WO1996006635A1 - Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound - Google Patents
Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound Download PDFInfo
- Publication number
- WO1996006635A1 WO1996006635A1 PCT/GB1995/002015 GB9502015W WO9606635A1 WO 1996006635 A1 WO1996006635 A1 WO 1996006635A1 GB 9502015 W GB9502015 W GB 9502015W WO 9606635 A1 WO9606635 A1 WO 9606635A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- salt
- bile
- acid
- bicarbonate
- Prior art date
Links
Classifications
-
- 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
-
- 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
- A61K38/23—Calcitonins
-
- 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
- A61K38/28—Insulins
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Definitions
- the present invention relates to pharmaceutical compositions and, in particular to orally administrable 5 compositions of proteins, peptides and other active molecules which are not generally easily absorbed from the gastrointestinal tract.
- Such route of administration which may be by means of syrup, elixir, tablets, capsules, granules, powders or any other convenient formulation, is 5 generally simple and straightforward and is frequently the least inconvenient or unpleasant route of administration from the patient's point of view.
- enteric coated formulations which are protected from the acid environment of the stomach but even so, relatively large molecules such as peptides and proteins are poorly absorbed by the small intestine.
- the bile salts improve absorption of biologically active materials because of their action on the cell membranes of epithelial cells.
- the cell membranes become more permeable, possibly because the detergent action of the bile salts removes lipids from cell membranes and causes them to become more fluid.
- One theory is that the increased permeability of the cell membrane enables the active materials to pass through the epithelial cells.
- the cytoskeletal structure of the epithelial cells is modified as a result of changes in cytoplasmic levels of sodium or calcium arising from increased membrane permeability. This would result in alteration of the integrity of the tight junctions so that there are gaps between the cells through which the active materials can pass. Whatever the mechanism, it seems clear that the increased absorption arises from the increased permeability of the cell membranes.
- bile salts have always been a problem because they have unacceptably high toxicity when used in the amounts required for them to exert their bioavailability improving effect. It has been suggested that the reason for this is that the increase in the permeability of epithelial cells brought into contact with bile salts results in an increased flow of ions into and out of the cell. In order for cells to remain viable, the intracellular concentrations of ions such as sodium, potassium and calcium ions must remain within relatively narrow ranges and it may be that the increased ion flow caused by the presence of bile salts causes the intracellular ion concentrations to move outside the ranges within which cells are viable. Thus, the problem with the use of bile salts as absorption enhancers is that they have always been considered to have an unacceptably low therapeutic index. Throughout the present specification the term "therapeutic index" has been used to refer to the ratio
- a pharmaceutical and/or veterinary composition comprising a biologically active material, a bile acid or salt and an agent adapted to adjust the pH of the gut to a pH value of from 7.5 to 9.
- WO-A-9012583 teaches a pharmaceutical composition comprising an active agent, a bile salt and an additional component of bile.
- additional bile salts and biliary lipids, in particular phospholipids are additional bile salts and biliary lipids, in particular phospholipids.
- bicarbonate a preferred pH adjusting agent useful in the invention
- bicarbonate salts were not envisaged as being useful components of a composition containing a bile salt and a pharmaceutically active agent.
- bicarbonate or other pH adjusting agents in effectively increasing the therapeutic index of bile salts was certainly not disclosed in this prior document.
- bile salt and bile acid are used inter ⁇ changeably because whether the salt or its conjugate acid is present will depend on the pH of the surrounding environment.
- solid formulations according to the invention may contain either a bile salt or a bile acid.
- the compositions as administered will often be of a pH such that if an acid is used, it will be converted into the salt form when in solution.
- a bile salt is used in the compositions of the present invention, it is preferred that there is a soluble counter-ion present such as sodium or potassium. It is also possible to use, for example, an ammonium ion but this is less preferred.
