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WO1997046222A1 - Formulation pediatrique pour inhibiteurs de la protease du vih - Google Patents

Formulation pediatrique pour inhibiteurs de la protease du vih Download PDF

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Publication number
WO1997046222A1
WO1997046222A1 PCT/US1997/009109 US9709109W WO9746222A1 WO 1997046222 A1 WO1997046222 A1 WO 1997046222A1 US 9709109 W US9709109 W US 9709109W WO 9746222 A1 WO9746222 A1 WO 9746222A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
hiv protease
glycerol
protease inhibitor
free base
Prior art date
Application number
PCT/US1997/009109
Other languages
English (en)
Inventor
Drazen Ostovic
Karen C. Thompson
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9613109.9A external-priority patent/GB9613109D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU31469/97A priority Critical patent/AU3146997A/en
Publication of WO1997046222A1 publication Critical patent/WO1997046222A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • HIV HIV
  • LAV low-density virus
  • HTLV-LTI HTLV-LTI
  • ARV advanced immune deficiency syndrome
  • a common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E. et al, Proc. Nat'l Acad. Sci..
  • Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et ah, Nature. 313. 277 (1985)].
  • Amino acid sequence homology provides evidence that the gol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al.. Science. 231. 1567 (1986); Pearl, L.H. et al, Nature. 329, 351 (1987)].
  • HIV protease inhibitors have unsatisfactory and unpleasant taste, e.g., CRDCIVAN® (trademark of Merck & Co. Inc.), which is a sulfate salt of
  • sulfate salt Converting the sulfate salt to insoluble free base improves taste and palatability, but oral bioavailability is reduced unacceptably, by a factor of up to about three. Furthermore, adding flavors or sweeteners or glycerol to aqueous solutions of the sulfate salt does not improve palatability.
  • Applicants have unexpectedly found that suspension or dispersion of HIV protease inhibitor particles, e.g., of CRIXIVAN®, in glycerol, substantially improves the palatability of the drug.
  • Dispersion or suspension in glycerol of HIV protease inhibitors, or pharmaceutically acceptable salt thereof improve palatabilty sufficiently to be suitable as pediatric formulations in the treatment of AIDS, ARL or HIV infection in children and infants.
  • This invention relates to a pediatric formulation of an HIV protease inhibitor, which is a dispersal or suspension of HIV protease inhibitor in a non-toxic, high viscosity, water-miscible liquid, to improve palatability.
  • a preferred liquid is glycerol.
  • the HIV protease inhibitor is the sulfate salt of
  • One formulation of the present invention comprises, in each ml of formulation, about 20 mg sweetener, sufficient flavor, between about 50 mg (free base equivalent) and about 400 mg (free base equivalent), of the sulfate salt of
  • the preceeding formulation is limited to an amount of HIV protease inhibitor, in each ml of formulation, of between about 100 mg (free base equivalent) and about 300 mg (free base equivalent).
  • the formulation is limited to an amount of HIV protease inhibitor, in each ml of formulation, of between about 50 mg (free base equivalent) and about 400 mg (free base equivalent) of the sulfate salt of
  • the residual volume being glycerol.
  • the formulation is limited to an amount of HIV protease inhibitor, in each ml of formulation, of between about 100 mg (free base equivalent) and about 300 mg (free base equivalent) of the sulfate salt of
  • the residual volume being glycerol.
  • the pediatric formulations of the present invention include HIV protease inhibitors such as CRIXIVAN®, and Compounds I, LI, III or IV.
  • HIV protease inhibitors such as CRIXIVAN®, and Compounds I, LI, III or IV.
  • the HIV protease inhibitor Compound CRIXIVAN® is synthesized by the protocol of Merck Case 18597Y, EP 0541 168, published 12 May 1993, U.S. 5,413,999, herein incorporated by reference.
  • CRIXIVAN® is the sulfate salt of N-(2(R)-hydroxy-l(S)- indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1 -(4-(3- pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))- pentaneamide.
  • Compound I is:
  • the pharmaceutically-acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N -methyl -D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen -containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the pediatric formulation of the present invention is useful in the inhibition of HIV protease, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS, in children or infants.
  • Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • a suitable carrier is any non-toxic, high viscosity liquid, such as certain oils, e.g., glycerides, partial esters of glycesor, and mixtures thereof.
  • the carrier is a non-toxic, high viscosity, water-miscible liquid, such as glycerol.
  • flavors and sweeteners are then added with continuous stirring.
  • the order of addition to drug of carrier, flavor or sweeteners can in principle be varied. In one preferred order, drug is first dispersed with glycerol or other carrier, then sweetener or flavor is added as needed. In another preferred order, sweetener and/or flavor are added first to glycerol, with heat to aid dissolution or dispersion, followed by addition of drug after cooling.
  • Another embodiment of the present invention is the dispersion in glycerol of drug, ie., an HIV protease inhibitor, without sweeteners or flavors.
  • drug ie., an HIV protease inhibitor
  • One preferred embodiment is the dispersion in glycerol of CRIXrVAN® without sweeteners or flavors.
  • the resulting dispersion should be dearated, typically by applying a vacuum.
  • the pediatric formulation may be packaged into a unit dose system, e.g., oral syringe, or into a multiple dose system, e.g, bottle with separate oral dosing syringe.
  • dosing volumes of the pediatric formulation can vary from about 0.5 ml of a 100 mg/ml suspension to about 1.66 ml of a 300 mg/ml suspension or may reach higher volumes, e.g., 2.5 ml of a 200 mg/ml suspension. Dispersions of between about 50 mg/ml and about 400 mg/ml are feasible, but the range of between about 100 mg/ml and about 300 mg/ml is preferred.
  • the level of sweeteners is typically about 20 mg/ml dispersion of high intensity sweeteners, but may be higher for simple sugars such as sucrose. In principle any sweetener may be used.
  • Suitably high intensity sweeteners include but are not limited to Magnasweet® (trademark of MAFCO), Acesulfame K, Aspartame or Saccharin. The actual level of sweetener can vary from effectively zero to about 300 mg/ml.
  • Suitable flavor systems include liquid flavors and flavors adsorbed onto solid substrate.
  • Suitable pediatric flavors include but are not limited to bubble gum, cherry, and orange.
  • the pediatric compositions When administered orally as a suspension, the pediatric compositions may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and other sweeteners/flavoring agents known in the art.
  • the formulations of this invention can be administered to humans in the dosage ranges specific for each compound.
  • CRIXIVAN® is administered orally in a dosage range between about 40 mg and about 4000 mg per day, divided into between one and four doses per day.
  • a preferred oral adult dosage range for CRIXIVAN® is between about 200 mg and about 1000 mg administered three times per day.
  • a preferred oral pediatric dosage range for CRIXIVAN® is between about 50 mg and about 800 mg administered three times per day.
  • Compound I or pharmaceutically acceptable salt thereof is administered orally at a dosage range of between about 100 mg and about 4000 mg per day.
  • a preferred oral dosage range for Compound I or pharmaceutically acceptable salt thereof is between about 200 mg and about 1000 mg administered three times per day.
  • Compound II is administered orally, e.g., as an elixir in 30% ethanol in water, at a dosage range of between about 100 mg and about 4000 mg per day.
  • a preferred oral dosage range for Compound II is between about 200 mg and about 1000 mg administered three times per day.
  • Compound III or pharmaceutically acceptable salt thereof is administered orally at a dosage range of between about 100 mg and about 4000 mg per day.
  • a preferred oral dosage range for Compound III or pharmaceutically acceptable salt thereof is between about 200 mg and about 1000 mg administered three times per day.
  • Compound rv or pharmaceutically acceptable salts thereof is administered orally as a dosage range of between about 100 mg and about 4000 mg per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, child vs. adult, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the formulations that follow are scaled to 1 ml quantities.
  • Bubble gum flavor q.s. glycerol to 1 ml
  • Bubble gum flavor q.s. glycerol to 1 ml

