WO1998022089A1 - Composition pharmaceutique a base de systeme matriciel lipidique - Google Patents

Composition pharmaceutique a base de systeme matriciel lipidique Download PDF

Info

Publication number
WO1998022089A1
WO1998022089A1 PCT/SE1997/001956 SE9701956W WO9822089A1 WO 1998022089 A1 WO1998022089 A1 WO 1998022089A1 SE 9701956 W SE9701956 W SE 9701956W WO 9822089 A1 WO9822089 A1 WO 9822089A1
Authority
WO
WIPO (PCT)
Prior art keywords
lipid
composition according
low molecular
peptide
hexarelin
Prior art date
Application number
PCT/SE1997/001956
Other languages
English (en)
Inventor
Brita Sjöström
Birgitta Olsson
Original Assignee
Pharmacia & Upjohn Ab
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 SE9604299A external-priority patent/SE9604299D0/xx
Application filed by Pharmacia & Upjohn Ab filed Critical Pharmacia & Upjohn Ab
Priority to AU51423/98A priority Critical patent/AU5142398A/en
Publication of WO1998022089A1 publication Critical patent/WO1998022089A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF] (Somatoliberin)
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases

Definitions

  • the present invention relates to a pharmaceutical composition based on a lipid matrix system having at least two lipid components and at least one bioactive compound.
  • the two lipid components are chosen from classes of different polarity in which at least one of the lipid components is bilayer forming.
  • the bioactive compound is a low molecular weight peptide which preferably stimulates the release of growth hormone and comprises 2-alkyl-D tryptophan and most preferably the peptide is hexarelin.
  • the composition can include polar solvents and preferably a water containing solvent.
  • Peptides are usually given parenterally but since parenteral administration often needs to be carried out by physicians or nurses and the fact that many patients find such therapy uncomfortable, a lot of effort is made in developing drug delivery forms applicable for other routes of administration.
  • R absorption enhancers for low molecular weight peptides.
  • Biosomes is an example of such an enhancer, here reported to enhance the intestinal permeability and oral bioavailability of both hydrophilic and lipid soluble compounds.
  • This drug delivery systems consists of a lipid matrix, which in excess of water spontaneously form lipid particles (Bruce, 1994; Bohlinder et al, 1994; Betageri et al, 1993). The system and its principles are disclosed in WO 92/05771. The mechanism(s) by which Biosomes ® increase the intestinal uptake is not fully understood. The toxicity appears to be minimal (Betageri et al, 1993).
  • the present invention relates to composition and processes as defined in the present claims.
  • hexarelin as a low molecular weight peptide and a lipid matrix comprising soybean phosphatidyl choline and medium-chain monoacylglycerol (30:70 w:w), which is suitable for effective enhancement of intestinal absorption of incompletely absorbed drugs.
  • medium chain is here meant a chain containing 8 to 12, preferably 8-10 carbon atoms.
  • the growth hormone release of hexarelin after oral administration is only about 0.3+0.1% as compared to after i.v. administration. (Ghigo et al., 1994).
  • Figure 1 Mean ⁇ SD (standard deviation) effective permeability coefficients (Peff ) of hexarelin in the absence (grey square) and presence (black square) of soybean phosphatidyl choline and medium chain monoacylglycerol matrix in the single-pass in situ perfused rat jejunum, ileum and colon. Estimates were obtained in the presence of the protease inhibitor Pefabloc ® SC.
  • Hexarelin is a low molecular weight peptide with six amino acids:
  • Hexarelin is a synthetic growth hormone-releasing peptide, shown to produce a substantial increase of growth hormone plasma levels in humans (Imbimbo et al, 1994; Ghigo et al., 1994). The compound is disclosed in the patent application WO
  • log KD is 2.2
  • log D is -2.3 at pH 6.5
  • MW is 887.
  • Lipid matrix A lipid based drug delivery system composed of medium chain monoacylglycerol and soy bean phosphatidyl cholin in a ratio of 70:30 w:w.
  • Atenolol is used as a reference substance with the permeability value and partition coefficient given in the literature .
  • log D is -1.8 at pH 7.4 and MW is 266.
  • log KD and log D are partition coefficients in octanol and a buffer, known in the art.
  • the perfusion solution (pH 6.5, 290 mOsm/L) contained 48 mM NaCl, 5.4 mM KCl, 28 mM Na2HP ⁇ 4, 43 mM aH2P ⁇ 4, 35 mM mannitol, 1 g/L polyethylene glycol
  • ⁇ PEG i n and ⁇ PEG out are the accumulated amounts of [ 14 C]PEG 4000 entering and leaving the intestinal segment during equilibrium, respectively.
  • the parallel-tube model was used to estimate the effective intestinal permeability coefficients (P e ff cm/s) for hexarelin and atenolol (Amidon et al., 1980; Komiya et al, 1980; Fagerholm et al, 1996):
  • Q zn is the perfusion flow rate
  • A is the mass transfer surface area within the intestinal segment assumed to be a cylinder area with the length (L) of 7-12 cm in the jejunum and ileum, and 1.5-6 cm in the colon, and radius (r) 0.18, 0.18 and 0.25 cm in the jejunum, ileum and colon, respectively ( Komiya et al 1980; Kararli 1995).
  • Rat jejunal Peff -estimates for highly soluble, stable, passively absorbed compounds can be used to predict the corresponding human coefficient (Peff,man) arid the extent of intestinal absorption in vivo in man (fa) (Fagerholm et al, 1996):
  • Hexarelin acetate (Bachem Feinchemikalien AG, Bubendorf, Switzerland) was dissolved in sterile water at a concentration of 26% (w/w), i.e. pure peptide 22.1
