VALACYCLOVIR FORMULATIONS

US 20090124639A1
Filed: 11/06/2008
Published: 05/14/2009
Est. Priority Date: 11/06/2007
Status: Abandoned Application

First Claim

Patent Images

1. A pharmaceutical composition comprising (a) valacyclovir or a salt thereof, and (b) at least one delivery agent selected from the following compounds, and pharmaceutically acceptable salts thereof:

(Genus a)2-HO—

Ar—

C(O)—

NR⁸—

R⁷—

COOH

Formula (1)whereinAr is phenyl or naphthyl, optionally substituted with OH, halogen, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy;

R⁷is C₄-C₂₀alkyl, C₄-C₂₀alkenyl, phenyl, naphthyl (C₁-C₁₀alkyl)phenyl, (C₁-C₁₀alkenyl)phenyl, (C₁-C₁₀alkyl) naphthyl, (C₁-C₁₀alkenyl) naphthyl, phenyl(C₁-C₁₀alkyl), phenyl(C₁-C₁₀alkenyl), naphthyl(C₁-C₁₀alkyl), or naphthyl(C₁-C₁₀alkenyl);

R⁸is hydrogen, C₁to C₄alkyl, C₂to C₄alkenyl, C₁to C₄alkoxy, C₁-C₄or haloalkoxy;

R⁷is optionally substituted with C₁to C₄alkyl, C₂to C₄alkenyl, C₁to C₄alkoxy, C₁-C₄haloalkoxy, —

OH, —

SH, and —

CO₂R⁹or any combination thereof;

R⁹is hydrogen, C₁to C₄alkyl or C₂to C₄alkenyl; and

R⁷is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof;

with the proviso that the compounds are not substituted with an amino group in the position alpha to the acid group;

(Genus b)2-OH—

Ar—

C(O)—

NH—

R¹—

R²

Formula (2)whereinAr is phenyl or naphthyl;

Ar is optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkenyl, C₂-C₄alkynyl, aryl, aryloxy, a heterocyclic ring, C₅-C₇carbocylic ring, halogen, —

OH, —

SH, CO₂R⁶, —

NR⁷R⁸, or —

N⁺R⁷R⁸R⁹Y⁻;

(a) R¹is C₁-C₁₆alkylene, C₂-C₁₆alkenylene, C₂-C₁₆alkynylene, C₆-C₁₆arylene, (C₁-C₁₆alkyl)arylene, or aryl (C₁-C₁₆alkylene);

R²is —

NR³R⁴or —

N⁺R³R⁴R⁵Y⁻;

R³and R⁴are independently hydrogen;

oxygen;

hydroxy;

substituted or unsubstituted C₁-C₁₆alkyl;

substituted or unsubstituted C₂-C₁₆alkenyl;

substituted or unsubstituted C₂-C₁₆alkynyl;

substituted or unsubstituted aryl;

substituted or unsubstituted alkylcarbolnyl;

substituted or unsubstituted arylcarbonyl;

substituted or unsubstituted alkanesulfinyl;

substituted or unsubstituted arylsulfinyl;

substituted or unsubstituted alkanesulfonyl;

substituted or unsubstituted arylsulfonyl;

substituted or unsubstituted alkoxycarbonyl;

substituted or unsubstituted aryloxycarbonyl;

R⁵is independently hydrogen;

substituted or unsubstituted C₁-C₁₆alkyl;

substituted or unsubstituted C₂-C₁₆alkenyl;

substituted or unsubstituted C₂-C₁₆alkynyl;

substituted or unsubstituted aryl;

substituted or unsubstituted alkylcarbonyl;

substituted or unsubstituted arylcarbonyl;

substituted or unsubstituted alkanesulfinyl;

substituted or unsubstituted arylsulfinyl;

substituted or unsubstituted alkanesulfonyl;

substituted or unsubstituted arylsulfonyl;

substituted or unsubstituted alkoxycarbonyl;

substituted or unsubstituted aryloxycarbonyl;

(b) R¹, R², and R⁵are as defined above; and

R³and R⁴are combined to form a 5, 6 or 7-membered heterocyclic ring;

or 5, 6 or 7-membered heterocyclic ring substituted with a C₁-C₆alkyl, C₁-C₆alkoxy, aryl, aryloxy, oxo group or carbocyclic ring;

or(c) R²and R⁵are as defined above; and

R¹and R³are combined to form a 5, 6 or 7-membered heterocyclic ring;

or 5, 6 or 7-membered heterocyclic ring substituted with a C₁-C₆alkyl, alkoxy, aryl, aryloxy, or oxo group or carbocyclic ring;

