Patent Application
20210196707
The invention relates to a stable oral liquid formulation of the pharmaceutical agent trimetazidine. Trimetazidine (1-(2,3,4-trimethoxybenzyl)piperazine) (“TMZ”) was first approved for use (as its hydrochloride salt) in Europe in 1978 under the tradename Vastarel® and is currently marketed in a number of countries, including Bulgaria, Cyprus, the Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Poland, Portugal, Romania, Slovakia, Slovenia, and Spain. An anti-ischemic compound, TMZ is principally used in the treatment of angina pectoris. The drug has never been approved by the U.S. Food and Drug Administration.
TMZ exerts its positive effects on cardiac ischemia through preventing the ATP level in cells from decreasing by maintaining proper energy metabolism of cells in a hypoxic or ischemic state, thereby guaranteeing normal functioning of the ion pump and normal operation of the transmembrane sodium-potassium flow and maintaining a stable internal environment of cells. The potential mechanisms of action for TMZ in myocardial ischemia are as follows (DiNapoli 2008):
Various formulations of TMZ are known in the art. Currently available formulations are 20 mg immediate release tablet and 35 mg modified release tablets. Typical dosing regiments are 20 mg three times per day or 35 mg twice per day. In addition, an oral solution of TMZ was available (marketed under the Vastarel brand) that contained 20 mg/ml (2%) trimetazidine dichlorohydrate in methyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol and purified water purified water. That composition was neither buffered nor pH-adjusted and so would, therefore, have had a pH of approximately 3.
There is also in the patent literature a published Chinese patent application that relates to oral trimetazidine formulations that have been pH adjusted to a pH of about 6.5 to 8. In the absence of buffer, those formulations rely on the buffering capacity of the active ingredient, which has an acidic pKa at about 4.45 and a basic pKa2 at about 9.14, predicting limited buffering capacity in the selected pH range. Consistently, the Chinese application discloses very high concentrations of TMZ, generally exceeding 10% (100 mg/mL).
The present invention is direct to a stable oral liquid pharmaceutical composition of trimetazidine having a pH of about pH 4 to about pH 8, comprising a therapeutically effective amount of trimetazidine or a pharmaceutically acceptable salt thereof, one or more orally acceptable buffers, and one or more orally acceptable preservatives that is effective in said pH range. In certain embodiments, the oral composition has a pH range of between about 4 and about 8, but more preferably between about 5 and about 7 and most preferably between pH of about 5.5 and about 6.5.
Other embodiments of the invention are directed to methods of treating patients with stable oral liquid pharmaceutical composition. The pharmaceutical composition is particularly suitable for treating a patient having a condition treatable by trimetazidine, such as cirrhosis and renal deficiency, and who has a decreased tolerance for acidic or highly basic oral solutions.
The inventive compositions are uniquely adapted to treat subjects, who cannot tolerate acidic or highly basic oral solutions. Such intolerance could arise, for example, from a dysfunction of the mucous membranes of the gastrointestinal tract or due to the presence of esophageal varices, which may bleed or are at risk for bleeding. In that regard, it is important that the present compositions have a pH range of between 4 and 8, but more preferably between 5 and 7 and most preferably between pH 5.5 and 6.5. Aside from becoming caustic, higher pH solutions tend to have a “slimy” and, thus, undesirable consistency and mouthfeel; for this reason, pH<7 is desirable. For most subjects, low pH products are not a problem. In fact, carbonated beverages typically have a very acidic pH of around 3. For subjects with impaired gastrointestinal tracts, this can be problematic and, thus, the inventive compositions are beneficially employed.
Patients suffering from liver cirrhosis often develop esophageal varices due to portal hypertension and are especially suitably treated with the inventive compositions. Thus, patients with decompensated cirrhosis, suffering from chronic liver failure or acute-on-chronic liver failure may also be treated with the inventive compositions. Patients with advance cirrhosis may also develop kidney dysfunction that may manifest, for example, as hepatorenal syndrome.
