and outcome data were collected at regular follow-up visits and at any unscheduled visits. Acute coronary syndrome (ACS)
a) without acute myocardial infarction (AMI) as evidenced by acute ischemic chest pain with elevated supranormal limits of serum troponin or (b) without elevated serum troponin,
Either unstable angina (UA), as evidenced by the recent accelerated progression of angina in patients with angiographic evidence of altered coronary anatomy in the patient Defined as (Unstable angina Braunwald classification IB and IIB). ACS
Was characterized as stent-related if there was evidence of significant in-stent stenosis or acute stent thrombosis. Out-of-hospital cardiopulmonary arrest, as defined by recovery from sudden collapse with sudden death or demonstrated cardiac arrest, ventricular tachycardia or ventricular fibrillation, as evidenced by the patient's death certificate It was defined as either lethal out-of-hospital cardiopulmonary arrest. Non-cardiogenic ischemic stroke was defined as a CT or MRI proven ischemic stroke that was judged by a neurologist not to be due to atrial fibrillation or intracranial hemorrhage.

The primary efficacy outcome was multiple items: ACS, lethal or non-lethal out-of-hospital cardiopulmonary arrest, or non-cardiogenic ischemic stroke. Secondary outcomes were (a) individual items of primary outcome and (b) items of ACS unrelated to stent disease.

Timeline: The prespecified study period was a minimum follow-up of 2 years for all patients. Therefore, the study ended on May 31, 2012. During May, all surviving patients were contacted by telephone to collect adherence and outcome data as of the last day of follow-up. Final outcome data were obtained from all patients and none were unobservable.

Statistical power: The control group had a mixed event rate of 8% (ACS, out-of-hospital cardiopulmonary arrest or non-cardiogenic ischemic stroke), a 2-year participant acceptance period and a 2-year participation. Assuming follow-up after a person's acceptance period, the planned sample size provided greater than 80% power to detect hazard ratios below 0.50 based on a two-sided significance level of 5%.

Data analysis: Rough statistics including mean and standard deviation were calculated for all baseline characteristics by treatment group. All times to event outcomes are either (1) the date of the event or death; or (2) the study termination date for patients who did not experience a well-defined event, minus the randomization date. Calculated in days according to. As specified previously, the primary efficacy analysis was based on the Intention-to-treat principle.
The intention-to-treat analysis included all subjects randomized and all events during the period from randomization to the end of the study. The test end date was set as May 31, 2012. A secondary, prespecified On-treat analysis was also performed in patients who were well tolerated and received therapy well beyond the first month of randomization. All events during the period from randomization to non-compliance with the colchicine treatment regimen were included in this analysis.

Time of event onset for all outcomes is expressed using Kaplan-Meier lots. The primary efficacy outcome was analyzed using the Cox proportional hazards model, which included treatment groups coded as control or colchicine. Similarly, secondary outcomes were analyzed. In addition, the primary analyzes include sex, age, diagnosis of diabetes, history of myocardial infarction, unstable angina, coronary artery bypass surgery, coronary angioplasty, aspirin, clopidogrel or both, high-dose statin therapy (40 mg or more of atorvastatin Stratified by therapy with β-blockers, calcium blockers and ACE inhibitors).

RESULTS: Eligibility of the study was evaluated in 901 patients with stable coronary artery disease who visited for regular outpatient cardiology reviews between August 2008 and May 2010. Of those patients, 297 (33%) did not meet the inclusion criteria for inclusion,
72 patients (8%) declined to participate and 532 patients (59%) were enrolled in the study. Of 532 cases, 250 were randomly assigned to the control group and 282 to the treatment group. Of the patients randomly assigned to the treatment group, 32 (11%) complained of early intolerance due to gastrointestinal side effects and subsequently reported that 7 patients chose not to resume therapy. All randomized patients 5
Thirty-two cases were followed for a study period of 24 months minimum to 44 months maximum. Median follow-up was 36 months.

