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    US20100143468A1

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    cu») United States 1 ‘US 201001434684 c2) Patent Application Publication co) Pub. No.: US 2010/0143468 Al MOORE et al. (54) TRANEXAMIC ACID FORMULATIONS (75) Inveators: —Kelth A. MOORE, Loveland, OFF (US): Ralph A. Heasley, Webster Grove, MO (US) Jeffrey Grelwe, Ft, Thomas, KY (US); John W. Facemire, Douglssille ‘GA (US): Jason D. Modest Minneapolis, MN (US) Comesponilence Address: Davidson, Davidson & Kappel, LLC 485 7th Avenue, 14th Floor New York, NY 10018 (US) (73) Assignee: Nanodyne Pharmaceut Newport, KY (US) (21) Appl.No: 12eT4181 (22) Filed Fe 26,2010 (43) Pub, Date Jun. 10, 2010 Related Application Data (63) Continuation of application No, 12/433,510, filed on Apr. 30,2009, which is scontinuation-in-part of appli= cation No, 12/228,489, filed on Aug. 13, 2008, which {is «continuation of application No, 11(072,194, fled ‘on Mat 4, 2005, now abandoned. (60) Provisional application No. 60550,113, filed of Mar 44,2004, provisional application No, 60/592,885, filed fom Jul, 30,2004, Publication Classification Gl) Ince. AGIK 9726, (2006.01) AGIK 31/195 (2005.01), AGIP 704 2006.01), (2) US.CL 241a7o: 514/561 on ABSTRACT Disclosed are modified release oral tranexamic acid formn- lations and methods of treatment therewith Patent Application Publication Jun. 10,2010 Sheet 1 of 7 US 2010/0143468 AI 1.3 g Tranexamic Acid g8hr (06°°, 14°°, 22°°) =? OMUCIINIMNI te € PUTMAN SE TUN WA oe §s eee HA 0 8 16 24 32 40 48 56 64 72 80 88 96 104112120 Time (h) FIG. 4 < 4.3 g Tranexamic Acid TID (08°, 14°°, 20°) 16, Boers oe 14 ge Nb 2gq8° Ba 12 oq! & ze" i ee ot A 2s Ee : 1 it iN gs + Ee 2 AgTLD Fa & 0 a 0° 12° 24° 36 48 60 72 84 96 108" 120 Time (h) FIG. 2 Patent Application Publication Concentration of Tranexamic id (meg/mL) Jun. 10,2010 Sheet 2 of 7 US 2010/0143468 AI Mean Plasma Tranexamic Acid Concentration (mogimL) versus Time (Semi-Log Scale) Modified Release Tablets 100.004 10.004 1.004 o.10-4 0.01 Immediate-Release Tablets oe Pharmacia Upjohn (Cyklokapron) IV Solution 20 30 40 Time (Hours Post-Dose) FIG. 3 Patent Application Publication Jun. 10,2010 Sheet 3 of 7 US 2010/0143468 AI Concentration of Tranexamic Acid (megimL) Plasma Tranexamic Acid Concentration (meg/mL) versus Time 100 90 80 70 60 50 40 30 20 10 (Linear Scale) o--© Modified Release Tablets #—+ Immediate-Release Tablets ‘o--e Pharmacia Upjohn (Cyklokapron) IV Solution 0 10 20 30 40 Time (Hours Post-Dose) FIG. 4 Patent Application Publication Jun. 10,2010 Sheet 4 of 7 US 2010/0143468 AI Dissolution Profiles of Prototypes Vs. Cyklokapron 3 100: ImmediateRelease] Tablets (IR) -- Delayed Release Tablets (DR) (in Base Stage) -&- Modified Release Tablets (MR) Cyklokapron % Release (Accumulative) oO 15 30 45 60 75 90 Time (minutes) FIG. 5 Dissolution Profiles of All Exhibit Batches Vs. Cyklokapron 110: 3 8 % Release (Accumulative) g 8 3045 6075 Time (minutes) FIG. 6 Patent Application Publication Jun. 10,2010 Sheet 5 of 7 US 2010/0143468 AI {LUGHT 2. MODERATE Measure #4 Ding you ros recat esta pei, your blod loss was: HEAVY 4, VERY HEAVY Weasure besdig imi you work outside or inside the home? {.NOTATALL 2, SLIGHTLY 3, MODERATELY A QUITEABIT § EXTREMELY Ding your mast recent mens chring this per was: 0, ABOUT THE SANE Measure #62 you menstrual leading improved sine youl: eri plese to ma (GREATDEAL 6.AGREAT DEAL BETTER 5.AGOOD DEAL BETTER 4.AN AVERAGE AMOUNT BETTER 3. SOMEWHAT BETTER DALITLEBETTER ‘ALMOST THE SAME Dung your mos! recent merstal pero, haw much your Weasure®s limit you in you physical activities? ‘.NOTATALL 2, SUGHTLY 3. MODERATELY 4. QUITE ABIT 5. EXTREMELY re Please mar [XJ al activites thet were limited by bie ing dna your reoent mens pod [Waking [Shopping Tevling! [Standing] Home