- Bile salts are naturally occurring surfactants. They are a group of compounds with a common "backbone" structure based on cholanic acid found in all mammals and higher vegetables. Bile salts may be mono-, di- or tri- hydroxylated; they always contain a 3 ⁇ -hydroxyl group whereas the other hydroxyl groups, most commonly found at
- C 6 , C 7 or C 12 may be positioned either above (?) or below
- amphiphilic polyhydric sterols bearing carboxyl groups as part of the primary side chain.
- the most common examples of these in mammals result from cholesterol metabolism and are found in the bile and, in derivatised form, throughout the intestine.
- the term may also apply to synthetic analogues of naturally occurring bile salts which display similar biological effects, or to microbially derived molecules such as fusidic acid and its derivatives.
- the bile salt may be either unconjugated or conjugated.
- unconjugated refers to a bile salt in which the primary side chain has a single carboxyl group which is at the terminal position and which is unsubstituted.
- unconjugated bile salts include cholate, ursodeoxycholate, chenodeoxycholate and deoxycholate.
- a conjugated bile salt is one in which the primary side chain has a carboxyl group which is substituted. Often the substituent will be an amino acid derivative which is linked via its nitrogen atom to the carboxyl group of the bile salt.
- conjugated bile salts include taurocholate, glycocholate, taurodeoxycholate and glycodeoxycholate.
- the quantity of bile acid contained in a single dose of the formulation will vary depending on the particular bile acid chosen and the rate and extent to which that bile acid dissolves in the aqueous fluid contained in the intestine.
- chenodeoxycholic acid and most other bile acids, this is likely to be within the range 10 mg to 1 g, preferably between 20 mg to 200 mg, and most preferably 30 mg to 100 mg.
- deoxycholic acid the maximum will generally not exceed 500 mg, in view of its slightly greater activity.
- compositions of the invention comprise an agent adapted to adjust the pH of the gut to a pH of from 7.5 to 9.
- the agent is "adapted" to adjust the pH either by its chemical nature or by the amount in which it is present or, usually, both.
- the optimum pH to which the gut is adjusted is in the range 7.8 to 8.3.
- the pH adjusting agent While simple agents adapted to adjust the pH of the gut into the range specified above may be successfully used in the invention, it is preferred that the pH adjusting agent also has the capability of buffering the gut to a pH within the stated range. This can give a more long lasting effect, which may be desired in many circumstances. Also, a buffer has a greater capacity to accommodate the patient-to-patient variability of endogenous gut pH, as well as the viability of gut pH seen over time in any individual patient; in particular, a buffer can act as a safety barrier to ensure that the pH of the patient's gut is not radically changed outside safe limits during the administration of formulations of the invention.
- bicarbonate is referred to by way of illustration of the principles involved, but the same principles apply equally to other agents capable of exerting a similar effect on intestinal pH.
- the amount of agent necessary to adjust the pH to within the range contemplated is difficult to determine directly because the intestinal pH can vary between 5 to 7, and its aqueous content can vary, as can its intrinsic buffering capacity, which acts to maintain a low pH. Consequently considerations aimed at determining the appropriate quantity of agent controlling pH need to take into account a "worst-case" scenario.
- An indication may be obtained by observing the pH achieved upon adding a potential pH-adjusting agent to a 50 mM solution of MES
- Concentrations useful in the invention are those that result in the adjustment of the pH to within the range 7.5 to 9; preferred concentrations result in an adjustment to within the range 7.8 to 8.3. (For reasons which will be explained below, the weight amount of pH adjusting agent is generally that which produces the desired concentration in 10 ml liquid.) Values for pH attained are shown below for the preferred bicarbonate at different concentrations, dispersed in distilled water or in MES.
- the minimum amount of bicarbonate useful in the invention in most cases is about 0.045 M, which yields a pH in the gut of about 7.5. This translates to about 40 mg sodium bicarbonate, for a 10 ml dispersion volume.