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une dispersion ou suspension d'inhibiteurs de la protéase du VIH dans le glycérol qui améliore l'appétibilité et le goût et convient à la préparation de formulations pédiatriques destinées à être utilisées dans le traitement des infections par le SIDA, le para-SIDA et le VIH chez des enfants et des nouveau-nés.
PCT/US1997/009109 1996-06-03 1997-05-30 Formulation pediatrique pour inhibiteurs de la protease du vih WO1997046222A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31469/97A AU3146997A (en) 1996-06-03 1997-05-30 Pediatric formulation for hiv protease inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1909796P 1996-06-03 1996-06-03
US60/019,097 1996-06-03
GBGB9613109.9A GB9613109D0 (en) 1996-06-21 1996-06-21 Pediatric formulation for HIV protease inhibitors
GB9613109.9 1996-06-21

Publications (1)

Publication Number Publication Date
WO1997046222A1 true WO1997046222A1 (fr) 1997-12-11

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PCT/US1997/009109 WO1997046222A1 (fr) 1996-06-03 1997-05-30 Formulation pediatrique pour inhibiteurs de la protease du vih

Country Status (2)

Country Link
AU (1) AU3146997A (fr)
WO (1) WO1997046222A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020057A3 (fr) * 2000-09-05 2002-05-10 Abbott Lab Systeme d'aromatisation pour compositions pharmaceutiques et procedes de fabrication de telles compositions
US6911214B2 (en) 2000-09-05 2005-06-28 Abbott Laboratories Flavoring systems for pharmaceutical compositions and methods of making such compositions
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US9107830B2 (en) 1999-11-12 2015-08-18 Abbvie, Inc. Inhibitors of crystallization in a solid dispersion

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346847A2 (fr) * 1988-06-13 1989-12-20 F. Hoffmann-La Roche Ag Dérivés d'amminoacides
EP0441307A1 (fr) * 1990-02-06 1991-08-14 Showa Yakuhin Kako Co., Ltd. Composition de sirop
US5296604A (en) * 1992-05-15 1994-03-22 Miles Inc. Proline derivatives and compositions for their use as inhibitors of HIV protease
WO1995020384A1 (fr) * 1994-01-28 1995-08-03 Abbott Laboratories Compositions pharmaceutiques contenant des inhibiteurs de protease du vih

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346847A2 (fr) * 1988-06-13 1989-12-20 F. Hoffmann-La Roche Ag Dérivés d'amminoacides
EP0441307A1 (fr) * 1990-02-06 1991-08-14 Showa Yakuhin Kako Co., Ltd. Composition de sirop
US5296604A (en) * 1992-05-15 1994-03-22 Miles Inc. Proline derivatives and compositions for their use as inhibitors of HIV protease
WO1995020384A1 (fr) * 1994-01-28 1995-08-03 Abbott Laboratories Compositions pharmaceutiques contenant des inhibiteurs de protease du vih

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
US9107830B2 (en) 1999-11-12 2015-08-18 Abbvie, Inc. Inhibitors of crystallization in a solid dispersion
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US6911214B2 (en) 2000-09-05 2005-06-28 Abbott Laboratories Flavoring systems for pharmaceutical compositions and methods of making such compositions
WO2002020057A3 (fr) * 2000-09-05 2002-05-10 Abbott Lab Systeme d'aromatisation pour compositions pharmaceutiques et procedes de fabrication de telles compositions
US8895051B2 (en) 2000-09-05 2014-11-25 Abbvie Inc. Flavoring systems for pharmaceutical compositions and methods of making such compositions
US8501219B2 (en) 2000-09-05 2013-08-06 Abbvie Inc. Flavoring systems for pharmaceutical compositions and methods of making such compositions
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form

Also Published As

Publication number Publication date
AU3146997A (en) 1998-01-05

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