Liquid dosage forms intended for pediatric use: Lisinopril & Meclizine
` B. Beidel, J. Bohan, C. D’Ippolito, E. Thudium, A. VanWert, H. Jacobs, and A.H. Kibbe
` Department of Pharmaceutical Sciences, School of Pharmacy, Wilkes University, Wilkes-Barre, PA
`
`
`
`
`
`
`
`
`
`
`
`
`
`Purpose
`
`Methods Continued
`
`Results
`
`The purpose of these studies was to develop a palatable, stable, oral liquid dosage form for
`two active pharmaceutical ingredients (API) (lisinopril and meclizine) that are only available as
`oral solid dosage forms to enable the Pediatric Trial Network to perform clinical studies in
`pediatric patients.
`
`Introduction
`
`Both lisinopril and meclizine were identified by the PTN as drugs of interest1 to undergo
`formulation analysis, stability and palitable testing for the Center for Research for Mothers and
`Children of the National Institutes of health's NICHD. A search of the literature revealed that
`neither was available as an oral liquid, but there were reports of them being incorporated in
`extemporaneously compounded oral liquids2,3. Lisinopril was soluble at reasonable
`concentrations but meclizine presented solubility issues2,3. Thus the focus of the studies for
`each drug differed.
`
`For lisinopril, the goal was to develop a diluent and study the stability and palatability properties
`of the formulation. The stability of the drug was studied as a function of pH, temperature, and
`presence of amino acids as potential stabilizing agents5. The literature also contained HPLC
`analytical methods of sufficient sensitivity and specificity to allow for stability studies to be
`performed on the selected formulations4.
`
`Meclizine, a piperazine containing compound is a first generation antihistamine used for the
`prevention of motion sickness and management of vertigo in children >12 years of age6.The
`solubility of meclizine in water is 0.1g/100mL. It is slightly soluble in dilute acids and alcohol9.
`The addition of chemically modified cyclodextrin to weak acid solutions was expected to
`increase solubility due to hydrophobic pocket interactions8. The addition of Tween 80 at a 2%
`concentration to a pH 4 citric acid buffer has demonstrated increased micelle formation when
`combined with piperazine containing compounds allowing for increased solubility7.
`Methods
`
`Analytical procedures were validated in accordance with the HPLC literature for each
`compound and a standard curve developed. Lisinopril solutions (10mg/10mL) were prepared
`under the following conditions: three solutions were prepared in a pH 4.75 acetic acid/sodium
`acetate buffer solution and stored at different temperatures (25, 35, 45°C). Three separate
`solutions were prepared with buffer adjusted to pH 4.2, 5.2, and 5.75 and stored at 45°C. The
`remaining three solutions were prepared with a 3:2 mol ratio of amino acid (glycine, alanine,
`and 50/50 glycine/alanine) to lisinopril. The lisinopril solutions were assayed after a period of
`210 days using HPLC.
`
`The mobile phase consisted of 0.03 M monobasic potassium phosphate adjusted to pH 4.1 with phosphoric acid
`and acetonitrile (80:20 vol/vol) with 0.004 M 1-Octanesulfonic acid sodium salt. The flow rate was set to 1.5
`mL/min through a C16 Column with UV detection at 215 nm. Retention time was ~4.0 minutes. Fresh standards
`were prepared along with a blank to ensure that no other ingredient interfered with the quantization of the API.
`Four replicates were assayed for each on the standards and the test solutions.
`
`In addition, five flavors were tested with Ora-Sweet/Ora-Plus solutions in order to determine a palatable diluent to
`mask the taste of the lisinopril solution. The diluents were first tested alone to optimize the product for
`sweetness, flavor, and consistency. Differing ratios of lisinopril solution (2 mg/mL in pH 4.75), flavoring, Ora-
`Sweet, and Ora-Plus were tested. The selected diluent mixtures were then tested with lisinopril.
