WO2012097160A1 - Méthode d'administration rectale pour des peptides thérapeutiques - Google Patents

Méthode d'administration rectale pour des peptides thérapeutiques Download PDF

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Publication number
WO2012097160A1
WO2012097160A1 PCT/US2012/021089 US2012021089W WO2012097160A1 WO 2012097160 A1 WO2012097160 A1 WO 2012097160A1 US 2012021089 W US2012021089 W US 2012021089W WO 2012097160 A1 WO2012097160 A1 WO 2012097160A1
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WO
WIPO (PCT)
Prior art keywords
max
composition
accordance
alkyl
therapeutic peptide
Prior art date
Application number
PCT/US2012/021089
Other languages
English (en)
Inventor
Bassam B. Damaj
Richard Martin
Original Assignee
Nexmed Holdings, 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
Application filed by Nexmed Holdings, Inc. filed Critical Nexmed Holdings, Inc.
Publication of WO2012097160A1 publication Critical patent/WO2012097160A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • This invention relates to delivery methods for therapeutic peptides with enhanced absorption properties.
  • Peptides are mediators of biological functions.
  • the unique intrinsic properties of peptides make peptides attractive therapeutic agents because peptides exhibit relatively high biological activity and specificity as well as relatively low toxicity.
  • Therapeutic peptides in vivo have drawbacks, however, such as relatively low stability, susceptibility to enzymatic degradation, and relatively poor tumor penetration in cancer treatments, to name a few. While therapeutic peptides are viable alternatives to other biopharmaceuticals, their stability and half-life in vivo continues to be a concern.
  • the human rectum is a body cavity in which drugs can be easily introduced and retained, and from which absorption is possible. In certain instances, it may be preferable to administer a drug rectally rather than orally, e.g. in cases of nausea or vomiting. Also, for a number of drugs the extent of rectal absorption has been reported to exceed oral values, likely due to avoidance of gastric degradation and hepatic first-pass metabolism. Addition of a permeation or absorption enhancer to the therapeutic peptide can further increase the absorption of the drug through the rectum and enhance the therapeutic effect.
  • the dosage form can include liquid, gel, cream, or suppository.
  • the present therapeutic peptide compositions embodying the present invention provide enhanced absorption when administered to a patient, thereby improving many fold the systemic levels of the administered peptide or permitting the administration of a reduced dose to achieve equivalent levels.
  • dosage forms can be used to administer therapeutic peptides rectally and alter the effect of the therapeutic peptide composition.
  • the therapeutic peptide compositions of the present invention comprise the therapeutic peptide and an alkyl ⁇ , ⁇ -disubstituted amino acetate as a permeation enhancer together with a physiologically acceptable carrier suitable for rectal delivery.
  • a physiologically acceptable carrier suitable for rectal delivery suitable for rectal delivery.
  • the dosage and dosage form of the therapeutic peptide in any given case depends on the condition being treated, as well as the particular therapeutic peptide that is used to treat the condition.
  • compositions comprise a therapeutic peptide and dodecyl 2-(N,N-dimethylamino) propionate hydrochloride.
  • FIGURE 1 is a graph of Biotinylated Rituximab (Biot-RITUXAN ® ) versus time in samples from animals after rectal administration of Biot-Rituxan in water and in an aqueous 20% dodecyl 2-(N,N-dimethylamino) propionate hydrochloride.
  • peptide refers to any compound containing two or more amino acid residues joined by an amide bond formed from the carboxyl group of one amino acid residue and the amino group of the adjacent amino acid residue.
  • the amino acid residues may have the L-form as well as the D-form, and may be naturally occurring or synthetic, linear as well as cyclic.
  • polypeptides and peptide dimers which can be peptides linked C- terminus to N-terminus (tandem repeats) or peptides linked C-terminus to C- terminus (parallel repeats).
  • therapeutic peptide denotes a bioactive peptide that has therapeutic utility.
  • Illustrative categories of therapeutic peptides suitable for practicing the present invention are hormones, monoclonal antibodies, antigen-binding fragments thereof, monoclonal antibody - drug conjugates, extracellular matrix (ECM) peptides, enzymes, cytokines, and the like.
  • ECM extracellular matrix
  • monoclonal antibody refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope.
  • antibody as used herein, also encompasses functional fragments of antibodies, including fragments of chimeric, humanized, primatized, veneered or single chain antibodies.
  • physiologically acceptable carrier suitable for rectal delivery refers to a diluent, adjuvant, excipient, or the like vehicle with which a therapeutic peptide is administered.