Management.” Yaeaton [Citing Stars [Leisure (10hte? (Sqatingor (18 {othe berdng down —[] Spars (Chicare {1 ardering Teasure #8 Comoaet to your previous mensual period, woud yousayyourlod ss 1. BETTER goto 6a) Ifyou mens leding worsened’ since yourlast prod, lease ince how much 7-AVERY GREAT DEAL WORSE 6 AGREAT DEAL WORSE §5.AGOOD DEAL WORSE 4 AN AVERAGE AMOUNT WORSE 5. SOMEWHAT WORSE 2 ALITTLE WORSE 1, ALMOST THE Sl WORSE ATALL Moasure #4 Dung your most recent menstrual period, how much ed you Deecnglmit youn your social o leisure activites? {.NOTATALL 2.SUGHTLY 3, MODERATE psiod how much dd you beeing 2. WORSE (ob) easure fb Measure He Was this @ marin or important change for you? 0.No AYES Patent Application Publication Jun. 10,2010 Sheet 6 of 7 US 2010/0143468 AI Menorrhagia Impact Measure #1 Percentage of Patients and Normals Indicating Each Response at Baseline (BL) and at Month 1 (M1) 100% S 90% 44S 80% 70% E 60% 8 50% 5 @ 40% 30% 20% 10% oe BOM a Mm Treatment Cohort Normal Cohort Measurement Period Uy FIG. 8 Limitations of Social & Leisure Activities (LSLA)in Women with HMB Treated with Modified Release Tranexamic Acid 35 Example 13 -- Example 14 3 -2- Placebo Example 13} + Placebo Example 14 2 80 5 a = 5 |Scale Response 2 ot p<0.0001 5. Extremely: <0.000T | 4. uite a Bit 3. Moderately 2Sighty 18 4.Not at all Pre-Treatment Post-Treatment FIG. 9 Patent Application Publication Jun. 10,2010 Sheet 7 of 7 US 2010/0143468 AI Example & Example 9 140 120 z = = 100 D Meaningful Clinical 5 20 Change to Meaningful & Women Change [ (36 ml) @ 60 = 5s § 40 = 20 0 \ c (n=112) 15) (n=67) (n=115) (n=72) “P-value vs placebo < 0.0001 Tranexamic Acid 3.9 g/day Tranexamic Acid 1.95 g/day Placebo FIG. 10 US 2010/0143468 AI ‘TRANEXAMIC ACID FORMULATIONS 10001} This application is a continuation of U.S. patent ‘application Ser. No. 12/438,510, filed Ape. 30,2009, which is 4 continuation-in-part of U.S. patent application Ser. No. 12/228.489, whieh is a continuation of U.S. patent applica- tion See. No, 11/072,194 fled Mar. 4, 2005, now abandoned, Which claims the nett of U.S, Provisional Application No 60550,113, fled Mar. 4, 2008, and USS. Provisional Appli ‘ation No, 60/392,885, filed Jul, 30, 2004, the disclosures of whicl are both hereby incorporated by reference in their entireties. FIELD OF THE INVENTION [0002] The invention is directed moxifed release oral Tranexamie acid formulations that preferably minimize or ‘eliminate undesirable side effects and methods of treatment ‘with these formulations. BACKGROUND OF THE INVENTION 10003] | Tranexamie seid ((rans-4-(aminomethy])eyelohex- aneearboxylie ac, Cyklokapron® (Pfizer) is an antifibrin- Iytic agent. That sit helps to prevent Isis or dissolution of aafibrinclot which farms the normal physiologic process of wis, Its mechanism of action i as a competitive + of plasminogen ativation, and as # noncompetitive of plasnin both plasminogen and plasmin are sei ‘ators of fibrinolysis and active elotlysing agents. Tranex- mic acid thus helps to stabilize flbrin clots, which in turn ‘maintains coagulation and helps to control bleeding 10004) -Tranexamic aid is usod w contro} excess bleeding, Jor example, excess bleeding that occurs during dental pro- ‘dures in hemophilises and for heavy bleeding during men- siruation (menorthagia). Women suffering from menorthagia fare typically treated orally with 500 mg tranexamic cid Tablets administered thre or four times daily witha total daily dose ranging fom 3 gramstlay (two tablets every eight hours) t 6 prams/day (ee tablets every six hours). How ‘ever, this twatment may cause adverse gastointesting] reac tions, incloding nausea, vomiting, dierhea, and ramping, ‘te. These gastrointestinal si effects are due tothe quantity ‘of tranexamie aeid andr rapid rate of release of tranexamnic