R⁴is hydrogen;

oxygen;

hydroxy;

substituted or unsubstituted C₁-C₁₆alkyl;

substituted or unsubstituted C₂-C₁₆alkenyl;

substituted or unsubstituted C₂-C₁₆alkynyl;

substituted or unsubstituted aryl;

substituted or unsubstituted alkylcarbonyl;

substituted or unsubstituted arylcarbonyl;

substituted or unsubstituted alkanesulfinyl;

substituted or unsubstituted arylsulfinyl;

substituted or unsubstituted alkanesulfonyl;

substituted or unsubstituted arylsulfonyl;

substituted or unsubstituted alkoxycarbonyl;

substituted or unsubstituted aryloxycarbonyl;

R⁶is hydrogen;

C₁-C₄alkyl;

C₁-C₄alkyl substituted halogen or —

OH;

C₂-C₄alkenyl;

or C₂-C₄alkenyl substituted halogen or —

OH;

R⁷, R⁸, and R⁹are independently hydrogen;

oxygen;

C₁-C₄alkyl;

C₁-C₄alkyl substituted with halogen or —

OH;

C₂-C₄alkenyl;

or C₂-C₄alkenyl substituted with halogen or —

OH; and

Y is halogen, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, or carboxylate;

whereinR¹, R², R³, and R⁴are independently hydrogen, —

OH, —

NR⁶R⁷, halogen, C₁-C₄alkyl, or C₁-C₄alkoxy;

R⁵is a substituted or unsubstituted C₂-C₁₆alkylene, substituted or unsubstituted C₂-C₁₆alkenylene, substituted or unsubstituted C₁-C₁₂alkyl(arylene), or substituted or unsubstituted aryl(C₁-C₁₂alkylene); and

R⁶and R⁷are independently hydrogen, oxygen, or C₁-C₄alkyl;

wherein(a) R¹, R², R³, and R⁴are independently H, —

OH, halogen, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkoxy, —

C(O)R⁸, —

NO₂, —

NR⁹R¹⁰, or —

N⁺R⁹R¹⁰R¹¹(Y⁻);

R⁸is hydrogen, —

OH, C₁-C₆alkyl, C₁-C₄alkyl substituted with halogen or —

OH, C₂-C₄alkenyl unsubstituted or substituted with halogen or OH, or —

NR¹⁴R¹⁵;

R⁹, R¹⁰, and R¹¹are independently hydrogen, oxygen, C₁-C₄alkyl unsubstituted or substituted with halogen or —

OH, C₂-C₄alkenyl unsubstituted or substituted with halogen or —

OH;

Y is halide, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, carboxylate, mesylate, fumerate, malonate, succinate, tartrate, acetate, gluconate, maleate;

R⁵is H, —

OH, —

NO₂, halogen, CF₃, —

NR¹⁴R¹⁵, —

N⁺R¹⁴R¹⁵R¹⁶(Y⁻), amide, C₁-C₁₂alkoxy, C₁-C₁₂alkyl, C₂-C₁₂alkenyl, carbamate, carbonate, urea, or C(O)R²²;

R⁵is optionally substituted with halogen, —

OH, —

SH, or —

COOH;

R⁵is optionally interrupted by O, N, S, or —

C(O)—

;

R¹⁴, R¹⁵and R¹⁶are independently H or C₁-C₁₀alkyl;

R²²is H, C₁-C₆alkyl, —

OH, —

NR¹⁴R¹⁵;

R⁶is substituted or unsubstituted C₁-C₁₆alkylene, C₂-C₁₆alkenylene, C₂-C₁₆alkynylene, C₅-C₁₆arylene, (C₁-C₁₆alkyl) arylene or aryl(C₁-C₁₆alkylene);

R⁶is optionally substituted with C₁-C₇alkyl or C₁-C₇cycloalkyl;

R⁷is —

N¹⁸R¹⁹R¹⁹or —

N⁺R¹⁸R¹⁹R²⁰Y⁻;