  • Such carriers can be solid carriers meltable at about body temperature and prepared using lipophilic or hydrophilic bases, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, tocopherols and the like, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents. Suppositories prepared using water soluble and oil soluble bases are particularly suitable.
  • Gels such as enzyme-degraded xyloglucan gels also are suitable vehicles for rectal delivery.
  • Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, or any compound found in the Handbook of Pharmaceutical
  • chelating agents such as ethylenediaminetetraacetic acid
  • agents for the adjustment of tonicity such as sodium chloride or dextrose may be present.
  • therapeutically effective amount refers to those amounts that, when administered to a particular subject in view of the nature and severity of that subject's disease or condition, will have a desired therapeutic effect, e.g. an amount which will cure, prevent, inhibit, or at least partially arrest or partially prevent a target disease or condition.
  • Illustrative hormones are the insulins, e.g., human insulin, bovine insulin, porcine insulin, biosynthetic human insulin (Humulin ® ) etc., somatostatin, vasopressin, calcitonin, estrogen, progestin, testosterone, glucagon, glucagon-like peptide (GLP-1) and its analogs, and the like.
  • the monoclonal antibodies can be of various types, such as mouse, chimera, humanized, or human.
  • Illustrative chimera-type monoclonal antibodies are Rituximab (RITUXAN ® ), Cetuximab (ERBITUX ® ), Infliximab
  • REMICADE ® Basiliximab
  • SIMULECT ® Basiliximab
  • Illustrative humanized monoclonal antibodies are Trastuzumab (HERCEPTIN ® ), Palivizumab
  • Illustrative monoclonal antibody-drug conjugate is monoclonal antibody A7-neocarzino-statin (A7-NCS).
  • Illustrative ECM peptides are fibronectin, vitronectin, tenascin, and the like.
  • Illustrative enzymes are glucocerebrosidase, rhDNase, hyaluronidase, urokinase, alpha galactosidase, beta galactosidase, and the like.
  • Illustrative cytokines are the ⁇ , ⁇ , and ⁇ interferons, the lymphokines, e.g., interleukin-2, interleukin-6, etc., and the like.
  • alkyl ⁇ , ⁇ -disubstituted amino acetates suitable for present purposes can be in a free base or salt form and are represented by the formula
  • n is an integer having a value in the range of about 4 to about 18;
  • R is a member of the group consisting of hydrogen, C 1 to C 7 alkyl, benzyl and phenyl;
  • R j and R 2 are members of the group consisting of hydrogen and C 1 to C 7 alkyl;
  • R 3 and R 4 are members of the group consisting of hydrogen, methyl and ethyl.
  • Preferred alkyl ( ⁇ , ⁇ -disubstituted amino)-acetates are C 4 to C 18 alkyl ( ⁇ , ⁇ -disubstituted amino)-acetates and C 4 to C 18 alkyl (N,N-disubstituted amino)-propionates as well as pharmaceutically acceptable salts and derivatives thereof.
  • DDAA dodecyl 2-(N,N-dimethylamino)-acetate
  • alkyl-2-(N,N-disubstituted amino)-acetates are known.
  • DDAIP dodecyl 2-(N,N-dimethylamino)-propionate
  • Steroids, Ltd. Chodecyl 2-(N,N-dimethylamino)-propionate
  • alkyl-2-(N,N-disubstituted amino)- alkanoates can be synthesized from more readily available compounds as described in U.S. Patent No. 4,980,378 to Wong et al, which is incorporated herein by reference to the extent that it is not inconsistent.
  • alkyl-2- ( ⁇ , ⁇ -disubstituted amino)-acetates are readily prepared via a two-step synthesis.
  • first step long chain alkyl chloroacetates are prepared by reaction of the corresponding long chain alkanols with chloromethyl chloroformate or the like in the presence of an appropriate base such as triethylamine, typically in a suitable solvent such as chloroform.
  • an appropriate base such as triethylamine
  • reaction temperature may be selected from about 10 degrees Celsius to about 200 degrees Celsius or reflux, with room temperature being preferred.
  • the use of a solvent is optional. If a solvent is used, a wide variety of organic solvents may be selected. Choice of a base is likewise not critical. Preferred bases include tertiary amines such as triethylamine, pyridine and the like. Reaction time generally extends from about one hour to three days.
  • the long chain alkyl chloroacetate is condensed with an appropriate amine according to the scheme:
  • n, R, R l5 R 2 , R 3 and R 4 are defined as before.
  • Excess amine reactant is typically used as the base and the reaction is conveniently conducted in a suitable solvent such as ether.
  • This second step is preferably run at room temperature, although temperature may vary. Reaction time usually varies from about one hour to several days. Conventional purification techniques can be applied to ready the resulting ester for use in a pharmaceutical compound.
  • alkyl ⁇ , ⁇ -disubstituted amino acetate such as DDAIP
  • the amount of alkyl ⁇ , ⁇ -disubstituted amino acetate, such as DDAIP, present in the therapeutic peptide compositions can vary, and depends in part on the particular peptide to be administered as well as the route of
