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Tranexamic acid formulations

a technology of tranexamic acid and formulation, which is applied in the direction of drug composition, extracellular fluid disorder, peptide/protein ingredients, etc., can solve the problems of significant decrease in health-related quality of life, nausea, vomiting, diarrhea, and cramping, and achieve less gi side effects and cns side effects

Inactive Publication Date: 2009-08-27
AMRING PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0032]It is a further object certain embodiments of the invention to provide a formulation comprising an amount of tranexamic acid which when released in the gastric contents provides fewer adverse effects than with certain current tranexamic acid therapy.

Problems solved by technology

However, this treatment may cause adverse gastrointestinal reactions, including nausea, vomiting, diarrhea, and cramping, etc.
These gastrointestinal side effects are due to the quantity of tranexamic acid and / or rapid rate of release of tranexamic acid, into the stomach with each dose, as well as the large quantity of excipients used in the tablet formulation that are introduced into the stomach.
Such side effects, in addition to the cramping, bloating, pain, and other symptoms that may accompany menses, are undesirable, and a formulation of tranexamic acid is needed which will reduce or eliminate these side effects.
Menorrhagia is often associated with a disruption in daily routines, work, and sexual activity leading to a significant decrease in health-related quality of life and time lost from work or school.
While Menorrhagia is rarely life threatening, when undiagnosed and untreated, it may over time cause iron deficiency anemia and increased fatigue, both of which affect normal life activities, relationships, social activities, and various aspects of mental well-being (irritation, anxiety).
However, the use of these quantitative and semi-quantitative methods is not practical in non-trial settings.
Oral contraceptives may not be a preferred therapy for some women because of age (younger females), unwanted side effects (nausea and vomiting, breakthrough bleeding, weight change, migraines and depression), and safety concerns (increased risk of thromboembolism, stroke, myocardial infarction, hepatic neoplasia and gall bladder-disease).
Binding of tranexamic acid to plasminogen does not prevent conversion of plasminogen to plasmin by tissue plasminogen activator, but the resulting plasmin / tranexamic acid complex is unable to bind to fibrin.
Menstrual bleeding disorders do not lend themselves to physician observation or to routine laboratory testing.
In addition a women's medical history has been found to be a poor predictor of menstrual blood loss.
An objective assessment of blood loss using the alkaline haematin assay has been shown to be reproducible but it is not suited for routine clinical use by healthcare providers.
To date no effective instrument for reliably diagnosing and / or monitoring the treatment of menstrual bleeding disorders has been developed despite the significant number of women who suffer from these conditions.
As the effects of menstrual bleeding disorders are primarily symptomatic, the subjective outcome namely symptom alleviation, cannot be objectively measured.
The study concluded that several questions on the questionnaire were difficult to answer for patients with heavy menstrual bleeding.
Such problems were suggested as possible interferences with the validity of the measure.
Jenkinson warns that because a subjective measure works well in one population or with one group, this cannot be taken to imply its appropriateness for all groups or conditions.
Ruta, D. A., Quality of Life Research 4, (33-40), 1995 finds that menorrhagia is a common problem in gynecological practice and that women seek professional help primarily because of the deleterious effect on their quality of life.
However the test is impractical and difficult to perform.
Requesting a patient to perform menses sample collection may be practical in the course of a clinical trial where procedures are specified and monitored however, in routine medical practice, the use of such a test procedure to diagnose and monitor a women's menstrual bleeding is impractical and the data generated is unreliable.

Method used

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  • Tranexamic acid formulations
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  • Tranexamic acid formulations

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0130]In Example 1, immediate release 650 mg tranexamic acid tablets were prepared having the ingredients listed in Table 1 below:

TABLE 1Quantityper batchQuantity perIngredient(kg)tablet (mg)Active IngredientTranexamic Acid, EP (650 mg / tab)84.50650.0Inactive IngredientsMicrocrystalline Cellulose, NF5.75344.25(Avicel PH 101)Microcrystalline Cellulose, NF10.66082.00(Avicel PH 102)Colloidal Silicon Dioxide, NF0.09750.75Pregelatinized Corn Starch, NF6.43549.50Croscarmellose Sodium, NF19.5015.00Povidone, USP (K value range 29-32)4.68036.00Stearic Acid, NF (powder)2.34018.00Magnesium Stearate, NF (powder)0.5854.50Purified Water, USP*17.550135.00Film Coating (Inactive Ingredients)**Opadry White YS-1-70034.110—Purified Water, USP36.990—*Purified water is removed during processing**6 kg excess prepared to account for losses during transfer