R¹⁸and R¹⁹are independently hydrogen, oxygen, hydroxy, substituted or unsubstituted C₁-C₁₆(alkyl, substituted or unsubstituted C₂-C₁₆alkenyl, substituted or unsubstituted C₂-C₁₆alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl (e.g. substituted or unsubstituted (C_1-6alkyl)carbonyl), substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkanesulfinyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfinyl), substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkanesulfonyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfonyl), substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl (e.g. substituted or unsubstituted (C_1-6alkoxy)carbonyl), or substituted or unsubstituted aryloxycarbonyl, or substituted or unsubstituted C₅-C₇heterocyclic ring (i.e., 5, 6, or 7-membered heterocyclic ring), wherein the substitutions may be halogen or —

OH; and

R²⁰is independently hydrogen, substituted or unsubstituted C₁-C₁₆alkyl, substituted or unsubstituted C₂-C₁₆alkenyl, substituted or unsubstituted C₂-C₁₆alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl (e.g. substituted or unsubstituted (C_1-6alkyl)carbonyl), substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkanesulfinyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfinyl), substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkanesulfonyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfonyl), substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl (e.g. substituted or unsubstituted (C_1-6alkoxy)carbonyl), or substituted or unsubstituted aryloxycarbonyl;

or(b) R¹-R¹⁶and R²⁰are as defined above; and

R¹⁸and R¹⁹combine to form a 5, 6, or 7-membered heterocyclic ring optionally interrupted with an oxo group and unsubstituted or substituted with C₁-C₆alkyl, C₁-C₆alkoxy, aryl, aryloxy, or carbocyclic ring;

whereinR¹, R², R³, and R⁴are independently H, —

OH, halogen, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, —

C(O)R⁸, —

NO₂, —

NR⁹R¹⁰, or —

N⁺R⁹R¹⁰R¹¹(R¹²);

R⁵is H, —

OH, —

NO₂, halogen, —

CF₃, —

NR¹⁴R¹⁵, —

N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻, amide, C₁-C₁₂alkoxy, C₁-C₁₂alkyl, C₂-C₁₂alkenyl, carbamate, carbonate, urea, or —

C(O)R¹⁸;

R⁵is optionally substituted with halogen, —

OH, —

S11, or —

COOH;

R⁵is optionally interrupted by O, N, S, or —

C(O)—

;

R⁶is a C₁-C₁₂alkylene, C₂-C₁₂alkenylene, or arylene;

R⁶is optionally substituted with a C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, —

OH, —

SH, halogen, —

NH₂, or —

CO₂R⁸;

R⁶is optionally interrupted by O or N;

R⁷is a bond or arylene;

R⁷is optionally substituted with —

OH, halogen, —

C(O)CH₃, —

NR¹⁰R¹¹, or —

N⁺R¹⁰R¹¹R¹²(R¹³)⁻;

R⁸is H, C₁-C₄alkyl, C₂-C₄alkenyl, or —

NH₂;

R⁹, R¹⁰, R¹¹, and R¹²independently H or C₁-C₁₀alkyl;

R¹³is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; and

R¹⁴, R¹¹and R¹⁶are independently H, C₁-C₁₀alkyl, C₁-C₁₀alkyl substituted with —

COOH, C₂-C₁₂alkenyl, C₂-C₁₂alkenyl substituted with —

COOH, —

C(O)R¹⁷;

R¹⁷is —

OH, C₁-C₁₀alkyl, or C₂-C₁₂alkenyl; and

R¹⁸is H, C₁-C₆alkyl, —

OH, —

NR¹⁴R¹⁵, or N⁺R¹⁴R¹⁵R¹⁶(R¹³); and

whereinR¹, R², R³, and R⁴are independently H, —

OH, halogen, —

OCH₃, —

NR¹⁰R¹¹or —

N+R¹⁰R¹¹R¹²(R¹³)⁻;

R⁵is H, —

OH, —

NO₂, —

NR¹⁴R¹⁵, —

N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻, amide, C₁-C₁₂alkoxy, C₁-C₁₂alkyl, C₂-C₁₂alkenyl, carbamate, carbonate, urea, or —

C(C)R¹⁸;

R⁵is optionally substituted with —

OH, —

SH, or —

COOH;

R⁵is optionally interrupted by O, N, S, or —

C(O)—

;

R⁶is a C₁-C₁₂alkylene, C₁-C₁₂alkenylene, or arylene;

R⁶is optionally substituted with a C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, —

OH, —

SH, halogen, —

NH₂, or —

CO₂R⁹;

R⁶is optionally interrupted by C or N;