- a saturated solution of bicarbonate in water has a pH of 8.01. From this it will be seen that, regardless of the concentration of preferred bicarbonate administered, the pH will not rise above 9.0. Under certain circumstances, it may be that a concentrated solution of a salt of the bile acid itself has sufficient capacity to raise the pH to the appropriate level, although the effect will not be as strong as for the preferred bicarbonate. Hence, it is possible, although not always desirable, for the pH adjusting agent to be the bile salt itself, or a different bile salt. The greater the buffering capacity of the composition, the longer that the pH specified above will prevail in the gut and hence the longer the benefits of the invention will prevail.
- compositions of the present invention are capable of effectively increasing the therapeutic index of the bile salt present in the composition.
- the beneficial effect is present both for conjugated and unconjugated bile salts but the action of the carbonate or bicarbonate ions on conjugated bile salts is slightly different from the action on unconjugated bile salts.
- conjugated bile salts With conjugated bile salts, the presence of sufficient bicarbonate or carbonate has the effect of increasing cell membrane permeability during the exposure of cells to a given amount of bile salt without affecting cell viability. This means that the amount of bile salt needed to obtain a given increase in permeability is reduced and so the permeability of the cells can be increased without increasing the adverse effects of the bile salt.
- the amount of pH adjusting agent will be such that when a unit dose of the composition is dispersed in the amount of liquid which would be present in the length of gut over which the composition would be distributed on administration to a patient, the pH adjusting agent concentration is at least about 0.01 M, although a more precise estimate can be had by reference to the MES buffer test referred to above.
- the concentration of bicarbonate or carbonate will be greater than 0.05 M and it is most preferred that the concentration is at least about 0.1 M although higher concentrations, for example up to 1 M can be used.
- a typical length of the small intestine over which a composition of the present invention would be likely to be distributed would be 30 cm and the amount of liquid which would be present in that length of gut would be likely to be about 10 ml.
- 30 cm as a suitable length is arbitrary and the invention is not intended to be limited to compositions which are distributed over this distance in the small intestine.
- a sustained release composition may disperse much more slowly and would therefore be distributed over a much longer length of the small intestine.
- compositions are familiar to those skilled in the art who would easily be able to determine the most suitable type of composition to meet a particular therapeutic requiremen . If the composition were adapted to be dispersed over a longer or shorter length of the small intestine then the amount of water in which a unit dose of the composition would be dispersed to give a particular concentration would be accordingly greater or smaller.
- the unit dose which is dispersed in water to determine the minimum amount of bicarbonate required will be the dose which would be administered to a patient at any one time. For liquid formulations, this will be a predetermined amount calculated by a physician or pharmacist. For solid formulations, such as tablets or capsules, the unit dose will generally be a single tablet or capsule. However, there may be circumstances in which a patient would be required to take more than one tablet or capsule, for example if large doses of active substance are needed, and in this case the amount of bicarbonate may be divided between two or more tablets or capsules.
- bile salts start to be converted to their conjugate acid at pH of about 6.8 or below and the acid form is insoluble in aqueous solutions. Since the buffering agent has the effect of buffering the compositions of the invention to a pH of about 7.5 or above, the solubilised bile salt will be present rather than the insoluble bile acid. A solubilised bile salt will be able to act on the epithelial cells when in solution, whereas this may not be possible in the solid acid form.
- a chelator of calcium ions such as a salt of a di- or tri-carboxylic acid (for example a citrate salt) , ethylenediaminetetraacetic acid (EDTA) , ethylene glycol bis- (/3-aminoethylether) N,N,N' ,N' - tetraacetic acid (EGTA) or phytate and other polyphosphorus compounds.
- a chelator of calcium ions such as a salt of a di- or tri-carboxylic acid (for example a citrate salt) , ethylenediaminetetraacetic acid (EDTA) , ethylene glycol bis- (/3-aminoethylether) N,N,N' ,N' - tetraacetic acid (EGTA) or phytate and other polyphosphorus compounds.
- citrate salt When a citrate salt is used as the calcium ion chelator, it is greatly preferred that it should be in a form soluble in water.
- the most suitable salts are therefore sodium and potassium citrate although in some circumstances ammonium citrate may also be used.