`
`For Meclizine, solubility was the primary concern and the following experiments performed. Various ratios of
`cyclodextrin: meclizine (1:1, 2:1, 3:1 and 4:1 mol/mol and w/w) were dissolved in sterile water and solutions were
`assessed based on the presence of un-dissolved particles after a 24 hour time period. Citric acid buffer solutions
`(pH 3.0, 3.5, 4.0, 4.5) were also prepared to determine the optimal pH for product solubility (meclizine 1mg/mL).
`These solutions were assessed for the presence of particles after 48 hours. Cyclodextrin (1 mol and 2 mol) was
`then added to the citric acid buffer solutions and solubility was reassessed after 24 hours. Additional solutions of
`ethanol/water (5%/95%) and ethanol/pH 4 citric acid buffer (5%/95%) were tested to determine effects of alcohol
`on meclizine (1mg/mL) solubility. A 2% Tween 80 solution buffered to pH 4 with citric acid was also evaluated.
`These results were all evaluated after 48 hours.
`
`Discussion
`The amount of lisinopril remaining at 210 days at each storage condition is listed in the table 1 below. The
`average relative standard deviation for the analytical procedure for lisinopril was 5%. For the palatability of
`lisinopril in solution, three trials were identified as successfully masking the product by providing adequate
`sweetness, flavor, and consistency. The three trials only differed by flavor (Bubblegum, Grape, and
`Watermelon) and the ratio was 10mL lisinopril solution (2 mg/mL in pH 4.75), 10 mL Ora-Sweet, and 10 mL
`Ora-Plus and 1 drop flavoring. The palatable lisinopril solution was not tested by the HPLC for stability.
`
`Initially, the 3:1 w/w cyclodextrin to meclizine ratio provided the best solubility results. Following additional
`mixing, particles of meclizine began to fall out of solution. A pH of 4 was selected based on increased
`solubility compared to other pHs solutions tested. The cyclodextrin mixture was unsuccessful, so other
`solutions were tested. A solution of ethanol and sterile water resulted in a stable liquid formulation; however,
`alcohol containing products should be avoided in pediatric preparations. The pH 4 buffer and alcohol solution
`resulted in a cloudy product and meclizine particles were visible on the bottom and sides of the flask. The
`alcohol solution similar to the cyclodextrin mixture was not considered acceptable. A final solution of Tween
`80, the citric acid buffer solution (pH 4) and meclizine (1mg/mL) resulted in a clear and stable formulation
`following continuous mixing for 3 hours. The concentration of meclizine was increased from 1mg/mL to
`2mg/mL following the addition of Tween 80 (2%) while still maintaining a clear solution.
`
`The final preparation of citric acid buffer (pH 4), Tween 80 (2%), and meclizine (2mg/mL) were stored at room
`temperature, 32°C, and 45°C for 182 days. Samples were obtained over this time period and assayed using
`HPLC to evaluate degradation and stability. The results were inconclusive due in part to the appearance of a
`degradant in the samples stored at the higher temperatures.
`
`Temp
`
`25
`
`35
`
`45
`
`45
`
`45
`
`45
`
`45
`
`45
`
`45
`
`pH
`
`4.8
`
`4.8
`
`4.8
`
`4.8
`
`4.8
`
`4.8
`
`5.8
`
`5.2
`
`4.2
`
`Stabilizer
`
`% Lisinopril Remaining at 210 days
`
`None
`
`None
`
`None
`
`Alanine
`
`Glycine
`
`Mix*
`
`None
`
`None
`
`None
`
`92%
`
`91%
`
`85%
`
`83%
`
`83%
`
`141%
`
`88%
`
`67%
`
`80%
`
`*Mix was 50/50 Ala/Gly and was an anomaly possibly due to an incorrect starting concentration.
`
`Conclusion
`
`A Lisinopril solution will show acceptable stability (at least 2
`years) if buffered to pH 5.75 and stored in the refrigerator at 5°
`C. Three different flavors were palatable when tested by the
`researchers. The addition of amino acids does not seem to
`improve the stability of the mixture.
`
`A clear palatable solution of meclizine using citric acid, and
`Tween 80 can be made and appears stable at room
`temperature. It has a weak aftertaste which should be
`acceptable.