R⁷is a bond or arylene;

R⁷is optionally substituted with —

OH, halogen, —

C(O)CH₃, —

NR¹⁰R¹¹or —

N⁺R¹⁰R¹¹R¹²(R¹³);

R⁸is H or C₁-C₄alkyl;

R⁹is 1, C₁-C₄alkyl, or C₂-C₄alkenyl;

R¹⁰, R¹¹, and R¹²are independently H or C₁-C₁₀alkyl;

R¹³is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;

R¹⁴, R¹⁵, and R¹⁶are independently H, C₁-C₁₀alkyl, C₂-C₁₂alkenyl, O, or —

C(O)R¹⁷;

R¹⁷is —

OH, C₁-C₁₀alkyl, or C₂-C₁₂alkenyl; and

R¹⁸is —

OH, C₁-C₆alkyl, —

NR¹⁴R¹⁵, —

N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻; and

whereinR¹⁹is —

NO₂or —

C(O)R²³;

R²⁰is a C₁-C₁₂alkylene or C₁-C₁₂alkenylene;

R²¹is a bond or arylene;

R²²is H or C₁-C₄alkyl; and

R²³is —

OH, C₁-C₆alkyl, or —

NH₂.

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Abstract

The present invention relates to valacyclovir formulations having improved bioavailability resulting in better efficacy and/or requiring less frequent administration.

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19 Claims

1. A pharmaceutical composition comprising (a) valacyclovir or a salt thereof, and (b) at least one delivery agent selected from the following compounds, and pharmaceutically acceptable salts thereof:
- (Genus a)2-HO—
  
  Ar—
  
  C(O)—
  
  NR⁸—
  
  R⁷—
  
  COOH
  
  Formula (1)whereinAr is phenyl or naphthyl, optionally substituted with OH, halogen, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy;
  
  R⁷is C₄-C₂₀alkyl, C₄-C₂₀alkenyl, phenyl, naphthyl (C₁-C₁₀alkyl)phenyl, (C₁-C₁₀alkenyl)phenyl, (C₁-C₁₀alkyl) naphthyl, (C₁-C₁₀alkenyl) naphthyl, phenyl(C₁-C₁₀alkyl), phenyl(C₁-C₁₀alkenyl), naphthyl(C₁-C₁₀alkyl), or naphthyl(C₁-C₁₀alkenyl);
  
  R⁸is hydrogen, C₁to C₄alkyl, C₂to C₄alkenyl, C₁to C₄alkoxy, C₁-C₄or haloalkoxy;
  
  R⁷is optionally substituted with C₁to C₄alkyl, C₂to C₄alkenyl, C₁to C₄alkoxy, C₁-C₄haloalkoxy, —
  
  OH, —
  
  SH, and —
  
  CO₂R⁹or any combination thereof;
  
  R⁹is hydrogen, C₁to C₄alkyl or C₂to C₄alkenyl; and
  
  R⁷is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof;
  
  with the proviso that the compounds are not substituted with an amino group in the position alpha to the acid group;
  
  (Genus b)2-OH—
  
  Ar—
  
  C(O)—
  
  NH—
  
  R¹—
  
  R²
  
  Formula (2)whereinAr is phenyl or naphthyl;
  
  Ar is optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkenyl, C₂-C₄alkynyl, aryl, aryloxy, a heterocyclic ring, C₅-C₇carbocylic ring, halogen, —
  
  OH, —
  
  SH, CO₂R⁶, —
  
  NR⁷R⁸, or —
  
  N⁺R⁷R⁸R⁹Y⁻;
  
  (a) R¹is C₁-C₁₆alkylene, C₂-C₁₆alkenylene, C₂-C₁₆alkynylene, C₆-C₁₆arylene, (C₁-C₁₆alkyl)arylene, or aryl (C₁-C₁₆alkylene);
  
  R²is —
  
  NR³R⁴or —
  
  N⁺R³R⁴R⁵Y⁻;
  
  R³and R⁴are independently hydrogen;
  
  oxygen;
  
  hydroxy;
  
  substituted or unsubstituted C₁-C₁₆alkyl;
  
  substituted or unsubstituted C₂-C₁₆alkenyl;
  
  substituted or unsubstituted C₂-C₁₆alkynyl;
  
  substituted or unsubstituted aryl;
  
  substituted or unsubstituted alkylcarbolnyl;
  
  substituted or unsubstituted arylcarbonyl;
  
  substituted or unsubstituted alkanesulfinyl;
  
  substituted or unsubstituted arylsulfinyl;
  
  substituted or unsubstituted alkanesulfonyl;
  
  substituted or unsubstituted arylsulfonyl;
  
  substituted or unsubstituted alkoxycarbonyl;
  
  substituted or unsubstituted aryloxycarbonyl;
  
