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Polar Hydrophilic Prodrugs of Amphetamine and Other Stimulants and Processes for Making and Using the Same

a technology applied in the field of polar hydrophilic prodrugs of amphetamine and other stimulants and processes for making and using the same, can solve the problems of increased blood pressure and heart rate, euphoric drugs, and significant reduction of abuse liability, so as to improve the duration of therapeutic effect, reduce the risk of abuse, and improve the effect of treatment

Inactive Publication Date: 2009-09-24
SHIRE PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present technology provides a slow / sustained controlled release composition of amphetamine that can be orally administered and reduces or eliminates the rebound effect, cardiovascular stress, and other common side effects associated with conventional stimulant treatment options. The technology also provides methods of controlled therapeutic delivery of amphetamine, with reduced or prevented abuse potential and improved safety for treating conditions such as ADHD, obesity, and narcolepsy. The technology also includes stimulant prodrugs that are resistant to abuse by injection or nasal routes of administration. The technology can be used for treating stimulant abuse and addiction, improving battle field alertness, and combating fatigue. The composition of the technology includes a polar hydrophilic ligand that can be a non-standard amino acid or other hydrophilic group. The oral bioavailability of the composition is controlled by the hydrolysis of the chemical linkage, which allows the stimulant to become available in its active form over an extended period of time. The technology also maintains its effectiveness and abuse resistance even after crushing the tablet or capsule."

Problems solved by technology

Again not wanting to be bound by any particular theory, it is also believed that such spikes in blood levels can lead to a euphoric drug “high” and cardiovascular effects like increased blood pressure and heart rate.
Although not wanting to be bound by any particular theory, it is believed that the treatment of such CNS conditions as noted above with compositions of the present technology results in substantially decreased abuse liability as compared to existing stimulant treatment modalities and dosage forms.

Method used

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  • Polar Hydrophilic Prodrugs of Amphetamine and Other Stimulants and Processes for Making and Using the Same
  • Polar Hydrophilic Prodrugs of Amphetamine and Other Stimulants and Processes for Making and Using the Same
  • Polar Hydrophilic Prodrugs of Amphetamine and Other Stimulants and Processes for Making and Using the Same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Comparative Study of Pharmacokinetic Parameters of Released d-Amphetamine Following Administration of a Polar Hydrophilic Prodrug of the Non-Standard Amino Acid Type (hArg-Amp) and a Standard Amino Acid Conjugate (Vyvanse™, Lys-Amp)

[0156]The pharmacokinetic parameters of d-amphetamine following oral administration of a non-standard amino acid conjugate of the present technology and a standard amino acid conjugate, Vyvanse™ (Lys-Amp), commercially available from Shire, Incorporated of Wayne, Pa. are studied in this example. The non-standard amino acid conjugate used in this example is the hydrochloride salt of hArg-Amp. The results are recorded in the table below:

TABLE 1Non-standard amino AcidVyvanse ™ %Parameter% amp1total Amp2AUC0-8 h94%100%AUC0-4 h77%100%AUCinf95%100%Cmax76%100%Tmax400%100%1Percent amphetamine released relative to Vyvanse ™ (at an equimolar concentration of amphetamine contained in the non-standard amino acid prodrug compared to the total amphetamine contained in ...

example 2

Preparation of Boc-hArg(NO2)-Amp

[0159]Boc-hArg(NO2)—OH (2.667 g, 8 mmol) was dissolved in DMF (25 ml). EDCI (2.30 g, 12 mmol), NHS (1.012 g, 8.8 mmol), d-amphetamine (1.269 g, 9.6 mmol) and DIEA (1.138 g, 8.8 mmol) were then added sequentially. The clear reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with pH 3 water (150 ml), and the product was extracted with EtOAc (3×50 ml). The combined extracts were washed with pH 3 water followed by saturated NaCl. The EtOAc layer was dried over anhydrous MgSO4. The product was recrystallized from EtOAc-Hexane two times to give 2.36 g of desired protected product.

[0160]The product was analyzed using 1H NMR (DMSO-d6) δ. The result shows 0.9-1.1 (m, 3H, Amp CH3), 1.1-1.2 (m, 2H, hArg γ CH2), 1.2-1.5 (m, 13H, Boc CH3, hArg β,δ CH2), 2.55-2.75 (m, 2H, Amp β CH2), 3.1 (m, 2H, hArg ε CH2), 3.75 (m, 1H, Amp α CH), 3.95 (m, 1H, hArg α CH), 6.65 (t, 1H, hArg guanidino NH), 7.1-7.3 (m, 5H, Amp Ar—H), 7.6-8....

example 3

Preparation of hArg-Amp-2HCl (l-homoarginine-d-amphetamine dihydrochloride)

[0161]Boc-hArg(NO2)-Amp (1.5 g) was dissolved in HPLC grade MeOH (120 ml) and to the clear solution was added the Pd—C catalyst (10%, Aldrich). A small stir bar was placed in the flask and the reaction mixture was stirred under a slow stream of hydrogen overnight after incorporating the 5-6N HCl in 2-propanol solution (1.5 ml). After the overnight reaction, the solution was filtered and the solvent evaporated. The white crystalline product was dried under vacuum to give 1.61 g of the Boc-hArg-Amp intermediate product.

[0162]The product (1.6 g) was dissolved in 80 ml of HPLC grade MeOH, and 5-6N HCl in 2-propanol (3.2 mL) was added to the solution. The reaction mixture was stirred overnight, solvent removed and re-dissolved in minimum amount of MeOH. The final product was crashed out with MTBE, and dried under vacuum at 30° C. for about 20 hours to yield 1.12 g of a white powder.

[0163]The white powder was analy...

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Abstract

Disclosed are polar, hydrophilic stimulant prodrug compositions comprising at least one stimulant chemically attached to a polar hydrophilic ligand, a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed.

Description

RELATED APPLICATIONS[0001]This application is a continuation of PCT / US08 / 53363, filed on Feb. 8, 2008, which claims priority to and benefit of U.S. provisional patent application No. 60 / 888,870, filed on Feb. 8, 2007, which are incorporated by reference in their entireties.FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002][Not Applicable]MICROFICHE / COPYRIGHT REFERENCE[0003][Not Applicable]BACKGROUND OF THE INVENTION[0004]The present technology describes, in general, novel prodrugs / compositions of the stimulant amphetamine (i.e., 1-phenylpropan-2-amine) as well as polar hydrophilic conjugates of amphetamine, salts thereof, other derivatives thereof, and combinations thereof. Additionally, the presently described technology also relates generally to the methods of making and using these new prodrugs / compositions.[0005]Stimulants, including amphetamine and its derivatives, enhance the activity of the sympathetic nervous system and / or central nervous system (CNS) and are prescribed for t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/195A61K31/135
CPCA61K47/48007A61K47/48038A61K47/4823A61K47/48107A61K47/48146A61K47/48053A61K47/51A61K47/542A61K47/544A61K47/551A61K47/557A61K47/61A61P25/00A61P25/18A61P25/20A61P25/22A61P25/24A61P25/26A61P25/32A61P25/36A61P3/04A61P43/00
Inventor MICKLE, TRAVIS C.
Owner SHIRE PLC
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