jd into the stomach with each dose, as well as the lage ‘quantity of excipients used in the tablet formulation that are Jntoduced into the stomach, Such side effets, in addition to the cramping, bloating, pain, and other symptoms that may accompany menses, are undesirable, and a formulation of teanexamie acid is needed which will reduce oF eliminate these side effets, Mensteval Bleeding 10005] | Menstrual Bleeding disorders encompass a number ‘of conditions including bleeding associated with uterine {Throds, endometriosis, or bleeding asa result of delieiencies inthecoiting process forexample, von-Willebrand’s disease. Studies suggest that as many as 11% of the women who ‘experience heavy menstnial bleeding, suffer from an ner ited bleoding disorder such as von Willebrand's disease. xoessive Menstrual Bleeding is menstration at relatively regular intervals but with excessive blood loss over the menses period which may he prolonged. Heavy Menstrial Bleeding (also referred to as “Menoerigia") is a serious, Jun. 10, 2010 persistent, and recurrent medical condition that is one ofthe ‘ost common complaints encountered by gynecologists and srimary care physicians (Palep-Singh, 2007). A 2005 survey (01273 obstetician/gynecologisis found tha they see anaiver ‘age of 18 to 25 symptomatic patients per month, Heavy Men- srual Bleeding is hypertibrinolytic condition defined as eyelic, normal intervals of menstruation with excessive vol- fume, Menorrhagia is aften associated with a disruption in daily routines, work, and sexual activity Teading 0 a signifi ‘ant decrease in health-related quality of life and time lost rom work or school. While Menorshagia is rately ie threat- ning, when undiagnosed aod untreated, it may over time «use iron deficioney ancmia and inereased fatigue, both of \whieaffect norma ie activities, relationships, socal acti ties, and various aspects of mental well-being (initation, ‘anxiety Lefl untreated it may he astociated with subsequent ‘morbidity including dysmenorthea, hospitalization, red blood cell ransfsions and ehronic pain. Annually, appeoxi- mately 10% of women of reproductive age report Menor shogia (Rees 1991; yan Fifkeren, 1992) and acoording to the Center for Disease Control (CDC), 3 million women al repro- uctiveage report Menorthagia yearly, 6% of whichhaveno known etiology. Stadies report that many as thirty percent ‘of premenopausal women perceive their menses tobe exces- [0006] Women suffering from menorthsgis often have arcater uterine fbrinoytie wetivty than women With noma tyelic menstrual Blood loss (MBL). High concentrations of plasminogen activators are fond in both the tends and men- Strual uid (Albrechtsen, 1986a,b). Rybo (1966) found sig- nificantly higher concentration of endometrial plasminogen ctvators in women with excessive menstnial blesding com- pared to Women With normal menstrual loss [0007] Causes of Menorthagia include pelvie diseases (myomata[fbroids}, adenomyosis or uterine polyps), intra terine contraceptive devices, and systemic disonlers (coat Jopathies such as thrombocytopenia or vom Willebrand's ease, and hypothyroidism). In contrast ro menorrhagi, the term “dysfunetional uerine bleeding’ refers Jonged or imegular bleeding from the en ‘unrelated to systemic disease (Wathen, 1995) and is usually associated with anovulation, Menoethagia is also distin: guished from other ovulatory bleoding disorders, such as ‘mettorshagia (intermeastraal bleeding), menometrorthagia (irregular heasy menstrual bleeding) and polymenorrea (menstrual eyele less than 21 days). Diagnosis of Menstrual Blood Lose 0008} In clinical trials, menstrl blood loss (MBL) is ‘sally delennined by measuring the amount of hemoglobia recovered from sanitary products during the menstrual eye, using thealkaline bematin method (Praser, 1994) However