WO1998001159A2 - Composition en vue d'une meilleure assimilation par les muqueuses de medicaments a molecules polaires - Google Patents

Composition en vue d'une meilleure assimilation par les muqueuses de medicaments a molecules polaires Download PDF

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Publication number
WO1998001159A2
WO1998001159A2 PCT/GB1997/001852 GB9701852W WO9801159A2 WO 1998001159 A2 WO1998001159 A2 WO 1998001159A2 GB 9701852 W GB9701852 W GB 9701852W WO 9801159 A2 WO9801159 A2 WO 9801159A2
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composition according
therapeutic agent
bile salt
agent
administration
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PCT/GB1997/001852
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English (en)
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WO1998001159A3 (fr
Inventor
Lisbeth Illum
Peter James Watts
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Danbiosyst Uk Limited
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Application filed by Danbiosyst Uk Limited filed Critical Danbiosyst Uk Limited
Priority to AU34539/97A priority Critical patent/AU722724B2/en
Priority to JP10504949A priority patent/JP2000515503A/ja
Priority to EP97930663A priority patent/EP0993305A2/fr
Priority to GB9900050A priority patent/GB2330533B/en
Publication of WO1998001159A2 publication Critical patent/WO1998001159A2/fr
Publication of WO1998001159A3 publication Critical patent/WO1998001159A3/fr
Priority to NO985956A priority patent/NO985956D0/no

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    • 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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • 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
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to novel compositions for enhancing the absorption of polar molecules from the mucosal surfaces of a mammal, in particular the proximal colonic region of the intestine of said mammal.
  • nafarelin buserelin and goserelin
  • growth hormone growth hormone releasing hormones
  • colony stimulating factors erythropoietin, somatostatin, interferons and heparins
  • erythropoietin growth hormone releasing hormones
  • somatostatin growth hormone releasing hormones
  • interferons growth hormone releasing hormones
  • heparins growth hormone releasing hormones
  • the absolute bioavailability i.e. the quantity reaching systemic circulation
  • parenteral administration e.g. less than 1 %).
  • Cyclosporin a polypeptide
  • aprotinin to reduce metabolic loss
  • various absorption promoting agents in the form of non- ionic surface active agents, natural bile salts and analogues thereof (such as sodium taurodihydrofusidate), phospholipids, chelating agents and acyl caraitine in order to improve transmucosal absorption.
  • Enhancers which have been employed include the natural bile salts and their ⁇ xtures with other materials such as oleic acid.
  • oleic acid For example, the ileocolonic delivery of insulin at 10 units/kg to the dog using a mixed micelle system comprising sodium glycocholate (30 mM) and a fatty acid (linoleic acid) at 40 mM has been described by Scott-Moncrieff and others (J. Pharm. Sci. 83, 1465 (1994)). The reported bioavailability was 1.4% .
  • bile salts and their derivatives and analogues are known to be good enhancing agents, not only when used in the gastrointestinal tract, but also when used in conjunction with other mucosal surfaces (such as those found in the nose, genitourinary tract, lung and buccal cavity), the problem exists that these materials cannot normally be used in man because of their irritant nature.
  • Conjugated bile salts have also been employed within me gastrointestinal tract. However, such materials are metabolised, leading to the problem that they possess poor absorption enhancing ability.
  • Unconjugated bile salts are also known to cause problems within the intestine, particularly in the large bowel, because of their secretory effects, which can give rise to gastrointestinal disturbances and diarrhoea. Indeed, in the past, unconjugated bile salts have been used as laxative agents.
  • compositions including therapeutic agents and non- metabolisable bile salt analogues including the synthetic bile salt derivative cholylsarcosine.
  • non-metabolisable bile salt analogues including cholylsarcosine, improve the absorption of poorly absorbed polar molecules across mucosal surfaces such as the gastrointestinal tract, the nose, the vagina, the buccal cavity and the rectum.
  • compositions according to the invention a composition for administration to a mucosal surface of a mammal comprising a bile salt analogue and a therapeutic agent, characterised in that the bile salt analogue is non-metabolisable, hereinafter referred to as "the compositions according to the invention” .
  • non-metabolisable we mean a compound which is not capable of being metabolised under normal conditions experienced within the gastrointestinal tract, for example a compound which cannot be hydrolysed below 40 °C at pHs within the range 5 to 8.
  • compositions according to the invention include cholylsarcosine, and other non-naturally occurring, non-metabolisable, conjugates of cholic acid and amino acids.
  • Preferred compounds which may be employed include cholylsarcosine.
  • Cholylsarcosine is a conjugated bile acid analogue that has been developed as a bile acid replacement agent. It is a synthetic conjugate of cholic acid and sarcosine.
  • compositions according to the invention may be used with therapeutic agents which are of a non-polar or a polar nature, we prefer that the therapeutic agent is a polar compound or polar molecule.
  • a polar compound or polar molecule is defined herein as a compound with a partition coefficient between water and octanol at pH 7.4 of less than 10.
  • the polar compound may possess a molecular weight from 100 Da to 100,000 Da. A preferred range is 300 Da to 30,000 Da.
  • polar molecule is uncharged.
  • polar compounds which are suitable for use in the compositions according to the invention, is provided by way of illustration and is not meant to be exclusive: cimetidine, ranitidine, sodium cromoglycate, bisphosphonates such as clodronate; angiotensin converting enzyme (ACE) inhibitors such as captopril and sampatrilat; polypeptide and protein-based drugs such as insulin, calcitonins, parathyroid hormone, fractions thereof or analogues thereof, luteinising hormone releasing hormones or analogues thereof such as nafarelin, buserelin, goserelin, growth hormone, growth hormone releasing factors or hormones, parathyroid hormone and parathyroid related hormones , colony stimulating factors , erythropoietin, somatostatin , ⁇ -, ⁇ - or ⁇ -interferon, proinsulin, glucagon
  • Combinations of any of the above therapeutic agents may be used.
  • compositions according to the invention include insulin, calcitonin, captopril, growth hormone, heparins, bisphosphonates, desmopressin, colony stimulating factors, ⁇ -interferon, ⁇ -interferon, erythropoietin, parathyroid hormone and parathyroid related hormones.
  • the compositions according to the invention may be administered orally, nasally, vaginally, buccally or rectally in a variety of pharmaceutically acceptable dosing forms, which will be familiar to those skilled in the art.
  • compositions for nasal administration may be administered as a solution via a nasal spray or as a powder via a nasal insufflator;
  • compositions for buccal administration may be administered via buccal patches or buccal tablets;
  • compositions for vaginal administration may be administered as gels or in the form of vaginal suppositories (pessaries);
  • compositions for rectal administration may be administered as suppositories.
  • the compositions according to the invention are administered orally, in the form of a tablet, a capsule or a pellet or a microsphere system, all of which may be formulated in accordance with techniques which are well known to those skilled in the art.
  • a process for the preparation of a composition according to the invention comprises mixing together a non-metabolisable bile salt analogue and a therapeutic agent in a pharmaceutically acceptable dosing form.
  • compositions according to the invention which may be administered orally may be adapted to deliver therapeutic agent to the small intestine or the colonic, especially the proximal colonic, region of the gastrointestinal tract.
  • a means is provided to prevent release of therapeutic agent until the formulation reaches the small intestine or colon.
  • Suitable systems include dosage forms coated with so-called enteric polymers that do not dissolve in the acidic conditions which exist in the stomach, but dissolve in the more alkaline conditions found in the small intestine of a mammal.
  • enteric coating materials include modified cellulose polymers and acrylic polymers, and in particular those sold under the trademark Eudragit ® .
  • a coated capsule system can be employed as described in international patent application No. PCT/GB94/ 12394, which provides a drug delivery composition for delivering a drug to the colonic region comprising a starch capsule containing the drug and wherein the starch capsule is provided with a coating such that the drug is predominantly released from the capsule in the colon and/or the terminal ileum.
  • Other colonic delivery systems which may be employed include those described in international patent application No. PCT/GB96/01933.
  • site specific delivery to the colon may also be achieved by using capsules or tablets that are coated in materials which are specifically degraded in the colonic environment by the action of microorganisms and/or the reductive environment found there.
  • materials include, but are not limited, to azo polymers and disulphide polymers (see, for example , international patent application No . PCT/BE91 /00006) , amy lose (see, Milojevic et al, Proc. Int. Symp. Contr. Rel. Bioact. Mater., 20, 288 (1993); Allwood et al, international patent application No. PCT/GB90/25373), calcium pectinate (see Rubenstein et al, Pharm.
  • compositions according to the invention may also be delivered to the colon using colon targeting systems including, but not limited to, the following systems:
  • the PulsincapTM System (WO 90/09168), which is an oral pulsatile delivery system, and may be configured to release its drug content at a predetermined time or place within the gastrointestinal tract.
  • the device essentially consists of an impermeable capsule body which contains the drug, sealed at the neck orifice with a hydrogel plug. A normal gelatin cap is then placed onto the body of the device. After ingestion, the gelatin cap dissolves allowing the plug to hydrate. At a predetermined, and controlled, time the swollen plug is ejected from the body of the device, thereby releasing the capsule contents and enabling the drug to be released.
  • the Time Clock Release SystemTM (Pozzi et al, APV Course on Pulsatile Drug Delivery, Komgswinter, May 20, 1992), which is a tablet system in which a tablet core containing the active drug is coated with a layer of pharmaceutical excipients. The excipients hydrate causing the surface layer to burst at a set time.
  • Another system which may be used is the Time Controlled Explosion System, as described in US 4871549 (incorporated herein by reference).
  • excipients may be employed in the compositions according to the invention.
  • further excipients which may be employed include diluents such as microcrystalline cellulose (e.g. Avicel ® , FMC), lactose, dicalcium phosphate and starch(es); disintegrants such as microcrystalline cellulose, starch(es) and cross-linked carboxymethylcellulose; lubricants such as magnesium stearate and stearic acid; granulating agents such as povidone; and release modifiers such as hydroxypropyl methylcellulose and hydroxypropyl cellulose. Suitable quantities of such excipients will depend upon the identity of the active ingredient(s) and particular dosing form which is used.
  • non-metabolisable bile salt analogues which may be employed in the compositions according to the invention will depend upon the mode of delivery which is employed.
  • the quantity of active ingredient in the formulation may be selected non-inventively by those skilled in the art in order to provide a concentration of between 0.5 and 1 % at the appropriate mucosal surface.
  • concentrations in a single unit oral dosage form weighing between 100 mg and 1.5 g, this will mean a quantity of between 10 and 90% w/w.
  • appropriate concentrations will be in the range 0.05 to 30% w/v of non-metabolisable bile salt analogue in the composition.
  • compositions accordmg to the invention have been found to have the advantage that they may be readily administered to the mucosal surfaces, are effective at a low dose, are minimally damaging to cells, and have no adverse effect on the normal physiology of the administered site.
  • the compositions according to the invention have the advantage that they permit the oral administration of drugs that are poorly absorbed from the gastrointestinal tract, or cannot be given orally by means of known techniques because of low bioavailability.
  • a method for the improved administration (in particular oral administration) of therapeutic agents which, in particular, are poorly absorbed via mucosal surfaces (in particular the gastrointestinal tract)
  • a composition according to the invention comprises administering a composition according to the invention to a patient, preferably a human patient.
  • compositions according to the invention will depend upon the agent which is used. However, it will be clear to the skilled person that doses of therapeutic agents can be readily determined non-inventively. For example estimates of dosage can be made from known mjectable products assuming that 10% of the dose is absorbed.
  • Insulin 20 i.u./kg
  • the invention is illustrated, but in no way limited, by the following examples.
  • the known enhancer material glycodeoxycholate was used as a positive control.
  • a formulation comprising insulin with no enhancer was used as a further control.
  • Figure 1 shows the plasma glucose concentration following colonic adrninistration to pigs of: (a) insulin in conjunction with the non- metabolisable bile salt analogue, cholylsarcosine; (b) insulin in conjunction with the deconjugated bile salt, glycodeoxycholic acid; and (c) control (no bile salt or analogue thereof).
  • Figure 2 shows the plasma glucose concentration following nasal administration to sheep of: (a) insulin in conjunction with the non- metabolisable bile salt analogue, cholylsarcosine; (b) insulin in conjunction wim the deconjugated bile salt, glycodeoxycholic acid; and (c) control (no bile salt or analogue thereof).
  • Formulations containing insulin together with added cholylsarcosine were evaluated in a pig model.
  • Sodium insulin (Proinsulin derived, Item code QD339G, Lot number 181 EM7, 28.1 IU/mg of pure insulin) was obtained from Eli Lilly and Company, Indianapolis, USA. The purity of the material, previously determined by spectrophotometry, was 88% . This is equivalent to 24.728 IU insulin/mg.
  • Glycodeoxycholic acid was obtained from Sigma, Poole, Dorset.
  • Avicel microcrystalline cellulose
  • Other dispersing agents which may be used include lactose and silica.
  • Cholylsarcosine was prepared according to the methods of J. Lillienau,
  • reaction mixture was decanted from the solid residue, washed with 0.5M NaOH (aq) , 0.5M HCl (aq) , water and brine, dried
  • the free acid prepared above did not easily dissolve in water or aqueous sodium hydroxide solution, but could be readily dissolved in aqueous
  • the components were weighed into plastic weighing boats, transferred to a glass bottle and mixed thoroughly by gentle shaking and men filled into a starch capsule (CapillTM; obtained from Capsugel, Switzerland).
  • the composition of the capsule blend was as follows, so as to provide a fill weight of about 200-220 mg:
  • the powder blends were then stored desiccated at 4°C until required.
  • the capsules were men administered to pigs.
  • the pigs had been surgically modified to insert a fistula into the terminal ileum, just above the ileo- caecal valve, and cannulated at the cephalic vein to allow repeated blood sampling.
  • Three pigs per group were used for the study, the mean weight ranged from 30-50 kg.
  • One capsule was administered to each pig, via me ileal fistula. Frequent blood samples were taken, plasma separated and analysed for glucose content. The insulin levels in the plasma were measured by a standard radioimmune assay.
  • Table 2 shows that the reduction in plasma glucose is accompanied by a corresponding rise in plasma insulin levels.
  • the maximum level was 23 mn 1 and a measured AUC of 599 mn/l .min.
  • the synthetic non-metabolisable bile salt derivative gives the same absorption enhancing effect as does a positive control in the form of a deconjugated bile salt, glycodeoxycholic acid.
  • a formulation of salmon calcitonin was prepared by mixing the drug with mannitol. The dose per capsule was 75 iu/kg. The cholylsarcosine was prepared as in Example 1 and was added at a concentration of 1.0 mg/kg. The mixture was filled into starch capsules (CapillTM available from Capsugel, Switzerland) and one capsule administered to each of five pigs. Each capsule was administered directly into the terminal ileum via a ileal fismla. Blood samples were collected via a venous access port. The blood was collected into 4 ml heparinized tubes, at 15 minutes prior to dosing and at 5, 15, 30, 45, 60, 75, 90, 120, 180, 240 and 300 minutes after dosing.
  • the plasma calcium levels were determined using a standard procedure.
  • Plasma calcium (% of basal concentration) Plasma calcium ⁇ % of basal concentration) Time before or Mean Std. Dev. Time before or Mean Std. Dev. after dosing (min) after dosing (min)
  • Insulin (161.76 mg; QD339G) was weighed into a 10 ml volumetric flask. The volume was made up to 10 ml with 14.65 mM phosphate buffer and me pH was checked.
  • bile salt formulations 25 mg of the bile salt required was dissolved in 2 ml of 14.65 mM phosphate buffer in a 5 ml volumetric flask. To this was added 2.5 ml of 400 IU/ml insulin stock solution. The contents of each flask were made up to 5 ml with 14.65 mM phosphate buffer.
  • the sheep were sedated with an intravenous dose of ketamine hydrochloride at 2.25 mg/kg. This was intended for animal restraint and also as a counter-measure against the animal sneezing during administration. The anaesthesia lasted for approximately 3 minutes.
  • a blueline umbilical cannula was inserted into the nostril of the sheep before delivery of the appropriate volume of solution (0.01 ml/kg).
  • Blood samples of 4.0 ml were collected from the cannulated jugular vein of the sheep at 20, 15 and 5 minutes prior to insulin administration and at 5, 10, 15, 20, 30, 40, 60, 75, 90, 120, 150, 180 and 240 minutes post- administration. Blood samples were mixed gently in 4 ml heparinised tubes (Lithium Heparin, 60 IU, Sarstedt, Leicester, U.K.), which were kept on crushed ice before plasma separation. The plasma was separated by centrifugation at 4°C and approximately 3200 rpm. Each plasma sample was divided into two aliquots, one for insulin analysis, and one for glucose analysis. The plasma was then stored at -20 °C awaiting insulin and glucose analysis.
  • 4 heparinised tubes Lithium Heparin, 60 IU, Sarstedt, Leicester, U.K.
  • Plasma glucose concentrations were analysed using the ERIS 6170 selective multitest analyser from Eppendorf (Olympus). The plasma glucose concentrations (percentage of basal value) are shown in Table 4 and Figure 2. TABLE 4
  • a formulation for the administration of low molecular weight heparin to man is prepared as follows:
  • the materials are blended in a V-blender and aliquots are filled into starch capsules (obtained from Capsugel AG, Switzerland) using a Bosch filling machine.
  • the formulation is sufficient for the preparation of 1,000 capsules.
  • the mean capsule fill weight is 370 mg.
  • the capsules are coated with a layer of polymers that will provide release in the colonic region of the gastrointestinal tract, according to the method provided in international patent application No. PCT/GB95/01458.
  • the method is as follows: Capsules are coated with a solution comprising 20 g of hydroxypropylmethylcellulose (Methocel ® ; ESM), 2 g of PEG 400 and 200 ml of water. Coating is performed using an Aeromatic STREA-1 fluid bed coater with bottom spray gun. The mean amount of HPMC applied to each capsule is 31 mg. 39 g of Eudragit ® L100 and 13 g of Eudragit S100 are dissolved in a mixture of 650 ml of isopropanol and 20 ml of water. 10 g of dibutyl phthalate is mixed into the Eudragit solution. Finally, 10 g of talc is carefully mixed into a paste using 100 ml of isopropanol plasticiser. The coating solution is applied using the Aeromatic STRE A- 1 fluid bed coater . The capsules coated with HPMC are coated with the Eudragit solution to a mean weight gain of 89 mg per capsule.
  • the dissolution performance of the capsules coated wim HPMC/Eudragit is tested using the USP Method 1 (baskets rotating at 50 rpm). For the first 2 h of the test, 0.1M HCl is used as the test medium. After 2 h, the test medium is changed to 0.05M phosphate buffer, pH 6.8. The dissolution vessels are visually inspected at regular intervals for the appearance of starch residue, which would indicate failure of the coating.
  • a formulation of sampatrilat (Pfizer Ltd., Kent, UK) was prepared by dissolving 1600 mg sampatrilat and 1600 mg cholylsarcosine in 50 ml of ultrapure water, with the pH adjusted to 7 with hydrochloric acid. 6.52 ml of the formulation (32 mg/ml sampatrilat) was administered directly into the terminal ileum, via an ileal fistula, in each of 6 pigs. The pigs were surgically prepared as described in Example 1. A simple solution of sampatrilat (32 mg/ml) was administered in the same pigs in a crossover design. Blood was collected in heparinised tubes 15 minutes prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96,

Abstract

L'invention concerne une composition à administrer sur la muqueuse d'un mammifère, comprenant un analogue de sel biliaire non métabolisable et un agent thérapeutique. L'analogue de sel biliaire non métabolisable est de préférence un conjugué d'origine artificielle d'acide cholique et d'un acide aminé, en particulier de la cholysarcosine. L'agent thérapeutique est de préférence une molécule polaire.
PCT/GB1997/001852 1996-07-06 1997-07-07 Composition en vue d'une meilleure assimilation par les muqueuses de medicaments a molecules polaires WO1998001159A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU34539/97A AU722724B2 (en) 1996-07-06 1997-07-07 Composition for enhanced uptake of polar drugs from mucosal surfaces
JP10504949A JP2000515503A (ja) 1996-07-06 1997-07-07 極性薬剤の粘膜表面からの摂取を増進するための組成物
EP97930663A EP0993305A2 (fr) 1996-07-06 1997-07-07 Composition en vue d'une meilleure assimilation par les muqueuses de medicaments a molecules polaires
GB9900050A GB2330533B (en) 1996-07-06 1997-07-07 Composition for enhanced uptake of polar drugs from mucosal surfaces
NO985956A NO985956D0 (no) 1996-07-06 1998-12-18 Blanding for forbedret opptak av polare medikamenter fra mukosale overflater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9614235.1A GB9614235D0 (en) 1996-07-06 1996-07-06 Composition for enhanced uptake of polar drugs from mucosal surfaces
GB9614235.1 1996-07-06

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WO1998001159A2 true WO1998001159A2 (fr) 1998-01-15
WO1998001159A3 WO1998001159A3 (fr) 1998-03-26

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JP (1) JP2000515503A (fr)
KR (1) KR20000023583A (fr)
AU (1) AU722724B2 (fr)
CA (1) CA2257563A1 (fr)
GB (2) GB9614235D0 (fr)
NO (1) NO985956D0 (fr)
WO (1) WO1998001159A2 (fr)

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WO2002009631A1 (fr) * 2000-07-27 2002-02-07 Umd, Inc. Administration de diphosphonates par voie vaginale
WO2004052405A1 (fr) * 2002-12-11 2004-06-24 Chong Kun Dang Pharmaceutical Corp. Formulations a administration par voie orale pour medicaments hydrophiles a faible capacite d'absorption
WO2005120467A2 (fr) * 2004-06-09 2005-12-22 Röhm Gmbh Forme posologique contenant l'agent actif cholylsarcosine
US7053076B2 (en) 2001-08-29 2006-05-30 Xenoport, Inc. Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs
US7153930B1 (en) 1999-07-30 2006-12-26 James Duncan Morrison Peptide transport
JP2012067115A (ja) * 1999-02-22 2012-04-05 Merrion Research Iii Ltd 促進剤を含む固体経口剤形
US8802114B2 (en) 2011-01-07 2014-08-12 Merrion Research Iii Limited Pharmaceutical compositions of iron for oral administration
US8828431B2 (en) 1999-02-22 2014-09-09 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
US8883203B2 (en) 2006-04-07 2014-11-11 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
US8999383B2 (en) 2008-05-07 2015-04-07 Merrion Research Iii Limited Compositions of GnRH related compounds and processes of preparation
US9089484B2 (en) 2010-03-26 2015-07-28 Merrion Research Iii Limited Pharmaceutical compositions of selective factor Xa inhibitors for oral administration
US9539302B2 (en) 2009-06-18 2017-01-10 Allergan, Inc. Safe desmopressin administration
CN108201531A (zh) * 2016-12-19 2018-06-26 湖南尔康湘药制药有限公司 高溶解性磺苄西林钠结肠靶向淀粉胶囊及其制备方法
US10265384B2 (en) 2015-01-29 2019-04-23 Novo Nordisk A/S Tablets comprising GLP-1 agonist and enteric coating

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US8828431B2 (en) 1999-02-22 2014-09-09 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
JP2012067115A (ja) * 1999-02-22 2012-04-05 Merrion Research Iii Ltd 促進剤を含む固体経口剤形
US7153930B1 (en) 1999-07-30 2006-12-26 James Duncan Morrison Peptide transport
WO2002009631A1 (fr) * 2000-07-27 2002-02-07 Umd, Inc. Administration de diphosphonates par voie vaginale
AU2001278920B2 (en) * 2000-07-27 2006-03-02 Umd, Inc. Vaginal delivery of bisphosphonates
US7727976B2 (en) 2001-08-29 2010-06-01 Xenoport, Inc. Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs
US7053076B2 (en) 2001-08-29 2006-05-30 Xenoport, Inc. Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs
WO2004052405A1 (fr) * 2002-12-11 2004-06-24 Chong Kun Dang Pharmaceutical Corp. Formulations a administration par voie orale pour medicaments hydrophiles a faible capacite d'absorption
WO2005120467A3 (fr) * 2004-06-09 2006-06-08 Roehm Gmbh Forme posologique contenant l'agent actif cholylsarcosine
WO2005120467A2 (fr) * 2004-06-09 2005-12-22 Röhm Gmbh Forme posologique contenant l'agent actif cholylsarcosine
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US9539302B2 (en) 2009-06-18 2017-01-10 Allergan, Inc. Safe desmopressin administration
US11419914B2 (en) 2009-06-18 2022-08-23 Serenity Pharmaceuticals Llc Safe desmopressin administration
US9089484B2 (en) 2010-03-26 2015-07-28 Merrion Research Iii Limited Pharmaceutical compositions of selective factor Xa inhibitors for oral administration
US8802114B2 (en) 2011-01-07 2014-08-12 Merrion Research Iii Limited Pharmaceutical compositions of iron for oral administration
US10265384B2 (en) 2015-01-29 2019-04-23 Novo Nordisk A/S Tablets comprising GLP-1 agonist and enteric coating
CN108201531A (zh) * 2016-12-19 2018-06-26 湖南尔康湘药制药有限公司 高溶解性磺苄西林钠结肠靶向淀粉胶囊及其制备方法

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CA2257563A1 (fr) 1998-01-15
GB9900050D0 (en) 1999-02-24
KR20000023583A (ko) 2000-04-25
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AU3453997A (en) 1998-02-02
JP2000515503A (ja) 2000-11-21
EP0993305A2 (fr) 2000-04-19
GB2330533A (en) 1999-04-28
GB2330533B (en) 2000-10-25
WO1998001159A3 (fr) 1998-03-26

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