  R⁵is independently hydrogen;
  
  substituted or unsubstituted C₁-C₁₆alkyl;
  
  substituted or unsubstituted C₂-C₁₆alkenyl;
  
  substituted or unsubstituted C₂-C₁₆alkynyl;
  
  substituted or unsubstituted aryl;
  
  substituted or unsubstituted alkylcarbonyl;
  
  substituted or unsubstituted arylcarbonyl;
  
  substituted or unsubstituted alkanesulfinyl;
  
  substituted or unsubstituted arylsulfinyl;
  
  substituted or unsubstituted alkanesulfonyl;
  
  substituted or unsubstituted arylsulfonyl;
  
  substituted or unsubstituted alkoxycarbonyl;
  
  substituted or unsubstituted aryloxycarbonyl;
  
  (b) R¹, R², and R⁵are as defined above; and
  
  R³and R⁴are combined to form a 5, 6 or 7-membered heterocyclic ring;
  
  or 5, 6 or 7-membered heterocyclic ring substituted with a C₁-C₆alkyl, C₁-C₆alkoxy, aryl, aryloxy, oxo group or carbocyclic ring;
  
  or(c) R²and R⁵are as defined above; and
  
  R¹and R³are combined to form a 5, 6 or 7-membered heterocyclic ring;
  
  or 5, 6 or 7-membered heterocyclic ring substituted with a C₁-C₆alkyl, alkoxy, aryl, aryloxy, or oxo group or carbocyclic ring;
  
  R⁴is hydrogen;
  
  oxygen;
  
  hydroxy;
  
  substituted or unsubstituted C₁-C₁₆alkyl;
  
  substituted or unsubstituted C₂-C₁₆alkenyl;
  
  substituted or unsubstituted C₂-C₁₆alkynyl;
  
  substituted or unsubstituted aryl;
  
  substituted or unsubstituted alkylcarbonyl;
  
  substituted or unsubstituted arylcarbonyl;
  
  substituted or unsubstituted alkanesulfinyl;
  
  substituted or unsubstituted arylsulfinyl;
  
  substituted or unsubstituted alkanesulfonyl;
  
  substituted or unsubstituted arylsulfonyl;
  
  substituted or unsubstituted alkoxycarbonyl;
  
  substituted or unsubstituted aryloxycarbonyl;
  
  R⁶is hydrogen;
  
  C₁-C₄alkyl;
  
  C₁-C₄alkyl substituted halogen or —
  
  OH;
  
  C₂-C₄alkenyl;
  
  or C₂-C₄alkenyl substituted halogen or —
  
  OH;
  
  R⁷, R⁸, and R⁹are independently hydrogen;
  
  oxygen;
  
  C₁-C₄alkyl;
  
  C₁-C₄alkyl substituted with halogen or —
  
  OH;
  
  C₂-C₄alkenyl;
  
  or C₂-C₄alkenyl substituted with halogen or —
  
  OH; and
  
  Y is halogen, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, or carboxylate;
  
  whereinR¹, R², R³, and R⁴are independently hydrogen, —
  
  OH, —
  
  NR⁶R⁷, halogen, C₁-C₄alkyl, or C₁-C₄alkoxy;
  
  R⁵is a substituted or unsubstituted C₂-C₁₆alkylene, substituted or unsubstituted C₂-C₁₆alkenylene, substituted or unsubstituted C₁-C₁₂alkyl(arylene), or substituted or unsubstituted aryl(C₁-C₁₂alkylene); and
  
  R⁶and R⁷are independently hydrogen, oxygen, or C₁-C₄alkyl;
  
  wherein(a) R¹, R², R³, and R⁴are independently H, —
  
  OH, halogen, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkoxy, —
  
  C(O)R⁸, —
  
  NO₂, —
  
  NR⁹R¹⁰, or —
  
  N⁺R⁹R¹⁰R¹¹(Y⁻);
  
  R⁸is hydrogen, —
  
  OH, C₁-C₆alkyl, C₁-C₄alkyl substituted with halogen or —
  
  OH, C₂-C₄alkenyl unsubstituted or substituted with halogen or OH, or —
  
  NR¹⁴R¹⁵;
  