Outcomes: Major outcomes occurred in 55/532 patients, including 15/282 patients (5.3%) assigned to colchicine treatment and 40/250 patients (16%) assigned to the control group ( Hazard ratio 0.33, 95% CI; 0.18 to 0.59, p <0
． 001, number required for treatment 11). We adjusted for the use of calcium channel blocker and beta blocker therapy and sensitized the primary outcomes. The results were consistent with the main analysis.

The effects of colchicine on primary outcomes were evident early on, with colchicine benefits continuing throughout the follow-up period. There was no evidence of a different therapeutic effect based on any clinical or therapeutic variable.

Suppression of primary outcomes was largely brought about by a reduction in the number of patients with ACS (
13/282 (4.6%) to 34/250 (13.4%) hazard ratio 0.33; 95% C
I; 0.18 to 0.63; p <0.001). Out-of-hospital cardiac arrest and non-cardiogenic ischemic stroke were rare but were suppressed in the treatment group.

Of the 47 patients with ACS, the event was stent-related in 8 (17%) (2 in each group had evidence of acute stent thrombosis and 2 in each group).
An example had evidence of in-stent stenosis). Further analysis shows that patients randomly assigned to treatment are unrelated to stent disease ACS (9/282 (3.2%))
30/250 (12%) hazard ratio 0.26, 95% CI; 0.12-0.55; p <
0.001), ACS associated with AMI (4/282 (1.4%) vs. 14/250 (5.
6%) hazard ratio 0.25, 95% CI; 0.08-0.76; p = 0.014), or ACS (5/282 (1.8%) vs. 16/250 (6) associated with UA. It was confirmed that the possibility of exhibiting a hazard ratio of 0.27, 95% CI; 0.10 to 0.75; p = 0.011) was low.

Of 39 patients who were randomly assigned to treatment and were not treated for more than the first month due to early intolerance or non-compliance, 4 (10%) had acute stent thrombosis (n =
1) and UA (n = 3). Patients who were well tolerated and adhered to therapy beyond the first month of randomization had significantly fewer events than controls (11/243).
(4.5%) to 40/250 (16%) hazard ratio 0.29, 95% CI; 0.15-0
． 56; p <0.001). The result of the on-treat analysis is the intent
-In agreement with the results based on the threat analysis.

Four patients died in the colchicine group, whereas 10 patients died in the control group. Of the 10 in the control group, 5 were probable causes of cardiogenicity; 2 were 2 after out-of-hospital cardiac arrest.
One died of cardiogenic shock after myocardial infarction and one died after bypass surgery. All four patients in the colchicine group died of noncardiac causes.

The study adds colchicine 0.5 mg / day to standard therapy in patients with stable coronary artery disease, significantly reducing the risk of cardiovascular events, including ACS, out-of-hospital cardiac arrest and non-cardiogenic ischemic stroke Clearly indicate what to do. Colchicine's benefit was achieved in the context of the widespread use of effective secondary prevention strategies, including high dose statins, as evidenced by the low event rate in the control group. The effects of adding colchicine were apparent early, were observed over time, and were largely guided by a decrease in ACS unrelated to stent disease.

[Example 7: Dose adjustment of sustained-release colchicine preparation]
Sustained-release preparations may be administered to patient populations of different weights to determine the appropriate dose.
Assuming that the 0.5 mg tablet results in a certain plasma level of colchicine in patients of average body weight, this particular level needs to be reached in all patients to achieve efficacy, PK analysis of 0.5 mg tablets in groups can be performed. It is expected to have lower blood levels (Cmax and AUC) in heavier patients, suggesting a need for dose adjustment to higher doses.

Study Objective: The main objective of this study is to compare the pharmacokinetics of 0.5 mg colchicine tablets in healthy human subjects of at least two different weight groups. In particular, blood colchicine levels are assessed at the time of treatment. The hypothesis tested is that administration of an equal amount of colchicine results in different colchicine levels depending on body weight. Body weight and colchicine levels are inversely related.