`
`Prior to submission of an IND on either drug the stability studies
`should be repeated under cGLP but the likelihood of success is
`high.
`
`References
`
`Pediatric Trial Network ( D.K. Benjamin et al Duke Clinical Research Institute)
`Thompson, Karen C, et al. “Characterization of an extemporaneous liquid formulation of lisinopril.” Am J Health-Syst Pharm. 60.
`(2003): 69-74.
`Nahata, Milap C, and Richard S Morosco. “Stability of Lisinopril in Two Liquid Dosage Forms.” Ann Pharmacother. 38. (2004):
`396-9.
`Xu, Quanyun A, and Lawrence A Trissel. Stability-Indicating HPLC Methods for Drug Analysis. 2nd Ed. Washington: American
`Pharmacists Association, 2003. 378-9.
`Aomatsu, Akira. Canada. Stabilized Pharmaceutical Preparations of Gamma-aminobutyric Acid Derivatives and the Process for
`Preparing the Same. 1999.
`Meclizine. In: Lexi-Comp Online™ [database on the Internet]. Hudson, OH: Lexi-Comp, Inc. [cited 2011 Feb 12]. Available
`from: http://www.crlonline.com/crlonline Subscription required.
`Ahmed, M O. “Comparison of impact of the different hydrophilic carriers on the properties of piperazine-containing drug.”
`European journal of pharmaceutics and biopharmaceutics official journal of Arbeitsgemeinschaft fur Pharmazeutische
`Verfahrenstechnik eV 51.3 (2001) : 221-225. Print.
`Long Walker Anderson, Murphy Edwin Curran: Injectable meclizine formulations and methods. Genebiology May 2009: WO
`2009/059120
`Reference Tables: Description and Solubility - M." USP29-NF24. United States Pharmacopeia. Web. 16 Feb. 2011.
`Printed by
`<http://www.pharmacopeia.cn/v29240/usp29nf24s0_alpha-2-22.html>.
`
`Flat Line Capital Exhibit 1005
`Page 1 of 1
`
`KVK-Tech, Flat Line Capital Exhibit 1005
`Page 1
`
`
` B. Beidel, J. Bohan, C. D’Ippolito, E. Thudium, A. VanWert, H. Jacobs, and A.H. Kibbe
` Department of Pharmaceutical Sciences, School of Pharmacy, Wilkes University, Wilkes-Barre, PA
`
`
`
`
`
`
`
`
`
`
`
`
`
`Purpose
`
`Methods Continued
`
`Results
`
`The purpose of these studies was to develop a palatable, stable, oral liquid dosage form for
`two active pharmaceutical ingredients (API) (lisinopril and meclizine) that are only available as
`oral solid dosage forms to enable the Pediatric Trial Network to perform clinical studies in
`pediatric patients.
`
`Introduction
`
`Both lisinopril and meclizine were identified by the PTN as drugs of interest1 to undergo
`formulation analysis, stability and palitable testing for the Center for Research for Mothers and
`Children of the National Institutes of health's NICHD. A search of the literature revealed that
`neither was available as an oral liquid, but there were reports of them being incorporated in
`extemporaneously compounded oral liquids2,3. Lisinopril was soluble at reasonable
`concentrations but meclizine presented solubility issues2,3. Thus the focus of the studies for
`each drug differed.
`
`For lisinopril, the goal was to develop a diluent and study the stability and palatability properties
`of the formulation. The stability of the drug was studied as a function of pH, temperature, and
`presence of amino acids as potential stabilizing agents5. The literature also contained HPLC
`analytical methods of sufficient sensitivity and specificity to allow for stability studies to be
`performed on the selected formulations4.
`
`Meclizine, a piperazine containing compound is a first generation antihistamine used for the
`prevention of motion sickness and management of vertigo in children >12 years of age6.The
`solubility of meclizine in water is 0.1g/100mL. It is slightly soluble in dilute acids and alcohol9.
`The addition of chemically modified cyclodextrin to weak acid solutions was expected to
`increase solubility due to hydrophobic pocket interactions8. The addition of Tween 80 at a 2%
`concentration to a pH 4 citric acid buffer has demonstrated increased micelle formation when
`combined with piperazine containing compounds allowing for increased solubility7.