- biologically active material includes, in particular, pharmaceutically active proteinaceous materials.
- the proteinaceous material may be a pure protein, or it may comprise protein, in the way that a glycoprotein comprises both protein and sugar residues.
- the material may be useful in human or veterinary medicine, either by way of treatment or prophylaxis of diseases or their symptoms, or may be useful cosmetically or diagnostically.
- proteinaceous biological material which can be provided as orally or rectally administrable formulations in accordance with this invention include protein or peptide hormones or hormone releasing factors such as insulin, calcitonin and growth hormone, whether from human or animals or semi- or totally synthetically prepared, or other bioactive peptides such as interferons including human interferon alpha and interleukins including IL-1, IL-2, IL-3, IL-4 and IL-5. Analogues and active fragments of these or other proteins may also be used.
- Biologically active materials may also be oligo- nucleotides such as antisense oligonucleotides and their analogues which may be useful for interfering with the replication of nucleic acids in virally infected or cancerous cells and for correcting other forms of inappropriate cell proliferation.
- Polysaccharides such as heparin are also suitable for use in the present invention as are combinations of one or more protein, nucleic acid or polysaccharide.
- the molecular weight of the biologically active material should preferably not be greater than about 20,000 Da. This is because, even with the increased permeability of the cells which comes about as a result of the use of the compositions of the present invention, it is no easy matter to achieve effective bioavailability with active molecules of greater size than this. In general, however, the smaller the size of the active molecule, the easier it becomes to deliver and it is therefore preferred that the biologically active molecule has a molecular weight of less than about 10,000 Da and, most suitably, less than about 5,000 Da.
- the amount of biologically active material present will naturally depend on its intrinsic potency. All that is necessary is that it is present in a sufficient amount that it manifests its desired activity when ingested. For pharmaceuticals, the amount administered will be under the guidance of the physician or clinician.
- excipients which may be present include lactose, employed as a filler, to ensure homogeneity of the composition, and to aid in handling of the preparation, Ac-di-solTM (cross-carmellose sodium) , a swelling agent which aids tablet disintegration, and polyvinyl pyrollidone, commonly used as a binding agent during granulation processes.
- lactose employed as a filler, to ensure homogeneity of the composition, and to aid in handling of the preparation
- Ac-di-solTM cross-carmellose sodium
- swelling agent which aids tablet disintegration
- polyvinyl pyrollidone commonly used as a binding agent during granulation processes.
- the formulation will usually be in a solid or, exceptionally, liquid form. Solid forms are preferred because the active material can easily be prevented from being digested in the stomach by enteric coating, and it is much easier to ensure that the active ingredient (s) and the bile salt reach the small intestine both intact and contemporaneously; this is much more difficult to achieve with a liquid formulation. If the composition is formulated as a solid, which should, for a prolonged shelf life, be substantially dry, it may be in tablet, bolus, powder, granular or microgranular form and may also contain appropriate fillers or binders which are well known to those skilled in the art. Powders, granules or microgranules may be encapsulated. As mentioned above, either a bile acid or a bile salt may be used in a solid formulation.
- Liquids suffer from the disadvantages referred to above. However, if for any reason it is particularly desired to formulate a composition of the invention as a liquid, an enteric coated capsule is probably the best means of administration of the contents, which may be a syrup or elixir.
- compositions may be formulated for rapid or sustained release or a combination of these two release forms may be used.
- the compositions can also be incorporated into immediate, delayed or pulsed release formulations.
- the amount of buffering agent included in the composition will be dependent upon the way in which the composition is formulated and the time taken for it to disperse in the gut and thus the amount of buffering agent included in a sustained release formulation will generally be much greater than the amount needed for a rapid release formulation.
- compositions of the invention may be prepared simply by admixing the ingredients using techniques well known to those skilled in the art of preparing pharmaceutical formulations.
- the invention also relates to a method of improving the bioavailability of an active material, the method comprising coadministering to a patient an active material, a bile salt and an agent adapted to adjust the gut to a pH of from 7.5 to 9.