The formulation of Example 1 was prepared as follows:[0131]1. Weigh all ingredients and keep in moisture resistant containers until ready for use.[0132]2. ...

example 2

[0144]Modified release 650 mg tranexamic acid tablets were prepared having the ingredients listed in the Table 2 below:

TABLE 2QuantityQuantityper batchper tabletIngredient(kg)(mg)Active IngredientTranexamic Acid, EP84.50650.0Inactive IngredientsMicrocrystalline Cellulose NF (Avicel PH 101)5.75344.25Colloidal Silicon Dioxide NF0.09750.75Pregelatinized Corn Starch, NF6.43549.50Hypromellose, USP (Methocel K3 Premium LV)19.110147.00Povidone, USP (K value range 29-32)4.68036.00Stearic Acid, NF (powder)2.34018.00Magnesium Stearate, NF (powder)0.5854.50Purified Water USP*17.550135.00*Purified water is removed during processing

The formulation of Example 2 was prepared as follows:[0145]1. Weigh all ingredients and keep in moisture resistant containers until ready for use.[0146]2. Measure water into a container. Mix povidone at medium speed until completely dissolved.[0147]3. Add tranexamic acid, microcrystalline cellulose (MCC), pregelatinized corn starch, and colloidal silicon dioxide to th...

example 3

[0157]In Example 3, modified release 650 mg tranexamic acid tablets were prepared as in Example 1 and coated with a film coating similar to the immediate release tablets of Example 2. The ingredients are listed in Table 3 below:

TABLE 3QuantityQuantityper batchper tabletIngredient(kg)(mg)Active IngredientTranexamic Acid, EP84.50650.0Inactive IngredientsMicrocrystalline Cellulose NF (Avicel PH 101)5.75344.25Colloidal Silicon Dioxide NF0.09750.75Pregelatinized Corn Starch, NF6.43549.50Hypromellose, USP (Methocel K3 Premium LV)19.110147.00Povidone, USP (K value range 29-32)4.68036.00Stearic Acid, NF (powder)2.34018.00Magnesium Stearate, NF (powder)0.5854.50Purified Water USP*17.550135.00Film Coating (Inactive Ingredients)**Opadry White YS-1-70034.305—Purified Water, USP38.750—*Purified water is removed during processing**6 kg excess prepared to account for losses during transfer

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Abstract

Disclosed are immediate release oral tranexamic acid formulations and methods of treatment therewith.

Description

[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 12 / 220,241, filed Jul. 23, 2008, which is a continuation of U.S. patent application Ser. No. 11 / 072,162, filed on Mar. 4, 2005, which claims priority from U.S. Provisional Application No. 60 / 550,113, filed Mar. 4, 2004, and U.S. Provisional Application No. 60 / 592,885, filed Jul. 30, 2004, the disclosures of which are hereby incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The invention is directed to oral tranexamic acid formulations and methods of treatment with these formulations.BACKGROUND OF THE INVENTION[0003]Tranexamic acid (trans-4-(aminomethyl) cyclohexanecarboxylic acid, Cyklokapron® (Pfizer) is an antifibrinolytic agent. That is, it helps to prevent lysis or dissolution of a fibrin clot which forms in the normal physiologic process of hemostasis. Its mechanism of action is as a competitive inhibitor of plasminogen activation, and as a noncompetitive inhibitor of pl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/195
CPCA61K9/2009A61K9/2027A61K9/2054A61K31/195A61K9/2846A61K9/2866A61K9/2059A61P7/04
Inventor MOORE, KEITH A.HEASLEY, RALPH A.GREIWE, JEFFREY S.FACEMIRE, JOHN W.MODEST, JASON D.
Owner AMRING PHARM INC
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