  R⁹, R¹⁰, and R¹¹are independently hydrogen, oxygen, C₁-C₄alkyl unsubstituted or substituted with halogen or —
  
  OH, C₂-C₄alkenyl unsubstituted or substituted with halogen or —
  
  OH;
  
  Y is halide, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, carboxylate, mesylate, fumerate, malonate, succinate, tartrate, acetate, gluconate, maleate;
  
  R⁵is H, —
  
  OH, —
  
  NO₂, halogen, CF₃, —
  
  NR¹⁴R¹⁵, —
  
  N⁺R¹⁴R¹⁵R¹⁶(Y⁻), amide, C₁-C₁₂alkoxy, C₁-C₁₂alkyl, C₂-C₁₂alkenyl, carbamate, carbonate, urea, or C(O)R²²;
  
  R⁵is optionally substituted with halogen, —
  
  OH, —
  
  SH, or —
  
  COOH;
  
  R⁵is optionally interrupted by O, N, S, or —
  
  C(O)—
  
  ;
  
  R¹⁴, R¹⁵and R¹⁶are independently H or C₁-C₁₀alkyl;
  
  R²²is H, C₁-C₆alkyl, —
  
  OH, —
  
  NR¹⁴R¹⁵;
  
  R⁶is substituted or unsubstituted C₁-C₁₆alkylene, C₂-C₁₆alkenylene, C₂-C₁₆alkynylene, C₅-C₁₆arylene, (C₁-C₁₆alkyl) arylene or aryl(C₁-C₁₆alkylene);
  
  R⁶is optionally substituted with C₁-C₇alkyl or C₁-C₇cycloalkyl;
  
  R⁷is —
  
  N¹⁸R¹⁹R¹⁹or —
  
  N⁺R¹⁸R¹⁹R²⁰Y⁻;
  
  R¹⁸and R¹⁹are independently hydrogen, oxygen, hydroxy, substituted or unsubstituted C₁-C₁₆(alkyl, substituted or unsubstituted C₂-C₁₆alkenyl, substituted or unsubstituted C₂-C₁₆alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl (e.g. substituted or unsubstituted (C_1-6alkyl)carbonyl), substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkanesulfinyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfinyl), substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkanesulfonyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfonyl), substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl (e.g. substituted or unsubstituted (C_1-6alkoxy)carbonyl), or substituted or unsubstituted aryloxycarbonyl, or substituted or unsubstituted C₅-C₇heterocyclic ring (i.e., 5, 6, or 7-membered heterocyclic ring), wherein the substitutions may be halogen or —
  
  OH; and
  
  R²⁰is independently hydrogen, substituted or unsubstituted C₁-C₁₆alkyl, substituted or unsubstituted C₂-C₁₆alkenyl, substituted or unsubstituted C₂-C₁₆alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl (e.g. substituted or unsubstituted (C_1-6alkyl)carbonyl), substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkanesulfinyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfinyl), substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkanesulfonyl (e.g. substituted or unsubstituted (C_1-6alkane)sulfonyl), substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl (e.g. substituted or unsubstituted (C_1-6alkoxy)carbonyl), or substituted or unsubstituted aryloxycarbonyl;
  
  or(b) R¹-R¹⁶and R²⁰are as defined above; and
  
  R¹⁸and R¹⁹combine to form a 5, 6, or 7-membered heterocyclic ring optionally interrupted with an oxo group and unsubstituted or substituted with C₁-C₆alkyl, C₁-C₆alkoxy, aryl, aryloxy, or carbocyclic ring;
  
  whereinR¹, R², R³, and R⁴are independently H, —
  
  OH, halogen, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, —
  
  C(O)R⁸, —
  
  NO₂, —
  
  NR⁹R¹⁰, or —
  
  N⁺R⁹R¹⁰R¹¹(R¹²);
  
  R⁵is H, —
  
  OH, —
  
  NO₂, halogen, —
  
  CF₃, —
  
  NR¹⁴R¹⁵, —
  
  N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻, amide, C₁-C₁₂alkoxy, C₁-C₁₂alkyl, C₂-C₁₂alkenyl, carbamate, carbonate, urea, or —
  
  C(O)R¹⁸;
  
  R⁵is optionally substituted with halogen, —
  
  OH, —
  
  S11, or —
  
  COOH;
  