- a bile salt and an agent adapted to adjust the gut to a pH of from 7.5 to 9 in the preparation of an agent for increasing the bioavailability of a biologically active material to be coadministered with the agent are provided.
- FIGURE 1 shows a comparison of the viability of Caco-2 cells after exposure to bile salts in vi tro in either balanced salt or bicarbonate solution, the results being expressed as maximum tolerated concentrations of bile salt in mg/ml;
- FIGURE 2 shows a comparison of neutral red permeability of Caco-2 cells in vi tro during and after exposure to conjugated bile salts in either HBSS or bicarbonate solution, the results being expressed as maximum tolerated concentrations of bile salt in mg/ml;
- FIGURE 3 is a comparison of neutral red permeability of Caco-2 cells in vi tro during and after exposure to unconjugated bile salts in either HBSS or bicarbonate solution, the results being expressed as maximum tolerated concentrations of bile salt in mg/ml;
- FIGURE 4 is a plot showing the percentage release of stain after incubation of stained cells with chenodeoxycholate in different buffers
- FIGURE 5 is a plot showing the percentage reduction in mitochondrial activity after incubation with chenodeoxycholate in different buffers
- FIGURE 6 is referred to in Example 3 and shows the effect of pH and bile salt concentration on uptake of salmon calcitonin (SCT) after administration intrajejunally in pigs; and
- FIGURE 7 is referred to in Example 4 and shows the enhancement of efficacy of solid dose oral insulin formulation when combined with bicarbonate. Preparation of Solutions for Use in Examples
- a neutral red stock solution was prepared at concentration of 0.5 mg/ml in DMEM (Dulbecco's Modified Eagle Medium) (pH 4.5) which was then diluted 1:10 with TCM (Tissue Culture Medium) or Hanks Balanced Salt Solution (HBSS) before use.
- DMEM Dulbecco's Modified Eagle Medium
- TCM Tissue Culture Medium
- HBSS Hanks Balanced Salt Solution
- HBSS Hanks Balanced Salt Solution
- a 0.1 M solution of sodium bicarbonate in distilled water was prepared (buffer solution) .
- Similar 0.1 M solutions of sodium acetate, sodium borate and sodium carbonate in distilled water were also prepared. These are also referred to in the examples as buffers.
- Test solutions were prepared containing various concentrations of a bile salt in either HBSS or in one of the 0.1 M buffer solution.
- the following bile salts were tested: Unconjugated Bile Salts: sodium cholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium deoxycholate;
- Conjugated Bile Salts sodium taurocholate, sodium glycocholate, sodium taurodeoxycholate, sodium glycodeoxycholate.
- a MTT stock solution was prepared at a concentration of 5 mg/ml in distilled water, which was then diluted 1:10 with TCM before use.
- Examples 1 and 2 are well known tests and conform to British Standards (BS 5750) .
- Caco-2 cells are well recognised by those skilled in the art to be the best available in vi tro model for intestinal cells.
- Test plates were set up by aliquotting 200 ⁇ l of a Caco-2 cell suspension containing 1 x 10 5 cells/ml into each well of a 96-well microtitre plate. The outermost wells were filled with 200 ⁇ l saline alone, to counteract the effects of evaporation. The cells were incubated in high glucose Dulbecco's modified eagles medium (DMEM) tissue culture medium (TCM) at 37°C, 5% C0 2 in air, for 8 days, with feeding where necessary. The cells were then used for performance of either an initial insult or a recovery study.
- DMEM Dulbecco's modified eagles medium
- TCM tissue culture medium
- Neutral red stain is actively taken up by viable cells.
- Cells with more permeable membranes will lose stain into the bathing medium and thus cell membrane permeability can be directly assessed after exposure to the test material by quantifying the stain remaining in the cell.
- cells are first stained and then incubated with test materials and measurements are made to determine the extent to which incubation with test materials has caused the stain to leak out of the cells during exposure. An exposure duration of 2 hours was used and the experiment was conducted according to the following protocol .