  • Pharmaceutically acceptable carriers suitable for rectal delivery include solid triglycerides (hard fats). Solid triglycerides are manufactured through direct esterification of glycerol with defined fatty acid blends and have precise properties regarding melting point, polarity (hydroxyl value), and consistency.
  • Suppository hard fats have a relatively low content of short chain fatty acids.
  • Drugs administered in suppository form can produce both local and systemic therapeutic action. Suppositories melt or dissolve in body fluids and release the drug.
  • Suppository bases can be water soluble or oil soluble bases.
  • Suppositories can be prepared by using lipophilic bases or hydrophilic bases.
  • the amount of drug released from water soluble bases e.g., hydrous and anhydrous PEG, is greater as compared to the amount of drug released from oil soluble bases, e.g. adeps solidus bases. This is likely due to PEG bases being more hydrophilic.
  • studies indicate that the drug release is higher from bases with low melting range as compared to those with high melting range.
  • drug release from the hydrous bases is better than drug release from the anhydrous base.
  • incorporation of water into the PEG base enhances release of the active ingredient.
  • the preferred combination for enhanced release and delivery of the therapeutic is the therapeutic peptide + a water soluble suppository base + DDAIP.HC1.
  • Carriers useful in the compounding of the rectal dosage form include the mixed glyceride fatty acids, such as WITEPSOL suppository bases.
  • WITEPSOL suppository bases examples of such suppository bases are:
  • the rectal dosage form in accordance with the invention preferably contains from about 5 mg to about 2000 mg of active substance, preferably from about 10 mg to about 500 mg.
  • the active substance: carrier weight ratio in the suppository in accordance with the invention is about 3 : 1 to about 1 : 100 and preferably about 1 : 1 to about 1 :3.
  • the active substance: enhancer weight ratio is about 1 : 100 to about 100: 1 preferably about 1 :500 to about 1 : 1.
  • the pharmaceutical composition for rectal administration in accordance with this invention is generally used as a rectal suppository or a preparation prepared by dispersing the pharmacologically-active substance and the other ingredients in a liquid oleaginous base to prepare a liquid preparation, e.g., suspension, ointment, gel, cream, etc. and by filling this preparation in soft gelatin capsules or syringes or tubes, e.g., administered as an enema.
  • a liquid preparation e.g., suspension, ointment, gel, cream, etc.
  • the rectal dosage forms in accordance with the invention can also contain adjuvants which are known per se for the purpose of achieving a desired consistency.
  • water-soluble carriers such as polyethylene glycol, polypropylene glycol, glycerogelatine, methylcellulose or carboxymethylcellulose can be present.
  • Wetting agents e.g. non-ionic, wetting agents such as
  • the rectal dosage forms can contain suitable emulsifying and dispersing agents, agents for adjusting the viscosity and coloring substances.
  • These dosage forms can be manufactured by melting the carrier together with the enhancer by warming, homogeneously dispersing the active substance and, if desired, customary therapeutically inert adjuvants for rectal dosage forms, in the melt obtained and formulating the dispersion obtained into suppositories, capsules, or other rectal delivery systems.
  • Biotinylated Rituximab (Biot-RITUXAN ® ) (about 25 mg/mL) in aqueous 20% DDAIP.HCl was administered rectally (single dose, 50 uL) to normal mice.
  • a second group of mice received Biotinylated Rituximab (Biot-RITUXAN ® ) (about 25 mg/mL) in water, also administered rectally (single dose, 50 uL).
  • Administered doses were approximately 35 mg/kg.
  • Samples of blood (50 ⁇ ) were collected from the animals in red serum tubes kept on ice. The collected samples were processed by centrifugation at about 3,000 RPM at 4°C for about ten minutes. The obtained supernatant serum was transferred to polypropylene tubes, placed into dry ice to freeze and then stored at -80°C until analyzed. The cellular fraction obtained by centrifugation was discarded.
  • Dosage forms suitable for rectal delivery of the therapeutic peptide compositions include solutions, suppositories, gels, creams, and the like.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention a pour objet des méthodes d'administration améliorées pour des compositions de peptides thérapeutiques comprenant un peptide thérapeutique, tel que le Rituximab, conjointement avec un améliorateur de perméation amino-acétate N,N-disubstitué d'alkyle, tel que le 2-(N,N-diméthylamino) propionate de dodécyle, et un véhicule approprié pour une administration rectale.
PCT/US2012/021089 2011-01-14 2012-01-12 Méthode d'administration rectale pour des peptides thérapeutiques WO2012097160A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161461232P 2011-01-14 2011-01-14
US61/461,232 2011-01-14