General Study Design: This study is designed as a randomized crossover study. n = Select at least 8 subjects according to body weight. When two groups are provided, 50% is a light weight group (for example, less than 65 kg) and 50% is a heavy weight group (for example, more than 90 kg).

Study period: The test drug is administered once. 24 hours blood PK (high frequency data collection)
Consists of.

Investigational methods and data analysis: Analytical chemistry methods (HPIC) or immunological methods (radioimmunoassay) may be used for the evaluation of colchicine. Collected data will be analyzed by appropriate data management and statistical software.

Target Population: The study population consists of healthy male subjects. For inclusion in this study, patients should be 25-40 years of age; weigh 50 kg or more and 120 kg or less; healthy; have no major comorbidities or contraindications competing for colchicine therapy; consent is obtained; It requires a willingness to be randomly assigned to the study. Criteria for: Ongoing therapy with other anti-inflammatory / immunosuppressive drugs; Treatment with drugs with known drug interactions with colchicine; Renal / liver disorders; Known hypersensitivity to colchicine Patients who do are excluded.

  Treatment plan: The drug will be given once in the morning of the study.

DATA COLLECTION PLAN: For blood PK, at short intervals over 24 hours from the start of the study (at a time sufficient to establish pharmacokinetic data, eg (pre-application) -1, +0.5 hours,
1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 7 hours, 10 hours, 12 hours,
Blood is collected (15 and 24 hours). Additional time points may be 24 and 72 hours after discontinuation of medication at the end of the study to determine drug holidays.

Example 8 Non-clinical Pharmacokinetic Study of Colchicine Sustained Release (SR) vs. Immediate Release (IR)
In this experiment, a sufficiently large number of suitable laboratory animals (eg, rodents such as mice or rats, at least 5 animals in each group) is used. The control drug is an IR tablet of colchicine. The study drug is an SR tablet of colchicine.

A control group of mice is administered a single initial dose of IR colchicine in the therapeutic range (colchicine plasma level range with observable therapeutic effect. In the experimental animal species used,
It is arbitrarily determined and set as the maximum level which is well below the LD50, and the minimum level which is about one sixth of the maximum level. ). The test group receives a single initial dose of SR colchicine of the same intensity. After 15 minutes, 30 minutes, 45 minutes, 1 hour, then 1
Blood is collected from each group every 1 hour until the lapse of 2 hours, and every 3 hours until the lapse of 24 hours. At the same time, excreta are collected from the cages of test and control animals after 3, 6, 12 and 24 hours (test and control animals must be housed in the same cage).

Primary measure: Colchicine plasma level. Secondary measurement: Quantification of colchicine and its metabolites in excreta to see if a lower degree of enterohepatic recirculation occurs in test animals compared to control animals. Blood samples are processed and colchicine levels in plasma are measured using HPLC analysis or an equivalent quantification method.

Results: Experiments are expected to show similar total absorption of colchicine (area under the curve) in test and control animals. However, in control animals, colchicine absorption peaks approximately 1 hour after administration and then declines rapidly. After 2-3 hours, colchicine levels are below the therapeutic range. In addition, the enterohepatic recirculation of unmetabolized colchicine can lead
After 6 hours, reabsorption occurs, represented by the characteristic second peak.

However, in subject animals (SR), colchicine levels rise more slowly,
The peak level of colchicine is not reached as observed in control animals. Peak levels are observed after 3-8 hours and then decrease slowly. Therapeutic colchicine levels persist for at least 12 hours. Due to the more complete metabolism of colchicine in the liver, less enterohepatic recirculation occurs and the second peak cannot be observed. As a secondary measure, the excretion of test and control animals is examined to see if there is a lesser degree of enterohepatic recirculation in test animals as compared to control animals. It can be shown that the ratio of unchanged colchicine to metabolized colchicine is higher in control animals compared to test animals. Therefore, SR colchicine results in a more complete metabolism of colchicine in the liver.