- TCM was removed from cell monolayers in each well and replaced with 200 ⁇ l of stain.
- the plates were incubated for 2 hours at 37°C, 5% C0 2 , and then checked for even staining and normal morphology.
- Stain was removed from each well and replaced with 150 ⁇ l of the appropriate buffer.
- Buffer was removed from wells in column 2 and replaced with 150 ⁇ l of test solutions at the highest concentration.
- 150 ⁇ l of test solutions was added to each of wells in column 3, mixed gently by aspiration repeatedly, and 150 ⁇ l transferred to wells in column 4. This process was repeated down the plate to obtain two ⁇ fold serial dilutions of test material along each row.
- One row on each plate was allocated to HBSS as a control, and one row for a buffer control if necessary.
- the cells were incubated for 2 hours at 37°C in 5% C0 2 .
- the stain was then aspirated from the wells and the plates incubated with shaking for 20 minutes in desorbing solution (100 ⁇ l/well) consisting of 1% glacial acetic acid in 50% ethanol .
- desorbing solution 100 ⁇ l/well
- absorbances were measured on a plate reader at 550 nm, and readings compared with buffer controls to assess leakage of the stain from the cells.
- the test is thus used as a measure of cell membrane permeability at the time of exposure to bile salts.
- TCM was removed from each well and replaced with 150 ⁇ l of the appropriate buffer.
- Buffer was removed from wells in column 2 and replaced with 150 ⁇ l of test solutions at the highest concentration.
- test solutions 150 ⁇ l of test solutions was added to each of wells in column 3, mixed gently by aspirating repeatedly, and 150 ⁇ l transferred to wells in column 4. This process was repeated down the plate to obtain two-fold serial dilutions of test material along each row.
- One row on each plate was allocated to HBSS as a control, and one row for a buffer control if necessary. The cells were incubated for 2 hours at 37°C in 5% C0 2 .
- the supernatant liquid was then removed from cell monolayers in each well and replaced with 200 ⁇ l of stain.
- the plates were incubated for 3 hours at 37°C, 5% C0 2 .
- the stain was then aspirated from the wells and the plates were then incubated with shaking for 20 minutes in desorbing solution (100 ⁇ l/well) consisting of 1% glacial acetic acid in 50% ethanol .
- Absorbances were measured on a plate reader at 550 nm, and readings compared with buffer controls to assess leakage of neutral red out of the cells after active uptake of the stain.
- the test is thus used as a measure of cell membrane permeability during the recovery period after exposure to bile salts.
- Test for Mitochondrial Activi ty MTT is a tetrazolium salt which is converted by mitochondrial dehydrogenases in viable cells to form an insoluble purple crystal. Dead cells would not effect this conversion. Crystal formation can be quantified colorimetrically and used to asses mitochondrial activity and therefore cell viability. The preparation of MTT stock solution, test solutions and buffer solution is described above.
- cells are first incubated with test materials and then incubated with MTT and measurements are made to determine the extent to which incubation with test materials has altered the mitochondrial activity of the cells.
- a two hour exposure period is used together with a three hour recovery period during which time staining is conducted.
- TCM was removed from each well and replaced with 150 ⁇ l of the appropriate buffer.
- Buffer was removed from wells in column 2 and replaced with 150 ⁇ l of test solutions at the highest concentration.
- test solutions 150 ⁇ l of test solutions was added to each of wells in column 3, mixed gently by aspirating repeatedly, and 150 ⁇ l transferred to wells in column 4. This process was repeated down the plate to obtain two-fold serial dilutions of test material along each row.
- One row on each plate was allocated to Hanks Balanced Salt Solution (HBSS - See Example 1) as a control, and one row for a buffer control if necessary. The cells were incubated for two hours at 37°C in 5% C0 2 .
- HBSS Hanks Balanced Salt Solution
- the cells were incubated for 2 hours at 37°C in 5% C0 2 .