Trimetazidine is principally eliminated by renal excretion and so exposure to the drug is enhanced in patients with renal insufficiency. Thus, in order to maintain appropriate dosing (without over-dosing), doses of trimetazidine should be reduced in order to maintain consistent levels of exposure.
In certain embodiments, a subject to be administered and treated with a composition of the present invention has renal dysfunction or impairment or is at risk of such dysfunction or impairment due to a condition such as liver cirrhosis. The degree of renal dysfunction or impairment will typically vary from subject to subject, but in preferred embodiments, the degree of dysfunction or impairment will be moderate to severe, or the subject will be at risk of developing moderate or severe renal impairment. In certain cases, subjects will have serum creatinine levels in excess of 1.5 mg/dL, or in excess of 2 mg/dL. In particular, subjects treatable according to the invention include subjects having moderate to severe renal dysfunction. In most cases, subjects will have a creatinine clearance rate of less than 60 ml/min and in many cases less than 30 mL/min.
In general, the present invention is directed to a stable oral liquid pharmaceutical composition of trimetazidine having a pH of about pH 4 to about pH 8, comprising a therapeutically effective amount of trimetazidine or a pharmaceutically acceptable salt thereof, one or more orally acceptable buffers, and one or more orally acceptable preservatives that is effective in said pH range. The liquid formulation is generally an aqueous formulation, using sterile water for example, and or saline, but other orally acceptable liquids can be used.
Subjects treatable in accordance with the inventive compositions may have some level of renal dysfunction or impairment or they may be at risk of such impairment due to a condition like liver cirrhosis. Treatable subjects preferably have or are at risk of having moderate or severe renal impairment. In certain cases, subjects will have serum creatinine levels in excess of 1.5 mg/dL or even 2 mg/dL. In particular, subjects treatable according to the invention include subjects having moderate to severe renal dysfunction. In most cases, subjects will have a creatinine clearance rate of less than 60 ml/min and in many cases less than 30 ml/min.
The compositions of the invention are also uniquely adapted for “infinite dosing.” Unlike a tablet or capsule, for example, liquid formulations can be dosed up or down in very small increments. For example, a 20 mg tablet can only accurately deliver 20 mg. A 2 mg/mL solution can be used to accurately deliver drug in 0.1 to 0.5 mg increments, depending on the sophistication of the delivery system. Some metered dosing system can accurately deliver volumes as small as 0.05 ml increments. A syringe may be used to accurately deliver volumes in 0.1 ml increments and a graduated plastic cap may be used to deliver volumes in increments of 0.5 mL.
The compositions according to the invention are stable at room temperature. This stability is exhibited not only in that the ingredients of the compositions do not degrade, but also in that they do not allow microbial growth, meaning that they also do not require refrigeration. Many antimicrobial agents are less effective or even ineffective at neutral pH. This is potentially problematic in that low pH itself is also a potent antimicrobial factor. Compositions at or near neutral pH are particularly at risk of not being pharmaceutically suitable from the perspective of microbiology.
The inventive compositions advantageously contain at least one preservative that is orally acceptable. Orally acceptable preservatives would generally be those listed on the Inactive Ingredient list maintained by the United States FDA (https://www.accessdata.fda.gov/scripts/cder/iig/). An orally acceptable preservative is generally one that is contained in a product that has previously been approved by the FDA in an oral formulation. The amount of an orally acceptable preservative in a composition according to the invention typically does not exceed the maximum daily exposure provided by the already-approved formulations. This amount may be termed the maximum allowable amount.
The minimum amount of orally acceptable preservative(s) is determined by measuring effectiveness. Thus, the minimum amount may also be referred to as the minimum effective amount. The effectiveness of an orally acceptable preservative or combinations thereof can be determined using standard antimicrobial preservative effectiveness testing, such as the United States Pharmacopeia (USP) method <51> in which Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis are inoculated into samples and monitored for growth over 28 days. The inventive formulations are considered to be Category 3 products and so they must meet the criteria for Category 3 products, enumerated below.
Examples of orally acceptable preservatives include amino benzoic acid esters (ie, “parabens”) and their salts, carboxylic acids, like succinate, propionate, malate, ascorbate, sorbic acid and tartaric acid, bisulfites, borate, benzoates, benzalkonium chloride. Parabens are particularly preferred in the present invention as preservatives because they generally are effective in the range of pH 4-8. Examples of parabens suitable for oral formulations include methylparaben, ethylparaben, propylparaben, butylparaben. Methylparaben, ethylparaben and combinations thereof are particularly preferred. On the other hand, other common oral formulation preservatives are generally only effective at more acidic pH and so would not work across the full range of contemplated pH values of the invention. For example, the effective upper pH limit for the following common preservatives is about: pH 6.5 for sorbates; pH 5.5 for propionates; and pH 4.5 for benzoates. The compositions of the invention do not contain benzoic acid.
The inventive compositions all contain an orally suitable buffer. Orally suitable buffers specifically include acetate, carbonate, and phosphate. Citrate has been found to be incompatible with trimetazidine and so the inventive formulations are prepared without citrate. It is widely known that the aforementioned buffers can be prepared using the free acids, various salt and hydrates of salts and combinations thereof. Potassium and sodium salts are particularly preferred. Moreover, mixtures of buffers can be employed to obtain the appropriate buffering range. Mixtures of mono- and di-basic sodium or potassium phosphate salts are commonly mixed to obtain a particular pH. Phosphate buffers are particularly suitable for the invention and most preferred. Similarly, carbonate and bicarbonate salts are mixed to obtain a particular pH. Optimal buffering usually is obtained around the PKa.
Some commonly used biological buffers are listed in the following table, along with the PKa values. While those previously used in formulations approved by the regulatory authorities would be particularly
The compositions of the invention all contain a therapeutically effective concentration of trimetazidine. The amount of trimetazidine can vary in the inventive compositions, but it generally is present at less than 5% weight/volume (w/v), measured either as the free base or as an acceptable salt. In any event, the maximum amount of trimetazidine is such that trimetazidine cannot effectively buffer the solution in the desired pH range. Preferred compositions contain less than 2% w/v such as 0.2% to 2%, or even less than 1% w/v, such as 0.1% to 1% trimetazidine. Particularly preferred compositions contain less than 0.5% w/v trimetazidine, such as 0.1% to 0.5%, and most preferred compositions contain from 0.1% to 0.3% w/v trimetazidine, measured either as the free base or as an acceptable salt.
In certain embodiments, the pharmaceutical composition may also contain an antioxidant. An antioxidant is understood herein to mean certain embodiments which are substances that inhibits oxidation. Such antioxidants include, but are not limited to, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium metabisulfite, sodium metabisulfite, anoxomer and maleic acid BP.
In certain embodiments, the pharmaceutical composition may also contain a flavoring agent. A “flavoring agent” is understood herein to mean certain embodiments which are substances that alters the flavor of the composition during oral consumption. A type of “flavoring agent” would be a sweetener. Preferred sweetners or flavoring agents would be microbially non-metabolizable. Especially preferred sweetners or flavoring agents would be carbohydrates such asxylitol and sorbitol. Such flavoring agents include, but are not limited to, acacia syrup, anethole, anise oil, aromatic elixir, benzaldehyde, benzaldehyde elixir-compound, caraway, caraway oil, cardamom oil, cardamom seeds, cardamom spirit, cardamom tincture-compound, cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid, citric acid syrup, clove oil, coca, coca syrup, coriander oil, dextrose, eriodictyon, eriodictyon fluidextract, eriodictyon syrup aromatic, ethyl acetate, ethyl, vanillin, fennel oil, ginger, ginger fluidextract, ginger oleoresin, glucose, glycerin, glycyrrhiza, glycyrrhiza elixir, glycyrrhiza extract, glycyrrhiza extract-pure, glycyrrhiza fluidextract, glycyrrhiza syrup, honey, non-alcoholic elixir, lavender oil, citrus extract or oil, lemon oil, lemon tincture, mannitol, methyl salicylate, nutmeg oil, orange-bitter-elixir, orange-bitter oil, orange flower oil, orange flower water, orange oil, orange peel-bitter, orange-peel-sweet-tincture, orange spirit-compound, compound, orange syrup, peppermint, peppermint oil, peppermint spirit, peppermint water, phenylethyl alcohol, raspberry juice, raspberry syrup, rosemary oil, rose oil, rose water, saccharin, saccharin calcium, saccharin sodium, sarsaparilla syrup, sorbitol solution, spearmint, spearmint oil, sucrose, syrup, thyme oil, tolu balsam, tolu balsam syrup, vanilla, vanilla tincture, vanillin or wild cherry syrup.
The invention also contemplates methods of treatment. Such methods of treatment comprise administering a stable oral liquid pharmaceutical dosage form of trimetazidine having a pH of about pH 4 to about pH 8, comprising trimetazidine or a pharmaceutically acceptable salt thereof, an orally suitable buffer and at least one preservative that is effective in said pH range. In preferred embodiments, the oral liquid pharmaceutical dosage form of trimetazidine is administered to a patient suffering from renal insufficiency or at risk of suffering from renal insufficiency. Renal insufficiency is generally defined with reference to serum creatinine concentrations that may be used to estimate glomerular filtration rate calculate creatinine clearance rate. Generally, renal insufficiency is defined as a serum creatinine level exceeding 1.5 mg/dL or a creatinine clearance rate of less than 60 mL/min. Renal failure is commonly defined as a serum creatinine level of 2 mg/dL or more or a creatinine clearance rate of less than 30 mL/min. In a preferred embodiment, treated subjects are at risk for or have renal insufficiency or renal failure as a consequence of liver cirrhosis. In other embodiments, treated subjects will have renal insufficiency or renal failure due to other reasons, such as age-related decline, acute kidney injury, chronic kidney injury, polycystic kidney disease, drug-induced nephropathy (including chemotherapy-induced nephropathy, idiopathic nephropathy and nephropathy due to other known causes. Such with renal insufficiency or renal impairment may be treated for their kidney problems or may be treated for other maladies treatable with trimetazidine, such as angina.
A typical method will reduce dosing by ⅓ for renally impaired subjects and then by ⅔ for subjects with renal failure. Thus, if a patient is receiving 60 mg of trimetazidine per day without renal insufficiency, a patient with renal insufficiency may receive 40 mg per day and a patient with renal failure may receive 20 mg per day. In one dosing regimen, patients without renal impairment receive 10 mL of a 2 mg/ml trimetazidine solution three times per day for a total of 60 mg/day. With renal impairment, patients will receive 6.7 mL of a 2 mg/ml trimetazidine solution three times per day for a total of 40 mg/day. With renal failure, patients will receive 3.3 mL of a 2 mg/mL trimetazidine solution three times per day for a total of 20 mg/day.
Embodiments of the present disclosure can be further defined by reference to the following examples, which are meant to exemplify aspects of the invention and should in no way be construed as limiting. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure. As used herein and in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly dictates otherwise.
In an attempt to identify excipients that are incompatible with trimetazidine, samples were prepared as binary formulations composed of trimetazidine and a single excipient or buffer. All of the samples were diluted in water, or buffer, at pH 6.0±0.1. All samples were packaged in 20 mL scintillation vials protected from light with PTFE caps.
Samples were stored upright under the following conditions for 8 weeks at 40° C./75% relative humidity. Samples were tested according the following table:
1Particulates are non-microbial amorphous fibers which appear in all of the API sample and placebos. Comparison of filtered and non-filtered samples do not indicate and type of precipitation. The likely source of the particulate matter is from the packaging components used for the study.