it js important to remember that blood accounts for only about ‘50% of total mensiial flow, with endometrial transndate ‘accounting forthe remainder (Fraser, 194). Total menstrual ‘ow can be estimated by weighing of sanitary produets or by comparisons with a pictrial blood loss assessment char. However, the use of these quantitative and semi-quanttative ‘methods isnot practical in pon-rial settings. Rather, the diag- ‘nosis of Menorrhagia in the healheare clinic is made by ‘medical providers on the basis of patient's perceived and self-reported medical history routine laboratory assessments fof the patient's general health status, and gynecological examinations, US 2010/0143468 AI 10009] Clinically heavy menstrual bleeding is sometimes defined as tol blood loss exceeding about 80 mal per cyele oF ‘menses lasting longer than seven days. The volume lst hans= ‘ever, varies widely: Clinically losses from about 30 sal to 60) rl, 60 to 80 mi, $0 100 mi, to as high as 1000 ml per eycle ‘are observed, Menstrual blood losses of $0 t0 60 ml are ‘associated with a negative iro balance and ion deficiency ‘anemia is diagnosed in about 67% of the women wh lose a ‘excess of 80 ml per day. Other criteria for diagnosing the ‘condition include measuring the number and size of blood. ‘lois in the meneges. or monitoring the use of pads or tam- ns. It sestimated that perhaps only ten pereent of women who perceive ther loss tobe excessive etualy fll within the linical definition. The 80 ml definition has been repeatedly ‘questioned, and alternative definitions broadened the blood Joss range used for patient evaluations [0010] Blood loss volume assessments commonly require the collection and preservation of menstrual padsor tampons, the extractionofthe pads and the aceuratemeasurement of the blood content, Wonten are insicted to collect ll sanitary ‘owls and tampons during the course ofthe menstrual diag- nosis period or the course of clinical study period. Blood Joss can be measured by extraction of the blood from the sanitary material with 5% sodium hydroxide followed with a spectrophotometri measurement of hematin st a wavelength ‘oF about 540 nm. The total blood los canbe ealeulated fora ‘individual by comparison of the patients plasma blood bemo- tlobin measurement with the collected Hemoglobin values [0011] The collection ofthe blood sample diseourazes the routine weof the test inthe diagnosis ori the treatment ofthe ‘condition, In the course of a routine visit with a physica ‘ther blood work may be appropriate but lacks a casual rela tion to the heavy bleeding disorder. The battery of routine oratory tests may elude patient blood hemoglobin, hac- matoerit, platelet count, bilirbin, serum creatinine and scrum ferntn, In sum, diagnosis in the rottine course of practice relies heavily cn the woman's perception a the vol- tame of blood lst during menses Diagnosis and Treatment of Heavy Menstrual Bleeding Dis- ‘orders (Menorrhogia) 10012] A number of medical and surgical interventions are available to teat menstrual bleeding disorders. Curently valle non-surgical treatments for heavy bleeding disor ders, include, hormonal treatments (oral contraceptives), high-dose progestin therapy desmopressin acetate, ethamsy~ Jate, nonsteroidal antiinflammatory drugs (NSAIDs), the antfibrinolytic drugs aminocaproe acid and tranexamic avi, ven with the drug treatments available, surgery remains @ ‘common treatment [0013] Although not approved for menorrhagia inthe US, tse of oral contraceptives for menorthagia is widely ‘accept, Oral contraceptives may not he a prefered therapy orsome women beeause of age (younger females), unwanted side effects (nausea and vomiting, breakthrough bleeding ‘weight change, migraines and depression), and safety cone ‘cerns (increased rsk of tomboembolism, stroke, myocar lal infarction, hepatic neoplasia and gall bladder discase), High-dose progestin (synthetic versions of the homone progesterone) may also be given o women with menorthagia, ‘ther orally or By a progestin-eleasing device inserted into the uterus (intrauterine device). Side effects include nausea, bloating, mood changes, and breast tenderness Jun. 10, 2010 [0014] Akhough itis typically «last esort, desmopres acetate is sometimes used to belp lighten meastraal flow ‘women With menorthagia, The effectiveness of desmopressin is thought to vary between individuals Skleelfeets include headache, tachycardia, facial Mushing, and rare reports of thromboembolism, [0015] NSAIDs are sometimes used to treat menorthagi as they may reduce blood flow while providing analgesia for ciated with the condition (Shaw, 1994), Side eflects ‘associated with chronie NSAID use include gastrointestinal bleeding, ulceration, and perforation; and renal eects such as hyperkalemia, hyponatremia, acute renal insulicieney, interstitial nephritis, anc renal papillary necrosis. [0016] Hysterectomy or endometrial esccton are options ifother forms of therapy are not effective or are unsuitable for some reason, Possible sungical complication include infec- ‘ion, uterine perforation, and other complications associated ‘with major surgery. [0017] _Aniiibrinlysi drugs such as e-amninocaproic acid and tranexamic acid (immediate-release formulation) have ‘een used to treat HMB in women with oF without a diag- nosed bleeding disorder (van Eijkeren, 1992; Bonnar, 1996; ‘Vermylen, 1968; Nilsson, 1965). The avilable evidence rom published iteraure suggests that tranexamic acid at doses of 4 piday (ypically 1g every 6 hours) is effective in the treatment of TIME and is associated with few side effects (Callender, 1970; Duna, 1999; Edlund, 1995; Preston, 1995). In Sweden, the erage dose of ranexamic acid to treat HMB is 39 widay (Rybo, 1991), Thus, tranexamiec acid is used extensively in Europe, Canada, Asia, Japan, Australia and [New Zealand treat mevorthogia, but snot approved fr this indication in the US, [0018] Tranexamic acid is « compestve inhibitor of plas- ‘minogen activation (see review by Dunn, 1999). Binding of ‘unexamie acd to plasminogen does not prevent conversion of plasminogen to plasmin by tissue plasminogen activator, but the resulting plasmin/tranexamie acid complex is unable to bind to fibrin. Thus, enzymatic breakdown of fibrin by plasmin (fibrinolysis) inhibited. At higher concentrations, {ranexamic eid isalso a noncompetitive iibitorof plasmin. [0019] Before medical and surgical interventions ean be initiated, diagnosis of a heavy menstrual bleeding disorder ‘must be accomplished [0020] Diagnosis and eatment of disease often depends on the patients perception and subsequent description of symip- toms the physician's evaluation ofthe patient's description, the physician observations ofthe patient and laboratory test results, Menstrial bleeding disorders do not lend themselves to physician observation or to routine laboratory testing Patient observations and the physician's evaluation of the patiet's description are subjective and thus variable, In ad- ‘ion a women's medical history has been found to be poor predictor of menstrual blood loss. Neither the duration of ‘menses nor the number of sanitary pads worn accurately coresponds to the woman's actual menstrual blood loss (Chimbira, FTaynes, year), An objective assessment of blood Joss using the alkaline hacmatin assay has been shown to be reproducible but itis not suited foe routine clinical use by healthcare providers. To date no effective instrament fore ably diagnosing andlor monitoring the treatment of mens bleeding disorders has hoen developed despite the significant ‘numberof women who suffer from these conditions. [0021] Previously, stdies