  R⁵is optionally interrupted by O, N, S, or —
  
  C(O)—
  
  ;
  
  R⁶is a C₁-C₁₂alkylene, C₂-C₁₂alkenylene, or arylene;
  
  R⁶is optionally substituted with a C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, —
  
  OH, —
  
  SH, halogen, —
  
  NH₂, or —
  
  CO₂R⁸;
  
  R⁶is optionally interrupted by O or N;
  
  R⁷is a bond or arylene;
  
  R⁷is optionally substituted with —
  
  OH, halogen, —
  
  C(O)CH₃, —
  
  NR¹⁰R¹¹, or —
  
  N⁺R¹⁰R¹¹R¹²(R¹³)⁻;
  
  R⁸is H, C₁-C₄alkyl, C₂-C₄alkenyl, or —
  
  NH₂;
  
  R⁹, R¹⁰, R¹¹, and R¹²independently H or C₁-C₁₀alkyl;
  
  R¹³is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; and
  
  R¹⁴, R¹¹and R¹⁶are independently H, C₁-C₁₀alkyl, C₁-C₁₀alkyl substituted with —
  
  COOH, C₂-C₁₂alkenyl, C₂-C₁₂alkenyl substituted with —
  
  COOH, —
  
  C(O)R¹⁷;
  
  R¹⁷is —
  
  OH, C₁-C₁₀alkyl, or C₂-C₁₂alkenyl; and
  
  R¹⁸is H, C₁-C₆alkyl, —
  
  OH, —
  
  NR¹⁴R¹⁵, or N⁺R¹⁴R¹⁵R¹⁶(R¹³); and
  
  whereinR¹, R², R³, and R⁴are independently H, —
  
  OH, halogen, —
  
  OCH₃, —
  
  NR¹⁰R¹¹or —
  
  N+R¹⁰R¹¹R¹²(R¹³)⁻;
  
  R⁵is H, —
  
  OH, —
  
  NO₂, —
  
  NR¹⁴R¹⁵, —
  
  N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻, amide, C₁-C₁₂alkoxy, C₁-C₁₂alkyl, C₂-C₁₂alkenyl, carbamate, carbonate, urea, or —
  
  C(C)R¹⁸;
  
  R⁵is optionally substituted with —
  
  OH, —
  
  SH, or —
  
  COOH;
  
  R⁵is optionally interrupted by O, N, S, or —
  
  C(O)—
  
  ;
  
  R⁶is a C₁-C₁₂alkylene, C₁-C₁₂alkenylene, or arylene;
  
  R⁶is optionally substituted with a C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, —
  
  OH, —
  
  SH, halogen, —
  
  NH₂, or —
  
  CO₂R⁹;
  
  R⁶is optionally interrupted by C or N;
  
  R⁷is a bond or arylene;
  
  R⁷is optionally substituted with —
  
  OH, halogen, —
  
  C(O)CH₃, —
  
  NR¹⁰R¹¹or —
  
  N⁺R¹⁰R¹¹R¹²(R¹³);
  
  R⁸is H or C₁-C₄alkyl;
  
  R⁹is 1, C₁-C₄alkyl, or C₂-C₄alkenyl;
  
  R¹⁰, R¹¹, and R¹²are independently H or C₁-C₁₀alkyl;
  
  R¹³is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;
  
  R¹⁴, R¹⁵, and R¹⁶are independently H, C₁-C₁₀alkyl, C₂-C₁₂alkenyl, O, or —
  
  C(O)R¹⁷;
  
  R¹⁷is —
  
  OH, C₁-C₁₀alkyl, or C₂-C₁₂alkenyl; and
  
  R¹⁸is —
  
  OH, C₁-C₆alkyl, —
  
  NR¹⁴R¹⁵, —
  
  N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻; and
  
  whereinR¹⁹is —
  
  NO₂or —
  
  C(O)R²³;
  
  R²⁰is a C₁-C₁₂alkylene or C₁-C₁₂alkenylene;
  
  R²¹is a bond or arylene;
  