Example 9 SR versus IR Nonclinical Safety Study of Colchicine
In this experiment, a sufficiently large number of suitable laboratory animals (eg, rodents such as mice or rats, at least 5 animals in each group) is used. The control drug is an IR tablet of colchicine. The study drug is an SR tablet of colchicine.

A control group of mice is administered a single dose of IR colchicine / day at a therapeutic intensity (colchicine plasma level range with observable therapeutic effect. In the experimental animal species used, L
It is arbitrarily determined and set as the maximum level well below D50, and the minimum level which is about one sixth of the maximum level. ). The test group receives a single dose of SR colchicine / day at the same intensity. Alternatively, test and control animals are dosed twice daily, once in the morning and once in the evening. The duration of the experiment is 2 weeks.

The primary measure is the development of gastrointestinal adverse events (eg, rapid abdominal pain, diarrhea, etc.). This is evaluated by three methods. Daily using a standardized method to check for signs of illness,
Observe the behavior of the test animal. Secondly, excreta are examined daily for morphology and the presence or absence of apoptotic neutrophils. Third, individual animals are sacrificed at the indicated time points and the small and large intestines are examined for histopathological signs of colchicine toxicity.

Results: Throughout the experiment, control animals may be expected to suffer more gastrointestinal adverse events than test animals. Therefore, SR colchicine exhibits a better safety profile than IR colchicine.

Example 10: Colchicine SR vs. IR Clinical Safety Study
If experimental animals are found to be unsuitable for investigating adverse events related to colchicine administration, comparable experiments will be conducted in humans. The experiment is performed in adult healthy subjects or in patients who additionally require colchicine. Target a sufficiently large number of people to reach statistical significance. The test and control drug treatments were colchicine SR or IR of 0.25 to 1 mg strength.
It consists of an oral solid dosage form. Administer high enough doses to reach therapeutic levels of colchicine. As an alternative to once daily dosing, the test drug is given twice daily as shown in Example 3 above. As an alternative to the control placebo effect, the placebo group is included in both experimental settings. The duration of the experiment is between 2 weeks and 1 month.

Many modifications and other embodiments of the inventions described herein will occur to those of ordinary skill in the art to which those inventions benefit from the teachings presented in the above description and the associated drawings. Therefore, the invention is not limited to the particular embodiments disclosed, but modifications and other embodiments are intended to be included within the scope of the appended claims and to the list of embodiments disclosed herein. It should be understood that this is intended. Although specific terms are used herein, they are used in their generic and descriptive sense only and not for purposes of limitation.

Claims (25)