have focused on the impact of of bleeding disorders on patients’ health related US 2010/0143468 AI ‘quality of if As the eects of menstual lean disonlers fe primarily symptomatic, the mibjetve tame namely Symptom alleviation, cannot be objectively mesure. [a rescirch fom Europcun counties where the sails ie drug tranexamie eid is curently aailabe, eament with this atibrinoytic has reduced heavy sense blading by 40.50% and improved the health-elated quality of life of affected women on measures of peal aetvy, work perfre mance, productivity, cleanliness, overall functioning and tiredness 0022] Jenkinson tl, Quaityin HealthCare 1996: 5; 912 ‘evaluated the validity and intemal reliability of the short Torm-36 SF36) health survey questionaire ia Women pre- senting with menonagia. The study conch that several ‘questions on the questionnaire were diel to answer for Patients with heavy’ menstrual bling. Sich problems wore figgested as posible interferences wih the validity ofthe mesure, enkinson was that because a subjective measure ‘works Wellinone popiation oe withone group. thiscannot Be takentoimplyisapproprateness forall uoops oreonditions 10023) aun in an abstract fom a seminar on Dystane- wal Uterine Bleeding, Feb. 23,1994, adicates hat es tionnaire was used in a Swedish study of 2208 women who described heir menstuation a excessive 10024] Winklerina study basedin parton the Falund work, ‘onclidd that the treatment of hemy menstrual blsding ‘with wanexamie acid increased the quality of lie of the treated patients. The Winkler sty ws an open abel scone tolled usage study which includ 849 patients. question. aire wae acl ror to tretment and aftr the ist an third mensintion The sty indiates that 80% of the Women ‘were stiafied with the tsatment The questionnaire aed $eries of eight question combined with an assessment by the Patients ofthe ehange in quantity of mensteal fw 025]. Ruts, D.A., Quulity of Life Reseach, 4, 03-40), 1995 finds that menorehagia isa common problem in syne ological practice and that women sce professions! hp Primarily ease ofthe doleterions effet onteir quality a Jie Ruta ecognirng the importance of evaluating the efx venessof the treatments developed a questionairebssedon the pe of questions Iroquenlly asked when aking # ayne- ‘ological history. A series of questions were devised which ‘ssesed fille factors including the duration ofthe perio, the regularity of the period, pain, problems with sling Saining interference With work, atrference With les Ruta conclu that the finial questionnaire may be ust in selecting patients for hysterectomy and asesing the out come of conservative treatment especially in combination withthe SE-6 questions Diagnostic Test for Menstraal Bleding [0026] The alkaline haematine test deseribed above pro- Vides quantitative assessments of the extent of menstrual bleeding. Thistestallows the physician to diagnose and moni- ‘orthe progress ofa women’s menstrual process. However the ‘est i impractical and dificult to perform. Tae test requires women fo capture used menstrual pads over the course of her Period, preserve the samples in seondition sch thatthe blood ‘content within the pad may be accurately extracted and quan- fitated. Requesting a patient to perform menses sample col- lection may be pructica in the course ofa clinical tial where procedures are specified and monitored however, in routine medical practice, the use of sucha test procedure to diagnose Jun. 10, 2010 ‘and monitora women’s the data generated [0027] The need remains o develop an assessment system Which replaces previously studied dianostievebnigues and ‘he alkaline haematine test and provides reliable measure of both the oceurrence of the disorder and the progress of the isorder The present inetion fills this need by providing a Heavy Menstrual