  • hexarelin acetate solution was subsequently blended with a mixture of medium chain monoglyceride (MG), (Scotia LipidTeknik AB, Sweden) and soybean phosphatidyl choline (PC), (Scotia LipidTeknik AB, Sweden), (70% MG/30% PC, w/w).
  • MG medium chain monoglyceride
  • PC soybean phosphatidyl choline
  • the amount of hexarelin solution in the mixture was 11,76 %(w/w).
  • the tube containing the mixture was filled with nitrogen whereafter it was sealed. Thereafter the tube was shaken moderately until the mixture appeared to be homogenous and clear ( about 1.5 h at 37 °C).
  • the hexarelin/ lipid mixture was than stored at -20°C until the perfusion study was performed.
  • an isotonic NaCl-solution (0.9 % w/w) was added to the thawed hexarelin/ lipid mixture in order to swell the lipids (for 10 minutes at 20 °C).
  • the amount of the NaCl-solution in the mixture was 82 %(w/ w).
  • perfusion buffer containing atenolol was added to the hexarelin/ lipid mixture.
  • the final dispersion contained hexarelin at a concentration of 0.15 mM, atenolol at a concentration of 0.83 mM and lipids at a concentration of 15 mM.
  • Hexarelin (0.15 mM) and atenolol (0.83 mM) were dissolved in perfusion buffer.
  • Hexarelin acetate was dissolved in sterile water to give 26% (w/w) (i.e. 22.1 % (w/w) pure peptide).
  • the hexarelin acetate solution was thereafter mixed with a mixture of MG and PC (70/30 w/w).
  • the amount of hexarelin solution in the mixture was 11.76 %(w/w).
  • the tube containing the mixture was filled with nitrogen whereafter it was sealed. The tube was shaken moderately until the mixture appeared to be homogenous and clear (1,5 h at 37 °C).
  • the hexarelin/ lipid mixture was then stored at -20°C until the perfusion study was performed.
  • Hexarelin (0.15 mM), atenolol (0.83 mM) and Pefabloc® SC (1.25 mM) were dissolved in perfusion buffer.
  • Atenolol was dissolved in sterile water to give 1.1% (w/w).
  • the atenolol solution was blended with a mixture of MG and PC (70/30 w/w).
  • the amount of atenolol solution in the mixture was 11.9 %(w/w).
  • the tube containing the mixture was filled with nitrogen whereafter it was sealed.
  • the mixture was then shaken moderately to give a clear dispersion (i.e. about 1.5 h at 37 °C).
  • the atenolol/ lipid mixture was then stored at -20°C until the perfusion study was performed.
  • compositions A, C and E are compositions according to the invention.
  • Study part II was identical to part I, with the exception that the serine protease inhibitor Pefabloc ® SC (0.3 g/L) was added to the perfusion solution, and that jejunal experiments were performed in 5 animals ( C and D).
  • the atenolol concentration was lower than in study parts I and II. These experiments were performed in the jejunum of 5 rats. Basal P e ff-estimates of atenolol have previously been determined in the rat (Fagerholm et al., 1996).
  • the intestinal segments were rinsed for 2-5 minutes with approximately 15 ml saline. This was undertaken in order to collect the remaining amounts of substances from the perfusion system. All perfusion syringes and perfusate samples were weighed, and the samples were frozen immediately and stored at -70°C until analysis.
  • the PEG recovery (PEGrec) was complete in all perfusion experiments, and the release of LDH into the intestinal lumen was generally not increased during exposure of the lipid matrix or Pefabloc ® SC (Table 1). This indicates a maintained intestinal viability, and absence of a pronounced mucosal damaging effect of these additives.
  • the LDH activity declined along the intestine, which could be explained by a decreased anatomical intestinal surface area, and a shorter residence time in the colon, where the perfused segments were shorter. It might also be explained by a lower secretion rate of LDH from intestinal cells, since the fluidity of the apical cell membranes decreases from the proximal to distal intestine (Kararli, 1995).
  • Peff -coefficients of hexarelin and atenolol obtained in the absence and presence of the lipid matrix and/ or Pefabloc ® SC, are presented in Table 2.
  • the estimated Peff -values of hexarelin demonstrated that this drug has a low intestinal permeability, which was neither different between intestinal regions nor influenced by Pefabloc ® SC (Table 2).
  • the low P e ff agrees with its hydrophilic character at physiological pH (log D -2.3 at pH 6.5), and high molecular weight (887 g/mole). Otherwise, hexarelin possesses highly lipophilic properties in its unionized form (log
  • hexarelin has the properties (amphiphilic, partitioning coefficient > 2, protonated at physiological pH) to be a substrate for these transport systems (Karlsson et al, 1993; Saitoh and Aungst, 1995; Fricker et al, 1996). It is however difficult to tell whether this mechanism is of importance for hexarelin or not, because the specificity, capacity, and the distribution of P-glycoproteins in the animal and human intestine are not fully clarified.
  • a drug delivery system of lipids can increase the effective permeability (Peff) of a hexapeptide, hexarelin, approximately 20 times using the in situ perfusion model in the rat jejunum.
  • Hexarelin might thus be suitable for oral delivery. It is predicted that hexarelin has an intermediate fractional absorption in humans after oral administration and that this is significantly enhanced in the presence of the lipid matrix. These additives seemed not to have a damaging effect on the intestinal mucosa.