`Methods
`
`Analytical procedures were validated in accordance with the HPLC literature for each
`compound and a standard curve developed. Lisinopril solutions (10mg/10mL) were prepared
`under the following conditions: three solutions were prepared in a pH 4.75 acetic acid/sodium
`acetate buffer solution and stored at different temperatures (25, 35, 45°C). Three separate
`solutions were prepared with buffer adjusted to pH 4.2, 5.2, and 5.75 and stored at 45°C. The
`remaining three solutions were prepared with a 3:2 mol ratio of amino acid (glycine, alanine,
`and 50/50 glycine/alanine) to lisinopril. The lisinopril solutions were assayed after a period of
`210 days using HPLC.
`
`The mobile phase consisted of 0.03 M monobasic potassium phosphate adjusted to pH 4.1 with phosphoric acid
`and acetonitrile (80:20 vol/vol) with 0.004 M 1-Octanesulfonic acid sodium salt. The flow rate was set to 1.5
`mL/min through a C16 Column with UV detection at 215 nm. Retention time was ~4.0 minutes. Fresh standards
`were prepared along with a blank to ensure that no other ingredient interfered with the quantization of the API.
`Four replicates were assayed for each on the standards and the test solutions.
`
`In addition, five flavors were tested with Ora-Sweet/Ora-Plus solutions in order to determine a palatable diluent to
`mask the taste of the lisinopril solution. The diluents were first tested alone to optimize the product for
`sweetness, flavor, and consistency. Differing ratios of lisinopril solution (2 mg/mL in pH 4.75), flavoring, Ora-
`Sweet, and Ora-Plus were tested. The selected diluent mixtures were then tested with lisinopril.
`
`For Meclizine, solubility was the primary concern and the following experiments performed. Various ratios of
`cyclodextrin: meclizine (1:1, 2:1, 3:1 and 4:1 mol/mol and w/w) were dissolved in sterile water and solutions were
`assessed based on the presence of un-dissolved particles after a 24 hour time period. Citric acid buffer solutions
`(pH 3.0, 3.5, 4.0, 4.5) were also prepared to determine the optimal pH for product solubility (meclizine 1mg/mL).
`These solutions were assessed for the presence of particles after 48 hours. Cyclodextrin (1 mol and 2 mol) was
`then added to the citric acid buffer solutions and solubility was reassessed after 24 hours. Additional solutions of
`ethanol/water (5%/95%) and ethanol/pH 4 citric acid buffer (5%/95%) were tested to determine effects of alcohol
`on meclizine (1mg/mL) solubility. A 2% Tween 80 solution buffered to pH 4 with citric acid was also evaluated.
`These results were all evaluated after 48 hours.
`
`Discussion
`The amount of lisinopril remaining at 210 days at each storage condition is listed in the table 1 below. The
`average relative standard deviation for the analytical procedure for lisinopril was 5%. For the palatability of
`lisinopril in solution, three trials were identified as successfully masking the product by providing adequate
`sweetness, flavor, and consistency. The three trials only differed by flavor (Bubblegum, Grape, and
`Watermelon) and the ratio was 10mL lisinopril solution (2 mg/mL in pH 4.75), 10 mL Ora-Sweet, and 10 mL
`Ora-Plus and 1 drop flavoring. The palatable lisinopril solution was not tested by the HPLC for stability.
`
`Initially, the 3:1 w/w cyclodextrin to meclizine ratio provided the best solubility results. Following additional
`mixing, particles of meclizine began to fall out of solution. A pH of 4 was selected based on increased
`solubility compared to other pHs solutions tested. The cyclodextrin mixture was unsuccessful, so other
`solutions were tested. A solution of ethanol and sterile water resulted in a stable liquid formulation; however,
`alcohol containing products should be avoided in pediatric preparations. The pH 4 buffer and alcohol solution
`resulted in a cloudy product and meclizine particles were visible on the bottom and sides of the flask. The
`alcohol solution similar to the cyclodextrin mixture was not considered acceptable. A final solution of Tween
`80, the citric acid buffer solution (pH 4) and meclizine (1mg/mL) resulted in a clear and stable formulation
`following continuous mixing for 3 hours. The concentration of meclizine was increased from 1mg/mL to
`2mg/mL following the addition of Tween 80 (2%) while still maintaining a clear solution.
`
`The final preparation of citric acid buffer (pH 4), Tween 80 (2%), and meclizine (2mg/mL) were stored at room
`temperature, 32°C, and 45°C for 182 days. Samples were obtained over this time period and assayed using
`HPLC to evaluate degradation and stability. The results were inconclusive due in part to the appearance of a
`degradant in the samples stored at the higher temperatures.
`
`Temp
`
`25
`
`35
`
`45
`
`45
`
`45
`
`45
`
`45
`
`45
`
`45
`
`pH
`
`4.8
`
`4.8
`
`4.8
`
`4.8
`
`4.8
`
`4.8
`
`5.8
`
`5.2
`
`4.2
`
`Stabilizer
`
`% Lisinopril Remaining at 210 days
`
`None
`
`None
`
`None
`
`Alanine
`
`Glycine
`
`Mix*
`
`None
`
`None
`
`None
`
`92%
`
`91%
`
`85%
`
`83%
`
`83%
`
`141%
`
`88%
`
`67%
`
`80%
`
`*Mix was 50/50 Ala/Gly and was an anomaly possibly due to an incorrect starting concentration.
`
`Conclusion
`
`A Lisinopril solution will show acceptable stability (at least 2
`years) if buffered to pH 5.75 and stored in the refrigerator at 5°
`C. Three different flavors were palatable when tested by the
`researchers. The addition of amino acids does not seem to
`improve the stability of the mixture.
`
`A clear palatable solution of meclizine using citric acid, and
`Tween 80 can be made and appears stable at room
`temperature. It has a weak aftertaste which should be
`acceptable.
`
`Prior to submission of an IND on either drug the stability studies
`should be repeated under cGLP but the likelihood of success is
`high.
`
`References
`
`Pediatric Trial Network ( D.K. Benjamin et al Duke Clinical Research Institute)
`Thompson, Karen C, et al. “Characterization of an extemporaneous liquid formulation of lisinopril.” Am J Health-Syst Pharm. 60.
`(2003): 69-74.
`Nahata, Milap C, and Richard S Morosco. “Stability of Lisinopril in Two Liquid Dosage Forms.” Ann Pharmacother. 38. (2004):
`396-9.
`Xu, Quanyun A, and Lawrence A Trissel. Stability-Indicating HPLC Methods for Drug Analysis. 2nd Ed. Washington: American
`Pharmacists Association, 2003. 378-9.
`Aomatsu, Akira. Canada. Stabilized Pharmaceutical Preparations of Gamma-aminobutyric Acid Derivatives and the Process for
`Preparing the Same. 1999.
`Meclizine. In: Lexi-Comp Online™ [database on the Internet]. Hudson, OH: Lexi-Comp, Inc. [cited 2011 Feb 12]. Available
`from: http://www.crlonline.com/crlonline Subscription required.
`Ahmed, M O. “Comparison of impact of the different hydrophilic carriers on the properties of piperazine-containing drug.”
`European journal of pharmaceutics and biopharmaceutics official journal of Arbeitsgemeinschaft fur Pharmazeutische
`Verfahrenstechnik eV 51.3 (2001) : 221-225. Print.
`Long Walker Anderson, Murphy Edwin Curran: Injectable meclizine formulations and methods. Genebiology May 2009: WO
`2009/059120
`Reference Tables: Description and Solubility - M." USP29-NF24. United States Pharmacopeia. Web. 16 Feb. 2011.
`Printed by
`<http://www.pharmacopeia.cn/v29240/usp29nf24s0_alpha-2-22.html>.
`
`Flat Line Capital Exhibit 1005
`Page 1 of 1
`
`KVK-Tech, Flat Line Capital Exhibit 1005
`Page 1
`
`
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