Publications (1)

Publication Number Publication Date
WO2012097160A1 true WO2012097160A1 (fr) 2012-07-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2566503A1 (fr) * 2010-05-04 2013-03-13 Nexmed Holdings, Inc. Composition de peptide thérapeutique et procédé
US8962595B2 (en) 2010-05-04 2015-02-24 Nexmed Holdings, Inc. Compositions of small molecule therapeutics

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6118020A (en) * 1999-05-19 2000-09-12 Nexmed Holdings, Inc. Crystalline salts of dodecyl 2-(N,N-dimethylamino)-propionate
US20070190019A1 (en) * 2003-06-23 2007-08-16 Chunfeng Guo Compositions and methods for topical administration
US20080226699A1 (en) * 2003-11-28 2008-09-18 Acrux Dds Pty Ltd Method and System for Rapid Transdermal Administration
US7645449B2 (en) * 2003-02-07 2010-01-12 Giorgio Stassi Sensitizing cells for apoptosis by selectively blocking cytokines
US20100239654A1 (en) * 2009-01-22 2010-09-23 Gerhard Winter Vesicular phospholipid gels comprising proteinaceous substances

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6118020A (en) * 1999-05-19 2000-09-12 Nexmed Holdings, Inc. Crystalline salts of dodecyl 2-(N,N-dimethylamino)-propionate
US7645449B2 (en) * 2003-02-07 2010-01-12 Giorgio Stassi Sensitizing cells for apoptosis by selectively blocking cytokines
US20070190019A1 (en) * 2003-06-23 2007-08-16 Chunfeng Guo Compositions and methods for topical administration
US20080226699A1 (en) * 2003-11-28 2008-09-18 Acrux Dds Pty Ltd Method and System for Rapid Transdermal Administration
US20100239654A1 (en) * 2009-01-22 2010-09-23 Gerhard Winter Vesicular phospholipid gels comprising proteinaceous substances

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2566503A1 (fr) * 2010-05-04 2013-03-13 Nexmed Holdings, Inc. Composition de peptide thérapeutique et procédé
EP2566503A4 (fr) * 2010-05-04 2013-10-02 Nexmed Holdings Inc Composition de peptide thérapeutique et procédé
US8962595B2 (en) 2010-05-04 2015-02-24 Nexmed Holdings, Inc. Compositions of small molecule therapeutics

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