Abstract

L'invention concerne une composition pharmaceutique basé sur un système matriciel lipidique comprenant au moins deux composants lipidiques et au moins un composé bioactif. Les deux composants lipidiques sont choisis dans des classes à polarité différente, un des composants lipidiques formant deux couches. Le composé bioactif est un peptide à bas poids moléculaire qui stimule de préférence la libération de l'hormone de croissance et comprend du 2-alkyl-D tryptophane et, idéalement, le peptide est de l'hexaréline. La composition de l'invention peut contenir des solvants polaires et de préférence un solvant contenant de l'eau.
PCT/SE1997/001956 1996-11-22 1997-11-21 Composition pharmaceutique a base de systeme matriciel lipidique WO1998022089A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51423/98A AU5142398A (en) 1996-11-22 1997-11-21 Pharmaceutical composition based on a lipid matrix system

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9604299-9 1996-11-22
SE9604299A SE9604299D0 (sv) 1996-11-22 1996-11-22 Pharmaceutical composition
US3217596P 1996-12-04 1996-12-04
US60/032,175 1996-12-04

Publications (1)

Publication Number Publication Date
WO1998022089A1 true WO1998022089A1 (fr) 1998-05-28

Family

ID=26662803

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1997/001956 WO1998022089A1 (fr) 1996-11-22 1997-11-21 Composition pharmaceutique a base de systeme matriciel lipidique

Country Status (2)

Country Link
AU (1) AU5142398A (fr)
WO (1) WO1998022089A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963367A (en) * 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
WO1994008605A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Microemulsions therapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963367A (en) * 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
WO1994008605A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Microemulsions therapeutiques

Also Published As

Publication number Publication date
AU5142398A (en) 1998-06-10

Similar Documents

Publication Publication Date Title
ES2199338T3 (es) Composiciones farmaceuticas en emulsion, que contienen (3'-desoxi-3'-oxo-mebmt)1-(val)2-ciclosporin.
US4548922A (en) Drug administration
JP4499282B2 (ja) 混合ミセル状薬剤の移送システム及び調製方法
US6350458B1 (en) Mixed micellar drug deliver system and method of preparation
CN1149984C (zh) 用于静脉注射的含有普鲁泊福的麻醉组合物
ES2309059T3 (es) Composiciones farmaceuticas en forma de micelas para aplicacion bucal y pulmonar.
US6451286B1 (en) Pharmaceutical compositions for buccal and pulmonary administration comprising an alkali metal alkyl sulfate and at least three micelle-forming compounds
PT86370B (pt) Processo para a preparacao de composicoes farmaceuticas para administracao por via nasal contendo fosfolipidos
TWI269652B (en) Transnasal anticonvulsive compositions and modulated process
US7820722B2 (en) Permeation enhancers
WO2002064115A1 (fr) Formulation pour l'administration d'insuline et procede de preparation de cette formulation
US20100311696A1 (en) Topical skin treatment composition
JP2003513019A (ja) トコール可溶性治療剤の組成物
MXPA02002267A (es) Sistema de suministro farmaceutico micelar mezclado y metodo de preparacion.
CA2446622C (fr) Sels d'acide isostearique utilises comme accelerateurs de permeation
BR112012015433B1 (pt) Composição farmacêutica substancialmente anidra para aplicação cutânea
JP2006501220A (ja) 薬剤の投与及び吸収促進方法
BG64668B1 (bg) Фармацевтични състави на пептиди, притежаващи малка разтворимост във физиологична среда
EP1517709A1 (fr) Systeme d'administration transdermique de medicaments
WO1998022089A1 (fr) Composition pharmaceutique a base de systeme matriciel lipidique
Motson Dissolution of common bile duct stones
US20110033527A1 (en) Opthalmic compositions of cyclosporin
WO1999043299A2 (fr) Formulations orales pour medicaments hydrophiles
JPS63303931A (ja) 経鼻投与用成長ホルモン放出活性物質製剤
CA2523576A1 (fr) Prophylactiques ou remedes pour l'hepatopathie

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA