WO1990012583A1 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques Download PDF

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Publication number
WO1990012583A1
WO1990012583A1 PCT/GB1990/000605 GB9000605W WO9012583A1 WO 1990012583 A1 WO1990012583 A1 WO 1990012583A1 GB 9000605 W GB9000605 W GB 9000605W WO 9012583 A1 WO9012583 A1 WO 9012583A1
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Prior art keywords
bile
composition
methanol
extract
pharmaceutically active
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PCT/GB1990/000605
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English (en)
Inventor
Michael John Story
Stephen John Barnwell
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Cortecs Limited
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Publication of WO1990012583A1 publication Critical patent/WO1990012583A1/fr

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    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/413—Gall bladder; Bile
    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid

Definitions

  • This invention relates to pharmaceutical compositions which: promote the solubility of drugs which are only poorly soluble in water; protect drugs when orally administered, from the hostile acidic and enzymatic environment of the stomach; protect the gastrointestinal mucosa from the harmful effects of such drugs as non-steroidal anti-inflammatory drugs (NSAIDs) ; increase the bioavailability of drugs, particularly those normally subject to significant hepatic first-pass metabolism; and/or contain generally inexpensive excipients.
  • the invention also relates to a method of formulating a pharmaceutically active agent into a pharmaceutical composition and to methods of administering drugs, as well as to the use of drugs and certain other ingredients in the preparation of pharmaceutically useful compositions.
  • 9 acids may be mono-, di- or tri-hydroxylated; they 0 always contain a 3-alpha hydroxyl group, whereas the 1 other hydroxyl groups, most commonly found at C g , C 7 or 2 c i2' ma Y k e positioned above (beta) or below (alpha) 3 the plane of the molecule. Many permutations of 4 hydroxyl configuration are possible, but certain 5 configurations are very much more common in nature than 6 others. In most animal species there is a recognised 7 pattern to the usual composition of the bile acids 8 found in the bile acid pool of individual animals. 9 0 Bile acids are synthesised .in vivo from cholesterol in 1 the liver by hydroxylation and other modifications.
  • Bile acids have various physiological functions. 1 Conjugated bile acids are secreted rapidly into the 2 bile by the liver, where they provide a means of 3 generating water flow by osmosis. It is in the duodenum that bile acids perform their major role as surfactants: they function to enhance the digestion and absorption of dietary lipids and lipid soluble vitamins. Bile acids also increase the action of pancreatic lipases.
  • a pharmaceutical composition comprising a pharmaceutically active agent, a bile salt and at least one additional component (other than water) of bile.
  • the additional component or one additional component,
  • the additional component, or one additional component may be a component of bile which is not a bile salt and which may be a biliary lipid such as a phospholipid.
  • Biliary lipids are believed to enhance micellisation and promote the lymphatic absorbtion of lipids and lipid-soluble vitamins. It is preferred to have more than one bile salt and one or more other biliary components (such as biliary lipids) present.
  • Native bile from most mammalian species contains large quantities of the phospholipid phosphatidylcholine.
  • the phosphatidylcholine found in bile is of a highly specific nature, quite different from that making up the structural elements of the membranes of hepatocytes and the cells surrounding the biliary tree.
  • biliary phosphatidylcholine The distinctive nature of biliary phosphatidylcholine is determined by its constituent fatty acids: palmitic acid (C:16) or pal itoleic acid (C16:l) being esterified to the snl-position, and either oleic acid (C18:l), linoleic acid (C18:2) or linolenic acid (C18:3) esterified to the sn2-position of the glycerol backbone of the phospholipid.
  • oleic acid C18:l
  • linoleic acid C18:2
  • linolenic acid C18:3
  • phosphatidylcholines which are derived from a metabolically compartmentalized synthetic pathway destined to produce phosphatidycholine for secretion from hepatocytes, is their ability to form expanded mixed micelles when combined with bile acids.
  • bile acids by acting as swelling amphiphiles they greatly enhance the ability of bile acids to act as surfactants.
  • bile acids have little tendency to solublize non-polar lipids such as cholesterol in the absence of phosphatidylcholine. This is important in vivo, where biliary phosphatidylcholine is believed to aid the incorporation of biliary cholesterol into bile acid mixed micelles.
  • biliary phosphatidylcholines are believed to enhance the icellization of lipids in the duodenum. This function may be carried out by intact phosphatidylcholine or equally as well by, and in conjunction with, its natural degradation products such as lysophosphatidylcholine and free fatty acids.
  • compositions in accordance with te present invention appear greatly to enhance solubilisation properties and/or drug delivery characteristics observed when compared to those in the studies using formulations containing purified bile acids.
  • the quantities of pure bile acids required to produce pharmacologically useful effects see Kimura et al, Chem. Pharm. Bull, 2J0 (10), 2468-72 (1979); Yamaguchi et al, Chem. Pharm. Bull, .34., (8), 3362-69 (1986)) as active excipients in a drug delivery system would preclude their incorporation in a conventional dose form.
  • the bile salt and additional biliary component may conveniently be provided by a naturally occurring mix of bile components including bile salts such as animal bile itself or an extract of bile.
  • the naturally occurring mix of bile components may be that naturally occurring, in any animal, preferably a domestic livestock animal, as the bile components would be available from the abattoir.
  • Suitable animal sources of bile components include oxen, pigs, sheep and other animals.
  • One suitable naturally occurring mixture of bile components may be produced simply by evaporating natural bile (for example ox bile) to dryness.
  • Ox bile extract is a dark yellow-greenish powder containing a variety of bile acids of which taurocholate is the most prevalent.
  • Bile acids themselves typically make up 50 to 60% of the dry weight of the powder, bile pigments 5 to 10%, and sulphated ash 10 to 20%; HPLC analysis indicates that for ox bile total bile aids account for 69% of dry weight, of which 17.5% is taurocholate, 14.1 % cholic acid, 7.4% taurochenodeoxycholate, 6.1% taurodeoxy- cholate, 1.7% taurolithocholate and 1% minor bile acids.
  • a crude (but in some circumstances suitable) naturally occurring mixture of bile components may be prepared simply by drying bile from the abattoir.
  • the bile may be subjected to four processing stages: evaporating, drying, milling and sieving.
  • crude bile may be first reduced to a concentrate. This may be done in one or more stages; in one embodiment of the invention, the crude bile is first reduced to a 50 to 60% concentrate, which is a paste which is then transferred to a further evaporation system to reduce it to a 70 to 80% concentrate.
  • the material may be finally dried to substantially complete dryness, for example in a vacuum oven over a period of about 4 days.
  • the resulting material has the consistency of brittle toffee and is hygroscopic in nature. This may be milled, for example 8
  • Milling can be carried out in a ball mill, for example for 2 hours, after which it may be sieved and packaged into appropriate containers.
  • a refined extract may be prepared by extraction with a simple organic solvent such as an alcohol (for example C ⁇ to C 4 alcohols) or a ketone (for example, acetone) .
  • a simple organic solvent such as an alcohol (for example C ⁇ to C 4 alcohols) or a ketone (for example, acetone) .
  • Methanol is a preferred extraction solvent.
  • the pharmaceutically active agent and the mixture of bile components are preferably intimately admixed together.
  • Such an intimate admixture may be produced by grinding a solid preparation of the pharmaceutically active a nt with solid bile salt mixture, crude or refined, as discussed above, to a very fine particle size, for example less than 100 microns or even less than 10 microns. It is however preferred to produce the intimate admixture by dissolving the pharmaceutically active agent and the bile salt mixture in a common solvent and evaporating the solvent off. It is particularly convenient if the same solvent is used for this purpose as is used to refine the bile components from a crude extract. As discussed above, alcoholic solvents such as methanol are particularly preferred.
  • formulatory excipients such as enteric coating materials, may be found to be soluble in the solvent of choice and, conversely, the solvent will often be chosen with the solubility of other excipients in mind.
  • the solvent can be evaporated off in a rotary evaporator, possibly under reduced pressure conditions, for small scale preparations or in a drum dryer on a larger scale.
  • compositions will be substantially non-aqueous, by which is meant containing less than 30, 20, 10 or even 5% water by weight.
  • compositions in accordance with the invention be produced in the form of pellets, as these can provide a suitable basis for further coating.
  • functional types of coating include: enteric coating to provide protection of the contents from ionic disturbances in high acid gastric media, as well as providing additional protection of the stomach from the drug; sustained release or controlled release coatings; and/or film coating for rapid release preparations.
  • Film coatings for rapid release are preferred, as bile salts are hygroscopic and uncoated pellets may be difficult to handle if left standing, as they may have a tendency to stick together to an unacceptable degree.
  • compositions in accordance with the invention which are pellets may be prepared by coating a solution (for example the preferred methanolic solution) of the pharmaceutical active ingredient and the bile salt mixture onto a suitable carrier such as granulated sugar crystals.
  • a suitable carrier such as granulated sugar crystals.
  • the crystals may be from 100 to 1000 microns in diameter, for example from 500 to 850 microns.
  • the coating can be conveniently achieved in a fluidised bed spray-coating machine, for example using the Wurster configuration, or in a semi-fluidised bed, for example using the bottom rotating plate con iguration, as in the ROTOR-GRANULATOR device manufactured by Glatt or the ROTO-PROCESSOR device manufactured by Aeromatic. (The words ROTOR-GRANULATOR and ROTO-PROCESSOR are trade marks. Top spraying is another suitable technique.
  • plasticisers and/or binding agents may be used when coating seed crystals or other matrix materials.
  • suitable plasticisers include polyvinyl pyrrolidone (povidone) , hydroxypropyl methyl cellulose (HPMC) , propylene glycol, polyethylene glycol or hydroxypropyl cellulose.
  • polyvinyl pyrrolidone povidone
  • HPMC hydroxypropyl methyl cellulose
  • propylene glycol polyethylene glycol or hydroxypropyl cellulose.
  • Lecithin is a suitable lipid solubilising agent, as are its naturally occurring breakdown products, lysolecithin and free fatty acids.
  • a particularly preferred excipient is a lymphatic absorbtion promoter.
  • lymphatic absorbtion promoter examples of such materials, which can be absorbed directly by enterocytes which surround the gastrointestinal tract, will be known to those skilled in the art.
  • long chain eg at least C 12 and preferably c i2 ⁇ c 24 ⁇ fatty acids and their mono-esters, such as with glycerol.
  • the acids and their esterified derivatives may be saturated or (mono- or poly-) unsaturated.
  • Lymphatic absorbtion promoters which have been found to perform well in the compositions of the present invention include oleic acid and glycerol mono-oleate.
  • lymphatic absorbtion promoter present in an amount of from 1 to 100% (w/w or v/w) based on the amount of active agent, preferably from 5 to 50% and typically from 10 to 35%.
  • compositions in accordance with the invention may be found to be relatively soluble in intestinal fluid, compared to the solubility in an acidic aqueous environment, such as is found in the stomach. This may be at least partly due to the formation of a dark gummy mass which is a complex formed by the components of the bile salt mixture in acidic conditions. Although the dark gummy mass does appear to dissolve in intestinal fluid, it takes longer to do so than if it had not been exposed to acid, and for this reason it is generally preferred that the mixture of the pharmaceutically active agent and the bile component mixture be protected from the acidic stomach environment. This can be achieved by enteric coating, as discussed above.
  • the mixture may be encapsulated in capsules such as hard gelatin capsules, but any convenient capsules can be used.
  • the present invention can be used to formulate practically any pharmaceutically active agent conveniently and relatively inexpensively.
  • the invention finds particular application in formulating those pharmaceutically active agents which need protection from the acidic environment of the stomach and/or those from which the gastrointestinal mucosa needs protection.
  • Non-steroidal anti-inflammatory drugs are examples of such pharmaceutically active agents.
  • NSAIDs can be categorised conveniently into six structural groups.
  • salicylic acids and esters including aspirin, benorylate, aloxiprin, salsalate and choline magnesium trisalicylate.
  • propionic acid derivatives including ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, benoxaprofen and suprofen.
  • oxicams including piroxicam.
  • acetic acid derivatives can be split into two subclasses.
  • Phenylacetic acids include diclofenac and fenclofenac; carbo- and heterocyclic acetic acids include indoles such as indomethacin and sulindac and pyrroles such as tol etin.
  • pyrazolones which include oxyphenbutazone , phenylbutazone, feprazone and azapropazone.
  • the fenamic acid derivatives include flufenamic acid and mefenamic acid.
  • NSAIDs there are some which can be formulated particularly satisfactorily by means of the present invention, particularly when using methanol as a solvent for both the NSAID and the bile salt mixture. These are: indomethacin, diclofenac, sulindac, naproxen, piroxicam and mefanamic acid.
  • the present invention is not only useful for formulating NSAIDs.
  • it is useful for formulating pharmaceutically active agents which are subject to significant hepatic first-pass clearance, as will now be discussed.
  • the implications of the first-pass effect are therefore that wide variations in systemic blood levels of a compound can be obtained from the same orally administered dose leading to the possibility of increased incidence of side-effects or toxic reaction if the dose is too high, or even to a failure to control symptoms at all if a very extensive first-pass effect is present.
  • compositions in accordance with the invention cause redirection from the portal blood to the lymphatic route of absorption from the gastrointestinal tract. That the lymphatic system avoids the liver is a function of its anatomy in that the major lymphatic vessels, into which the gastrointestinal lymph system drains, come together in the thoracic duct, which then empties directly into the systemic circulation.
  • the pharmaceutically active agent is one which is normally subject to significant hepatic IS "
  • Such pharmaceutically active agents include, but are not restricted to, a number of cardiovascular agents.
  • Cardiovascular agents which may in particular be formulated by means of the present invention include propranolol, etoprolol, verapamil, nifedipine and diltiazem, either in the form of the free compound or, where appropriate, as a salt. Atenolol and nadolol are not subjected to first-pass metabolism but may nevertheless be formulated with advantage in accordance with the invention, for example in order to increase their generally poor absorbtion.
  • a process for the preparation of a pharmaceutical composition comprising admixing a pharmaceutically active agent, a bile salt and at least one additional component (other than water) of bile.
  • the bile salt and the additional component(s) can be a premixture, such as by being part of a naturally occurring mixture of bile components, before the pharmaceutically active agent is mixed.
  • the invention can be used in a method of chemotherapeutic treatment of a human or animal patient, the method comprising the lb
  • the invention also encompasses the use of a pharmaceutically active agent, a bile salt and at least one additional component (other than water) of bile (which may be provided by a naturally occurring mixture of bile components) in the preparation of a pharmaceutical composition.
  • Crude bile, collected from the abattoir, is pumped into a stainless steel tank and heated by steam coils and reduced to a 50 to 60% concentrate.
  • the resulting paste is transferred to an open steam jacketed evaporating pan system and reduced further to a 70 to 80% concentrate.
  • Final drying of the material took place in a vacuum oven over a period of about 4 days.
  • the resulting material had the consistency of brittle toffee and was hygroscopic in nature.
  • the solid material was milled into a powder in a ball mill for 2 hours and then sieved and packaged into fibre-board drums lined with polythene bags.
  • Pig bile powder which is light brown in colour, was prepared in a similar fashion to ox bile powder, as described in Preparation 1.
  • Examples 28 to 46 illustrate the possible use of an alternative animal source of biliary material for use in pharmaceutical preparations .
  • Pig bile has a different bile acid composition to ox bile since it contains mainly hyocholic acid instead of cholic acid.
  • Example 1 A dense crystalline product was obtained which was slowly soluble in pH 6.8 phosphate buffer solution.
  • Example 2 4.0g of crude ox bile extract, as prepared in Example 1, was dissolved in 25g methanol and the solution was boiled for 30 minutes following cooling and filtering through a WHATMAN No. 4 filter. 4.0g sulindac and 0.5g povidone were dissolved in the filtrate which was taken up to 100ml with methanol. The solution was evaporated to dryness as described in Example 1 and fine soft crystals were produced which dissolved rapidly and completely in pH 6.8 buffer solution.
  • the resulting pellets were sieved between 500 and 1400 microns to remove fines and oversize, and they were then sprayed with a film coat consisting of 25g of hydroxypropyl methylcellulose dissolved in 300ml methanol.
  • the resulting pellets were essentially spherical with a smooth glossy surface. They had a bulk density of 0.82g/ml and a potency of 126mg indomethacin per gram. They readily dissolved in pH 6.8 buffer solution.
  • These pellets were filled into size "1" hard gelatin capsules with a mean fill weight of 398mg, giving a potency of 50mg indomethacin per capsule.
  • Crude ox bile extract (Preparation 1) 150 Indomethacin 75 Povidone 20 Sucrose (500-800 micron) 115
  • This formulation allows for a 40mg sustained release coat.
  • 300g of crude ox bile extract was dissolved in lOOOg methanol. The solution was boiled for 30 minutes, left to stand overnight, and then pressure filtered. 300g indomethacin and 60g povidone were dissolved in the filtrate which had to be made up to 7.2 litres with methanol so as to achieve full dissolution of the indomethacin. The resulting solution was sprayed onto 340g sucrose (500-850 micron) in a UNI-GLATT fluidized bed as described in Example 9. The resulting pellets dissolved satisfactorily in pH 6.8 phosphate buffer solution.
  • Example 10A allow a higher solubility of indomethacin in the spraying solution, and hence a reduced volume of coating solution to be sprayed.
  • the solution was boiled for 30 minutes, allowed to stand overnight and pressure filtered.
  • the potency of the pellets is such that, after adding a film coating or controlled release coating, lOOmg of diclofenac will be filled into a Size "1" gelatin capsule.
  • Pellets of sulindac were prepared according to the methods described for Example 9, using the following proportions of materials, but excluding the final film coat:
  • the resulting pellets after having a final film coating, could be filled in to Size "1" hard gelatin capsules to give a potency per capsule of lOOmg sulindac. If 200mg capsules are required, the above coating represents one-quarter of the coating solution requirements. Splitting of the batch into two sub-batches would be necessary when using the . UNI-GLATT fluidised bed after half the total coating solution has been applied.
  • the resulting pellets had a bulk density of 0.86 g/ml and a potency such that 20mg piroxicam could be achieved when the pellets were filled into Size "2" capsules.
  • the pellets readily dissolve in pH 6.8 phosphate buffer solution.
  • Example 15 The procedure described in Example 15 was followed, using the following ingredients: Crude ox bile extract powder 5.0g Methanol 15.Og Propranolol base l.Og
  • Example 15 The procedure described in Example 15 was used , with the following ingredients :
  • Example 15 The procedure outlined in Example 15 was used, with the following ingredients:
  • Example 15 The procedure outlined in Example 15 was used, with the following ingredients: 2 ⁇
  • Example 15 The procedure outlined in Example 15 was used, with the following ingredients:
  • Example 15 The procedure outlined in Example 15 was used, with the following ingredients:
  • Pig bile extract powder 5.0g Methanol 15.Og Ketoprofen l.Og
  • Pig bile extract 5.0g Methanol 15.Og Diclofenac l.Og
  • Pig bile extract 5 Og Methanol 15.Og Sulindac l.Og
  • Pig bile extract powder 5.0g Methanol 15.Og Indomethacin 1.Og
  • Pig bile extract 5.0g Methanol 15.Og Atenolol l.Og
  • Pig bile extract 5.0g Methanol 15.Og Diltiazem HCl l.Og
  • Pig bile extract 5.0g Methanol 15.Og Diltiazem base l.Og
  • Pig bile extract 5.Og Methanol 15.Og Propranolol HC1 l.Og
  • Pig bile extract 5.0g Methanol 15.Og Propranolol base l.Og
  • the aim of the simple dissolution study was to obtain a basic idea of how each formulation would behave under the varying pH conditions experienced in the stomach and duodenum.
  • Three separate solutions were used, U.S.P. intestinal fluid simulated pH 7.4 (no enzymes), U.S. . intestinal fluid simulated pH 1.27 (no enzymes), and distilled water.
  • Tests were carried out in small glass bottles, containing either 120mg or 60mg of each formulation depending upon whether the 5:1 or 2:1 excipient to active ratio material was used. Separate dissolution studies were carried out at 25°C and 37°C using 10ml of each test solution.
  • Verapamil (5:1) formed an emulsion but remained in solution, while nifedipine (5:1) remained in solution for a few minutes before forming a precipitate and may therefore require higher ratios of ox bile extract.
  • Atenolol (5:1) ii) Diltiazem (5:1) iii) Metoprolol (5:1) iv) Atenolol (2:1) v) Metoprolol (2:1)
  • Atenolol (5:1) ii) Diltiazem (5:1) iii) Propranolol base (5:1) iv) Diltiazem (2:1) v) Metoprolol (2:1)
  • Formulation A Ox bile extract and propranolol base, in the ratio 5:1 by weight as prepared in Example 16.
  • the total dose was 12mg/kg body weight (equivalent dose of propranolol 2mg/kg) .
  • Formulation B Ox bile extract and propranolol hydrochloride, in the ratio 5:1 by weight as prepared in Example 15.
  • the total dose was 12mg/kg body weight (equivalent dose of propranolol 2mg/kg) .
  • Lymph and blood samples were taken 5 minutes after administration of the test solution and then at 15 minute intervals for 240 minutes. All samples were collected in heparin to prevent coagulation. Blood samples were centrifuged to remove red blood cells and stored at 4°C. Plasma samples were extracted by passing plasma through VAC-ELUTE mini-C 18 columns. Propranolol was eluted from the columns with a mixture of acetonitrile and 0.1M hydrochloric acid (1:1 v/v) , analysed by high pressure liquid chromatography and quantified by comparison with authentic standards using fluorescence detection.
  • Pig D in addition to Pig B, received formulation B because of hepatic portal vein and lymphatic catheter failure in Pig B.
  • the portal vein cannula was defective throughout the study, whereas the lymphatic cannula became obstructed about 45 minutes after administration of the test solution.
  • lymph flow for each pig was recorded before and after administration of the test solutions.
  • levels of propranolol found in the lymph samples collected were measured.
  • the cumulative amount of propranolol secretion in the lymph was derived from the lymph flow and the rate of lymphatic secretion of propranolol. Table 1 below shows the total amount of propranolol secreted into the lymph after the time indicated.
  • This example concerns the combination of bile acids , propranolol HCl and the monogly ⁇ eride glycerol mono-oleate.
  • composition of the enteric coating solution was:
  • This example concerns the use of the unsaturated fatty acid oleic acid together with ox bile extract and propranolol HCl.
  • the components were mixed with and recrystallized from excess (800%) alcoholic solution.
  • the resulting green crystalline solid was packed into hard gelatin capsules and sealed using a LICAPS Test Kit supplied by CAPSUGEL.
  • the capsules were subsequently enteric coated using hydroxypropyl methylcellulose phthalate (HP55) .
  • the enteric coating solution contained:
  • This clinical trial was a three way cross-over study using nine subjects.
  • the dose used in each case was 80mg of propranolol in the form of two separate formulations in accordance with the invention: D179, produced in Example 51 (Treatment A) and D180, produced in Example 50 (Treatment B) ; or Inderal (ICI) (Treatment C) .
  • Subjects were fitted with a venous catheter and an initial blood sample taken. Further blood samples were taken at lh, 2h, 3h, 4h, 5h, 6h, 8h, 12h and 24h.
  • Plasma samples were collected into EDTA Vacutainers (trade mark) and plasma retained after centrifugation for 15 minutes at 2500 rpm to remove red blood cells. Plasma samples were immediately frozen and then stored at -20°C until analysed using the HPLC method described previously.
  • the plasma levels of propranolol determined in each sample col lected from the subj ects during each treatment were recorded against time .
  • a comparison of the area under the curve (AUC) achieved with each treatment is listed in Table 1.
  • the mean increase in AUC of Treatment B over control was 35% while the mean increase using Treatment A was 20%.
  • a further comparison between treatments was made on the basis of peak plasma concentrations (See Table 2) .
  • the mean increase in peak plasma propranolol levels was 56% using Treatment B and 37% using Treatment A compared to control Treatment C.

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Abstract

Des agents actifs pharmacologiquement sont formés d'un sel biliaire et d'au moins un composant additionnel de la bile. Le sel biliaire et le composant additionnel peuvent provenir d'un mélange de bile existant naturellement, comme c'est le cas d'un extrait méthanolique de bile animale (d'origine bovine, par exemple). Un activateur d'absorption lymphatique comme l'acide oléique ou le glycérol mono-oléate peut également être présent. Les compositions pharmaceutiques répondant à cette formulation peuvent bénéficier d'une biodisponibilité accrue, plus particulièrement lorsque le métabolisme de premier passage hépatique est réduit. Les médicaments anti-inflammatoires non-stéroïdiens et les agents cardiovasculaires sont tout particulièrement adaptés à la formulation au moyen de cette invention.
PCT/GB1990/000605 1989-04-20 1990-04-20 Compositions pharmaceutiques WO1990012583A1 (fr)

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GB898909022A GB8909022D0 (en) 1989-04-20 1989-04-20 Pharmaceutical compositions

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993025192A1 (fr) * 1992-06-12 1993-12-23 Cortecs Limited Compositions pharmaceutiques contenant des anti-inflammatoires non steroidiens et des acides biliaires
US5391377A (en) * 1990-10-19 1995-02-21 Cortecs Limited Biphasic release formations for lipophilic acids
WO1995016438A1 (fr) * 1993-12-13 1995-06-22 Cortecs Limited Formulations de gelule a liberation biphasee
US5567592A (en) * 1994-02-02 1996-10-22 Regents Of The University Of California Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal
US5665386A (en) * 1995-06-07 1997-09-09 Avmax, Inc. Use of essential oils to increase bioavailability of oral pharmaceutical compounds
US5716928A (en) * 1995-06-07 1998-02-10 Avmax, Inc. Use of essential oils to increase bioavailability of oral pharmaceutical compounds
US5853748A (en) * 1994-08-31 1998-12-29 Cortecs (Uk) Limited Pharmaceutical compositions
US5916566A (en) * 1995-06-07 1999-06-29 Avmax, Inc. Use of benzoin gum to inhibit P-glycoprotein-mediated resistance of pharmaceutical compounds
US6551623B1 (en) 1993-09-09 2003-04-22 Lorus Therapeutics Inc. Immunomodulating compositions from bile
US6596319B2 (en) 1995-03-16 2003-07-22 Lorus Therapeutics Inc. Immunomodulating compositions for treatment of immune system disorders
US7622130B2 (en) 2004-05-19 2009-11-24 Los Angeles Biomedical Research Institute at Harbor UCLA-Medical Center Methods and compositions for the non-surgical removal of fat
US7754230B2 (en) 2004-05-19 2010-07-13 The Regents Of The University Of California Methods and related compositions for reduction of fat
US8846066B2 (en) 2004-05-19 2014-09-30 The Regents Of The University Of California Methods and related compositions for reduction of fat and skin tightening
US20150064794A1 (en) * 2012-03-30 2015-03-05 Phares Pharmaceutical Research N.V. Biorelevant compositions
US9186364B2 (en) 2009-03-03 2015-11-17 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US9737549B2 (en) 2011-04-05 2017-08-22 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
WO2020236802A1 (fr) * 2019-05-20 2020-11-26 Poviva Corp. Compositions comprenant des agents biologiquement actifs et des sels biliaires
US11344561B2 (en) 2011-02-18 2022-05-31 Allergan Sales, Llc Treatment of submental fat

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US5391377A (en) * 1990-10-19 1995-02-21 Cortecs Limited Biphasic release formations for lipophilic acids
AU671285B2 (en) * 1992-06-12 1996-08-22 Cortecs Limited Pharmaceutical compositions containing NSAID and bile acids
WO1993025192A1 (fr) * 1992-06-12 1993-12-23 Cortecs Limited Compositions pharmaceutiques contenant des anti-inflammatoires non steroidiens et des acides biliaires
US5942248A (en) * 1992-06-12 1999-08-24 Cortecs Limited Pharmaceutical composition containing a low detergent effect bile salt and an active compound that undergoes biliary excretion and/or enterohepatic recycling
US6551623B1 (en) 1993-09-09 2003-04-22 Lorus Therapeutics Inc. Immunomodulating compositions from bile
WO1995016438A1 (fr) * 1993-12-13 1995-06-22 Cortecs Limited Formulations de gelule a liberation biphasee
US6153218A (en) * 1993-12-13 2000-11-28 Provalis Uk Limited Biphasic capsule formulation
US6004927A (en) * 1994-02-02 1999-12-21 Regents Of The University Of California Method for increasing bioavailability of orally administered pharmaceutical compounds
US5567592A (en) * 1994-02-02 1996-10-22 Regents Of The University Of California Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal
US6028054A (en) * 1994-02-02 2000-02-22 The Regents Of The University Of California Method for increasing bioavailability of oral pharmaceutical compositions
US5853748A (en) * 1994-08-31 1998-12-29 Cortecs (Uk) Limited Pharmaceutical compositions
US6596319B2 (en) 1995-03-16 2003-07-22 Lorus Therapeutics Inc. Immunomodulating compositions for treatment of immune system disorders
US5916566A (en) * 1995-06-07 1999-06-29 Avmax, Inc. Use of benzoin gum to inhibit P-glycoprotein-mediated resistance of pharmaceutical compounds
US6121234A (en) * 1995-06-07 2000-09-19 Avmax, Inc. Use of essential oils to increase bioavailability of orally administered pharmaceutical compounds
US5716928A (en) * 1995-06-07 1998-02-10 Avmax, Inc. Use of essential oils to increase bioavailability of oral pharmaceutical compounds
US5665386A (en) * 1995-06-07 1997-09-09 Avmax, Inc. Use of essential oils to increase bioavailability of oral pharmaceutical compounds
US10058561B2 (en) 2004-05-19 2018-08-28 The Regents Of The University Of California Methods and related compositions for reduction of fat and skin tightening
US7754230B2 (en) 2004-05-19 2010-07-13 The Regents Of The University Of California Methods and related compositions for reduction of fat
US8846066B2 (en) 2004-05-19 2014-09-30 The Regents Of The University Of California Methods and related compositions for reduction of fat and skin tightening
US7622130B2 (en) 2004-05-19 2009-11-24 Los Angeles Biomedical Research Institute at Harbor UCLA-Medical Center Methods and compositions for the non-surgical removal of fat
US9186364B2 (en) 2009-03-03 2015-11-17 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US9724356B2 (en) 2009-03-03 2017-08-08 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US10071105B2 (en) 2009-03-03 2018-09-11 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US10500214B2 (en) 2009-03-03 2019-12-10 Allergan Sales, Llc Formulations of deoxycholic acid and salts thereof
US11179404B2 (en) 2009-03-03 2021-11-23 Allergan Sales, Llc Formulations of deoxycholic acid and salts thereof
US11344561B2 (en) 2011-02-18 2022-05-31 Allergan Sales, Llc Treatment of submental fat
US9737549B2 (en) 2011-04-05 2017-08-22 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US10946030B2 (en) 2011-04-05 2021-03-16 Allergan Sales, Llc Formulations of deoxycholic acid and salts thereof
US20150064794A1 (en) * 2012-03-30 2015-03-05 Phares Pharmaceutical Research N.V. Biorelevant compositions
WO2020236802A1 (fr) * 2019-05-20 2020-11-26 Poviva Corp. Compositions comprenant des agents biologiquement actifs et des sels biliaires

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