Patent us20170043019 – topiramate compositions and methods of making and using the same – google patents anoxia fetal

More recently, topiramate has been studied for treatment of seizures and neuroprotection in neonates suffering from hypoxic-ischemic encephalopathy. See, e.G., U.S. Pat. No. 6,921,775, the entire content of which is hereby incorporated by reference. Specifically, periventricular leukomalacia is a form of hypoxic-ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic-ischemic injury to developing cerebral white matter. It has been demonstrated that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23-32 weeks gestation, the period of highest risk for periventricular leukomalacia, and that administration of topiramate post-insult in vivo, is protective against selective hypoxic-ischemic white matter injury and decreases the subsequent neuromotor deficits.Anoxia fetal


topiramate attenuates AMPA-kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA-kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX).

In addition, orally administered topiramate is quickly absorbed, and about 70% of an oral topiramate dose is excreted in the urine as unchanged drug. The remainder is extensively metabolized by hydroxylation, hydrolysis, and glucuronidation. It has been previously found that the bioavailability of an oral topiramate dose is about 80%. However, an oral dose can be susceptible to factors that limit its bioavailability such as first-pass hepatic metabolism and/or limited absorption in the gastro-intestinal tract.Anoxia fetal thus, the bioavailability of an oral dose can differ significantly from the bioavailability of an injectable dose. In addition, pediatric patients have a 50% higher clearance and consequently shorter elimination half-life for topiramate compared to adults. Consequently, the plasma concentration for the same mg/kg dose may be lower in pediatric patients compared to adults. Thus, identification of an injectable topiramate dosage regimen for both adults, pediatric subjects and neonates is also needed, which requires determination of the bioavailability and pharmacokinetic behavior of injectable topiramate in these subject populations.

BRIEF SUMMARY OF THE INVENTION•

Thus, the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient(s) which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions.Anoxia fetal the formulation can be provided as a stock solution, which is diluted with a liquid carrier composition such as dextrose, saline, plasma, or lactated ringer’s solution prior to administration to a patient. The formulation can be provided at a concentration of topiramate that is suitable for administration without dilution. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The formulation can further include a preservative, a solubilizing agent, an antioxidant, a buffering agent, an acidifying agent, a complexation enhancing agent, saline, dextrose, a lyophilizing aid (for example, bulking agents or stabilizing agents), an electrolyte, another therapeutic agent, an alkalizing agent, an antimicrobial agent, an antifungal agent, an antibacterial agent (e.G., a parabens or thimersol) or a combination thereof.Anoxia fetal prolonged absorption of the injectable compositions (e.G., by IM injection) can be brought about by the use in the compositions of agents delaying or modifying the absorption, for example, aluminum monostearate, oleaginous vehicles, less soluble salt forms, or poloxamers (block copolymers). The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders of topiramate which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.Anoxia fetal the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, sulfoalkyl cyclodextrin in water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.

In some embodiments, the compositions of the present invention are stable at about 25° C. For a period of at least 3 months, at least 6 months, at least 1 year, at least 1.5 years, at least 2 years, or at least 3 years.Anoxia fetal in some embodiments, the present invention provides a liquid topiramate composition comprising topiramate and a sulfoalkyl ether cyclodextrin, wherein the composition contains less than about 10% or less, about 5% or less, about 3% or less, about 2% or less, or about 1% or less of a topiramate degradant after storage at 25° C. For a period of at least 6 months, at least 1 year, at least 1.5 years, or at least 2 years. In some embodiments, the present invention provides a liquid topiramate composition comprising topiramate and a sulfoalkyl ether cyclodextrin, wherein the composition contains about 10% or less, about 5% or less, about 3% or less, about 2% or less, or about 1% or less of a topiramate degradant after storage at 40° C.Anoxia fetal for a period of at least 6 months, at least 1 year, at least 1.5 years, or at least 2 years.

In some embodiments of the invention, the sulfoalkyl ether cyclodextrin to topiramate mole ratio is about 0.01 to about 1.4. In some embodiments, sulfoalkyl ether cyclodextrin to topiramate mole ratio is about 0.05 to about 1.4, about 0.1 to about 1.4, about 0.5 to about 1.4, about 0.5 to about 1, about I to about 1.4, or about 1 to about 5. In some embodiments, the sulfoalkyl ether cyclodextrin to topiramate mole ratio is about 1.4 or greater. In some embodiments, the sulfoalkyl ether cyclodextrin to topiramate mole ratio is about 1.4 to about 5, about 1.4 to about 3, or about 1.4 to about 2. Based on the molecular weight for topiramate (339.36 g/mol) and the average molecular weight of the sulfoalkyl ether cyclodextrin of formula III (2163 g/mol), a topiramate to sulfoalkyl ether cyclodextrin molar ratio of 1:1.4 is equivalent to a weight ratio of 1:8.9.Anoxia fetal thus, in some embodiments a composition of the present invention comprises topiramate in a concentration of about 5 mg/ml to about 100 mg/ml and a sulfoalkyl ether cyclodextrin in a concentration of about 45 mg/ml to about 890 mg/ml, or topiramate in a concentration of about 5 mg/ml to about 50 mg/ml and a sulfoalkyl ether cyclodextrin in a concentration of about 45 mg/ml to about 450 mg/ml, or topiramate in a concentration of about 10 mg/ml to about 20 mg/ml and a sulfoalkyl ether cyclodextrin in a concentration of about 90 mg/ml to about 180 mg/ml.

The LC/MS procedure was as follows: 25 mg [ 13C] 6-TPM was weighed on a cahn electrobalance, transferred into a 2 dram vial, and dissolved in 2.5 ml of 10% w/v C APTISOL® aqueous solution.Anoxia fetal the 10% w/v C APTISOL® aqueous solution was prepared by weighing 10 g of C APTISOL® (adjusted for water content) and dissolving it in 100 ml of water. Reference unlabeled topiramate (obtained from sigma-aldrich co. Or toronto research chemicals, inc.) was prepared in an identical fashion. Separation of topiramate was performed using reverse phase chromatography, and detection used electrospray ionization (ESI) in negative-scan mode. Five replicate 0.02 ml injections were run for both the [ 13C] 6-TPM and the non-isotopically labeled reference standard. The chromatographic conditions consisted of a mobile phase of 50% methanol and 50% ammonium acetate buffer (˜ph 6.9). The flow rate was 0.5 ml/min and the column packing material was 3.5 μm particle size reverse-phase Z ORBAX® XDB(C8) (E.Anoxia fetal I. Du pont de nemours and co.) in a column of 150 mm length×3.0 mm I.D. Isotopic purity was determined by scanning from 50 m/z to 500 m/z for 30 minutes. Measuring the relative abundance of the ions at 339 m/z and quantitative estimates of content was done by direct comparison of the mean peak area ratios of [ 13C] 6-TPM and the internal standard deuterated topiramate (“TPM-d12”) with the topiramate reference.

The stable-isotope topiramate was formulated with C APTISOL® for intravenous administration. The resulting composition contained 1% w/v topiramate and 10% w/v C APTISOL®. The manufacturing procedure was as follows:

• 1) 200 g of C APTISOL® (adjusted for water content) was dissolved in 2.0 L of deionized sterile water to generate a 10% w/v C APTISOL® solution;

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• 2) 20 g of [ 13C] 6-TPM was added to the 10% w/v C APTISOL® solution;

• 3) the solution was stirred for 24 hours at room temperature;

• 4) ampoules were sterilized in preparation for filling;

• 5) all equipment to be used was prepared and sterilized;

• 6) the solution was transferred to a class 100 clean room for sterile filtration;

• 7) before, during and after the transfer, the filling area was monitored for viable flora;

• 8) the solution was sterile filtered through a 0.22 μm D URAPORE® (millipore corp.) filter into a sterile receiver in a class 100 area;

• 9) at the end of the filtration the integrity of the filter was tested;

• 10) the ampoules were then filled and sealed under a nitrogen flush; and

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• 11) the ampoules were stored at 2® C. To 8® C. Prior to administration.

Example 4 stability of [ 13C] 6-TPM/C APTISOL® formulation•

Topiramate was detected using a LC/MS method employing the electrospray ionization (ESI) and negative scan mode. This method is designed to measure both unlabeled topiramate and the stable-isotope topiramate using a negative ESI and SIM mode of liquid chromatograph mass spectrometer. The analytes were separated using Z ORBAX® LC8/LC18 and a mobile phase consisting of ammonium acetate buffer and methanol. The data generated using C HEMS TATION® software (agilent) and quantified using deuterated topiramate (“TPM-d12”, internal standard). Patient samples were run along with a 7-concentration standard curve (run in triplicate) and nine quality control samples (low, med and high also run in triplicates), analyzed in human plasma using liquid extraction with methyl-tert-butylether and negative ion electrospray mass spectrometry.Anoxia fetal the quantitative analysis was performed using selective ion monitoring mode for topiramate at m/z=338 and m/z=350 for TPM-d12 in the negative mode. The unlabeled topiramate calibration curve ranged from 0.05 μg/ml to 10 μg/ml.

G. Pharmacokinetics analysis•

TABLE

Extrapolated stability data for formulations A-F at 5° C. And 25° C. For 1.5 years

And 2 years, wherein the RCA concentrations are based on data from arrhenius plots of

Stability data measured for formulations A-F at 40° C., 50° C. And 60° C. At 6-12 weeks.

Data points

Last time

Used in

Point

Temp

RCA @

RCA @

T 90

T 90

Ref.

Analysis

Collected

(° C.)

T = 1.5 yrs

T = 2 yrs

(1.5 yr.) a

(2 yr.) a

A

6-60° C.

12 weeks

5° C.

0.07%

0.07%

PASS

PASS

6-50° C.

25° C.

1.33%

1.77%

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PASS

PASS

6-40° C.

B

3-60° C.

6 weeks

5° C.

0.08%

0.08%

PASS

PASS

5-50° C.

25° C.

0.56%

0.71%

PASS

PASS

6-40° C.

C

3-60° C.

6 weeks

5° C.

0.10%

0.10%

PASS

PASS

5-50° C.

25° C.

0.81%

1.05%

PASS

PASS

6-40° C.

D

6-60° C.

12 weeks

5° C.

0.72%

0.91%

PASS

PASS

6-50° C.

25° C.

13.10%

17.43%

FAIL

FAIL

8-40° C.

E

6-60° C.

12 weeks

5° C.

0.45%

0.60%

PASS

PASS

6-50° C.

25° C.

10.74%

14.32%

FAIL

FAIL

8-40° C.

F

3-60° C.

6 weeks

5° C.

0.13%

0.14%

PASS

PASS

5-50° C.

25° C.

0.96%

1.24%

PASS

PASS

5-40° C.

AThe “PASS” or “FAIL” rating is based on the stability of topiramate having at least a 90% recovery at 1.5 years and 2 years, respectively.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.Anoxia fetal the terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.E., meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.Anoxia fetal