  R²²is H or C₁-C₄alkyl; and
  
  R²³is —
  
  OH, C₁-C₆alkyl, or —
  
  NH₂.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
- - 2. A pharmaceutical composition of claim 1, wherein the delivery agent is selected from the group consisting of SNAC, SNAD, 4CNAB, and pharmaceutically acceptable salts thereof.
  - 3. The pharmaceutical composition of claim 1 wherein the delivery agent is SNAC or a pharmaceutically acceptable salt thereof.
  - 4. The pharmaceutical composition of claim 1 wherein the delivery agent is wherein the delivery agent is SNAD or a pharmaceutically acceptable salt thereof.
  - 5. The pharmaceutical composition of claim 1 wherein the delivery agent is 4-CNAB or a pharmaceutically acceptable salt thereof.
  - 6. The pharmaceutical composition of any one of claims 1-5, further comprising at least one component selected from the group consisting of povidone, starch, pregelatinized starch, magnesium stearate, crospovidone, cellulose, microcrystalline cellulose, fumed silicon dioxide, polysorbate, calcium phosphate, dibasic calcium phosphate, gelatin, and croscarmellose sodium.
  - 7. The pharmaceutical composition of any one of claims 1-6 comprising from about 200 mg to about 400 mg of valacyclovir or a salt thereof.
  - 8. The pharmaceutical composition of any one of claims 1-6 comprising from about 300 mg to about 350 mg of valacyclovir or a salt thereof.
  - 9. The pharmaceutical composition of any claims 1-8, wherein the pharmaceutical composition provides acyclovir bioavailability substantially equivalent to 500 mg valacyclovir formulations marketed as Valtrex®
    - under U.S. FDA NDA No. (U.S. FDA NDA Nos. 20-550, 20-550/S21, 20-550/S19, 20-550/S10, 20-550/S13, 20-550/S16, 20-550/S12, 20-550/S
      
      005) when administered to a human.
  - 10. A dosage unit form comprising:
    - (A) the pharmaceutical compositions of any one of the preceding claims; and
      
      (B) (a) an excipient,(b) a diluent,(c) a disintegrant,(d) a lubricant,(e) a plasticizer,(f) a colorant,(g) a dosing vehicle, or(h) any combination thereof.
  - 11. The dosage unit form of claim 10, wherein the dosage unit form is in the form of a tablet, a capsule, a particle, a powder, a sachet, or a liquid.
  - 12. The dosage unit four of claim 10, wherein the dosing vehicle is a liquid selected from the group consisting of water, aqueous propylene glycol, phosphate buffer, 1,2-propane diol, ethanol, and any combination thereof.
  - 13. A method for administering an effective amount of valacyclovir a patient in need of thereof, comprising the step of orally administering the pharmaceutical composition of any one of claims 1-12.
  - 14. A method of treating a viral infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of the pharmaceutical composition of any one of claims 1-12.
  - 15. A method of treating a condition or disorder caused by a virus in a patient in need thereof, comprising the step of administering an animal an effective amount of the pharmaceutical composition of any one of claims 1-12.
  - 16. The method of claim 15, wherein the condition or disorder is caused by a virus selected from the group consisting of herpes simplex 1, herpes simplex 2, varicella zoster virus, cytomegalovirus and Epstein-Barr virus.
  - 17. A method of improving the bioavailability of valacyclovir in an animal in need thereof, the method comprising the step of administering the composition of any one of claims 1-12.
  - 18. A method of preparing a valacyclovir pharmaceutical composition comprising the step of mixing at least one delivery agent compound of claim 1 and valacyclovir or a salt or prodrug thereof.
  - 19. A kit comprising any of the pharmaceutical compositions of claims 1-12.

Specification

Resources

Litigation Campaign Assessment

Current Assignee
NOVO Nordisk North America Operations A/S
Original Assignee
Emisphere Technologies, Inc. (Novo Nordisk A/S)
Inventors
Uddin, Akm Nasir, Bender, Lewis, Majuru, Shingai, Oyewumi, Moses

Application Number

US12/266,510
Publication Number

US 20090124639A1
Time in Patent Office

Days
Field of Search
US Class Current

514/263.380
CPC Class Codes

A61K 2300/00   Mixtures or combinations of...

A61K 31/522   having oxo groups directly ...

A61K 45/06   Mixtures of active ingredie...

A61P 31/22   for herpes viruses

VALACYCLOVIR FORMULATIONS

First Claim

2 Assignments

0 Petitions

Accused Products

Abstract

18 Citations

19 Claims

Specification

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VALACYCLOVIR FORMULATIONS

First Claim

2 Assignments

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

18 Citations

19 Claims

Specification

Subscription Required

Use Cases

Quick Links

Others