2Appears to be undissolved ethylparaben
1Appears to be undissolved ethylparaben
Placebo samples were not analyzed and results are not presented.
Full results are reported for trimetazidine samples. Only paraben results are presented for placebo samples.
1Relative Retention Time 1.90 identified as process impurity B
Three prototypes, the compositions of which are set out below, were tested for preservative activity as follows.
At day 14 after inoculation E. coli demonstrated more than 5.0 log reduction, S. aureus demonstrated more than 4.8 log reduction, B. cepacia demonstrated more than 4.3 log reduction; P. aeruginosa demonstrated 1.7 log reduction. C. albicans and A. brasiliensis demonstrated no growth at day 14.
At day 28 after inoculation E. coli demonstrated more than 5.0 log reduction, S. aureus demonstrated more than 4.8 log reduction, B. cepacia demonstrated more than 4.3 log reduction; P. aeruginosa demonstrated 4.0 log reduction. C. albicans and A. brasiliensis demonstrated no growth at day 28.
A test sample meets the USP Specifications for category 3 products if there is a 1.0 log reduction of bacterial organisms at day 14 with no increase at day 28. Fungal organisms must demonstrate no increase from the initial inoculum during the 28-day test period.
This sample passes the USP Antimicrobial Preservative Effectiveness Test for Category 3 products.
At day 14 after inoculation E. coli demonstrated more than 5.0 log reduction, S. aureus demonstrated more than 4.8 log reduction, B. cepacia demonstrated more than 4.3 log reduction; P. aeruginosa demonstrated 1.5 log reduction. C. albicans and A. brasiliensis demonstrated no increase at day 14.
At day 28 after inoculation E. coli demonstrated more than 5.0 log reduction, S. aureus demonstrated more than 4.8 log reduction, B. cepacia demonstrated more than 4.3 log reduction; P. aeruginosa demonstrated more than 4.5 log reduction. C. albicans and A. brasiliensis demonstrated no increase at day 28.
A test sample meets the USP Specifications for category 3 products if there is a 1.0 log reduction of bacterial organisms at day 14 with no increase at day 28. Fungal organisms must demonstrate no increase from the initial inoculum during the 28-day test period.
This sample passes the USP Antimicrobial Preservative Effectiveness Test for Category 3 products
At day 14 after inoculation E. coli demonstrated 3.7 log reduction, S. aureus demonstrated 4.5 log reduction, B. cepacian demonstrated 4.0 log reduction; P. aeruginosa demonstrated 4.5 log reduction. C. albicans and A. brasiliensis demonstrated no increase at day 14.
At day 28 after inoculation E. coli demonstrated 3.3 log reduction, S. aureus demonstrated more than 4.8 log reduction, B. cepacia demonstrated more than 4.3 log reduction; P. aeruginosa demonstrated more than 4.5 log reduction. C. albicans and A. brasiliensis demonstrated no increase at day 28.
A test sample meets the USP Specifications for category 3 products if there is a 1.0 log reduction of bacterial organisms at day 14 with no increase at day 28. Fungal organisms must demonstrate no increase from the initial inoculum during the 28-day test period.
This sample passes the USP Antimicrobial Preservative Effectiveness Test for Category 3 products.
The present application is continuation of U.S. Non-Provisional Ser. No. 16/277,986, filed Feb. 15, 2019, which claims the benefit of U.S. Provisional Application No. 62/788,881, filed Jan. 6, 2019, U.S. Provisional Application No. 62/685,384, filed Jun. 15, 2018, and U.S. Provisional Application No. 62/632,389, filed Feb. 19, 2018. Each of the above-referenced applications is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62788881 | Jan 2019 | US | |
| 62685384 | Jun 2018 | US | |
| 62632389 | Feb 2018 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16277986 | Feb 2019 | US |
| Child | 17149650 | US |