A colchicine sustained-release preparation,
(A) granules containing up to 0.6 mg of colchicine or a pharmaceutically acceptable salt thereof and a binder comprising hydroxypropylmethylcellulose (HPMC) in an amount of 1% to 30% by weight of the formulation; ) A release-retarding agent admixed with the granules, wherein the release-retarding agent is in an amount of 5% to 40% by weight of the formulation, and the release-retarding agent is HPMC and lactose monohydrate. And at least one pharmaceutical agent containing the same amount by weight, wherein the viscosity of the HPMC of the release retardant is higher than the viscosity of the HPMC contained in the granules, and (c) at least one pharmaceutical agent mixed with the granules. to look at including the acceptable excipient,
A colchicine sustained release formulation, wherein the formulation is uniform .   The formulation according to claim 1, wherein the pharmaceutically acceptable excipient is starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC), or a mixture thereof. ..   The formulation according to claim 1 or 2, wherein the sustained-release formulation has a tablet form. The viscosity of the HPMC granules is 6 mPa ^* s, the viscosity of the HPMC of said release retardant is 4000 mPa ^* s, the formulation according to any one of claims 1-3. In vitro at least about 70 percent of the colchicine, at 37 ° C., to release within 2 hours, the formulation according to any one of claims 1-4. The formulation according to any one of claims 1 to 6 , wherein the pharmaceutically acceptable excipient is one or more of a binder, a filler, a lubricant and a lubricant. The pharmaceutically acceptable excipient comprises a binder, which is one or more of starch, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), and polyvinyl alcohol. Item 7. The formulation according to any one of items 1 to 6 . Said pharmaceutically acceptable excipient comprises a filler, which filler is sucrose, lactose, especially lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid. One or more of :, sodium alginate, divinylbenzene methacrylate (DVB), cross-linked polyvinylpyrrolidone (PVP), microcrystalline cellulose, potassium polacriline, sodium starch glycolate, starch, and pregelatinized starch. The formulation according to any one of 1 to 7 . The pharmaceutically acceptable excipient comprises a lubricant, which is one or more of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and tricalcium phosphate. Item 9. The formulation according to any one of items 1 to 8 . The formulation according to claim 9 , wherein the total amount of lubricant in the formulation is between 0.5% and 5% by weight of the formulation. The pharmaceutically acceptable excipient comprises a lubricant, which is glyceryl behenate, stearic acid, hydrogenated vegetable oil, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, monostearic acid. glycerin, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, is one or more of the DL- leucine, and colloidal silica, any of claim 1-10 The preparation according to Item 1. The formulation according to claim 11 , wherein the total amount of lubricant in the formulation is between 0.5% and 5% by weight of the formulation. The formulation is selected from the group consisting of tablets, pills, capsules, caplets, suppositories, transdermal patches, creams, sublingual formulations, eye drops, gels, ointments, troches, pouches, powders. dosage form, or a combination of the surgically insertable medical devices, formulation according to any one of claims 1 to 12. A dosage form is liquid or gel of the formulation, the formulation according to any one of claims 1 to 12.   The formulation of claim 3, wherein the tablet has a compressive strength of between 30N and 130N. The colchicine or the total amount of a pharmaceutically acceptable salt thereof in the formulation, is 0.6mg from dose per 0.5 A formulation according to any one of claims 1 to 15. A formulation according to any one of claims 1 to 16 for use in the prevention and / or treatment of atherosclerotic vascular disease (AVD) or atherosclerosis. 18. The formulation of claim 17 , wherein the AVD or atherosclerosis is cardiovascular atherosclerosis, peripheral vascular atherosclerosis, and / or iliac femur / renal atheroma. 19. A formulation according to any one of claims 1 to 18 for use in combination with a second agent for preventing a cardiovascular event in a patient with a confirmed stable coronary artery disease. 20. The formulation of claim 19 , wherein the cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest or non-cardiogenic ischemic stroke. Further comprising a statin formulation according to any one of claims 1 to 20. FIG. 22. The formulation of claim 21 , wherein the statin is mixed with the formulation. 23. The formulation of claim 21 or 22 , wherein the statin is one or more of atorvastatin, rosuvastatin, simvastatin, pravastatin, and salts thereof. A process for preparing a colchicine sustained release tablet comprising:
(A) Forming granules by dissolving 0.5 mg to 0.6 mg of colchicine or a pharmaceutically acceptable salt thereof in water, an acceptable solvent,
(B) In step A, a binder comprising hydroxypropylmethylcellulose (HPMC) in an amount of 1% to 30% by weight of the tablet and lactose monohydrate in an amount of 10% to 80% by weight of the tablet. And a filler comprising pregelatinized starch to form wet granules,
(C) drying the wet granules of step B,
(D) blending the granules dried in step C with a release-retarding agent, wherein the release-retarding agent is in an amount of 5% to 40% by weight of the tablet, and the release-retarding agent is , seen containing at HPMC and lactose monohydrate and the same parts by weight, the viscosity of the HPMC of said release retardant is higher than the viscosity of the HPMC contained in the granules, the steps,
(E) finally obtained granules in step D only contains a step of compressing into tablets,
Process for preparing a colchicine sustained release tablet , wherein said tablet is uniform . 25. The process of claim 24 , wherein in step D talc is added as a lubricant and stearic acid is added as a lubricant.