Blceding Iastrament (FIMBI) which is cele of igroing nd mir he weston of 2 fat with a menstrual bleeding disorder {0028) “There alo remains» need to provide Heavy Men- strual Bleeding (FMB) therapy’ that is sul, efficacious and ‘only administered during the monthly period of heavy men- sruation, addresses the excessive fibrinolysis implicated ia ‘many eauses of menorrhagia, and fills currently recognized ‘unmet medical need inthe US. Therapy for HMB is expected to reduce the incidence and extent of iron-deficiency anemia, and to provide a aozhormodal medical therapy option ia ied of the numerous invasive procedures (eg. transcervcal endometrial resection) and major surgery (hysterectomy) performed annually. SUMMARY OF THE INVENTION 0029} Formulations of trancxamic acid which minimize or climinate the undesirable gastrointestinal side effects in paliets on oral tranexamic oid therapy, c.g. women treated Tor menorthagia (heavy menstrual bleeding) are disclose. “The present invention is directed in part to meslified release ‘formulation, formulated so tat therelease a ranexamic acid thereot From the dosage form oocur in a designed fashioa to prevent a bolus of tranexamic acid being inteoduced into the ‘Stomach and available for dissolution in the gastric contents Such modified release formulations reduce the concentration ‘of tanexamie aed dissolved in the stomach contents such as eg, preventing large holus of tranexamic acid being inteo- ‘duced inthe stomach, The beneficial effet of this redveed tranexamie aed concentration isto lower theamount of tan- ‘examic acid in the gastric contents so tha there are fewer adverse effects with ranexamie acid therapy. This reduction inadverse effects preferably results in improved patient com- pliance with therapy, because preferably patients will not intentionally miss taking a dose to avoid these adverse side elfets. Physicians will also preferably be more likely to initiate and maintain tranexansie seid estment for their ints because of the reduced patient complaints {0030 Tes an object ofthe vention vo provide an ort ‘dosage form comprising traexamic acid which is stable for administration ona two of three times a day basis to humans. [031] It is a further object ofthe invention to provide a nodilied release oral dosage form comprising tranex ‘acid and a modified release material which provides for the ‘modified release of the wanexamie seid and is suitable for ‘administration ona two or thre times «day basis. [0032] It sa further object of certain embodiments of the present invention to provide a modified release oral dosage {orm comprising tranexaiic acid and a modified release vateial which minimizes or eliminates the undesirable gas- teointestinal side effects inpatients on onal tranexamic acid therapy while maintaining or improving the therapeutic effect of tranexanie wei, [0033] It ise further object of certain embodiments of the present invention to provide a method of treating a patient Sulfering from heavy menstrual bleeding (menomrhagia) by ‘orally administering to the patient one or more dosage foen US 2010/0143468 AI comprising ranexamic acid and a modified release material which provides for therapeutically effective loves of tne ‘amie eid stable for two ote times day axis 10034} The above advantapes ad objees and oters canbe achieved by virtue ofthe resent invention which i directed in par to a madi release oral dosage form eompesing tranexanic sid ora pharmaceutically soeptblesal thereat ‘anda muified ease material which provides forthe mod fied release of the tanexamic seid or pharmaccutclly accopiahe salt thereof fom the dosage form such thatthe ‘dosage form i suitable for administration on wo or thse nes a day basis sid osage form proving an in-vitro

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