- the supernatant liquid was then removed from cell monolayers in each well and replaced with 200 ⁇ l of MTT.
- the plates were incubated for 3 hours at 37°C, 5 C0 2 , and the wells examined to assess the level of staining by eye. The stain was then aspirated from the wells and the plates were incubated with shaking for 20 minutes in desorbing solution (100 ⁇ l/well) consisting of 0.1 M HCl in anhydrous isopropanol .
- Absorbances were measured on a plate reader as the difference between 550 and 650 nm, and readings compared with buffer controls to assess change in mitochondrial activity. A reduction in staining below that for controls indicates a reduction in mitochondrial activity, and is highly indicative of a toxic action of materials in the incubation medium.
- Examples 1 and 2 are set out in Tables 1 and 2, and Figures 1 to 5 which illustrate the effects exerted by conjugated and unconjugated bile acids in the presence of high pH buffers, using bicarbonate as a particular example.
- Ursodeoxycholate HBSS 1.25 0.313 0.625 Bicarb. 0.313 1.25 1.25
- Tables 1 and 2 show the results of the experiments described in Examples 1 and 2.
- the first columns of the tables list the bile salts which were present in the test media and the test media themselves are set out in the second column.
- the test medium was either HBSS or the 0.1 M sodium bicarbonate solution.
- results for the neutral red assays during and after exposure to bile salt give the maximum concentration of bile salt in mg/mL at which the permeability of the cell remains unaffected (compared with cells incubated in medium with no bile salt) .
- results in the MTT column represent the maximum concentration of bile salt at which the viability of the cell remained unaffected after incubation.
- Table 1 gives the results for the unconjugated bile salts and shows that, in each case, the figures in the Neutral Red (After Exposure) and MTT column are higher for the bile salts administered with bicarbonate than for those administered with HBSS although there is no significant difference in the figures in the Neutral Red (During Exposure) column.
- Table 2 gives the results for the conjugated bile salts and shows that, in each case, the figures in the Neutral Red (During Exposure) column are increased when the bile salt is administered in the presence of bicarbonate while the figures in the Neutral Red (After Exposure) and MTT columns are the same. This indicates that much less bile salt is needed to increase the permeability of the cells when they are incubated with bile salts in the presence of bicarbonate than when bicarbonate is not present.
- Figures 1 to 3 are graphical representations of the results presented in Tables 1 and 2.
- Figure 1 shows the effect of bicarbonate on the viability of cells incubated with bile salt solutions as measured by the MTT viability test.
- Figure 2 shows the results for cell permeability as measured by the neutral red assay both during and after incubation with conjugated bile salts. It can be seen that during exposure, the amount of bile salt needed to increase the permeability of cells is considerably lower in the presence of 0.1 M bicarbonate than in the presence of HBSS. However, after exposure, the permeability of the cells returns to normal. This means that for a given amount of bile salt, cell permeability can be significantly increased during exposure. However, after exposure, the viability of the cells remains unchanged with reference to control (cells incubated with bile salts and HBSS with no bicarbonate) .
- Figure 3 is similar to Figure 2 but in this case the results for unconjugated bile salts are presented. In this case it can be seen that bicarbonate has no clear cut effect on the permeability of the cells during exposure to the bile salt but that after exposure, the maximum concentration of bile salt which can be administered without causing an increase in cell permeability is increased and thus the cell permeability is significantly decreased in the presence of bicarbonate.
- Figure 4 is a plot showing the percentage release of stain in the neutral red recovery assay after exposure of stained cells to bile salt at different pH values, using chenodeoxycholate as an example. This plot shows quite clearly that much less stain is released from cells which have been incubated at pH above 7.5, and this is an indication that the prospects for both short- and long- term recovery of the cells are much better under conditions of elevated pH.
- Figure 5 which is a plot showing the percentage reduction in mitochondrial activity after incubation with chenodeoxycholate in different buffers, indicates that a marked reduction in toxicity is achieved under conditions of elevated pH.
- the pH 7.0 medium was prepared using HBSS containing 3% (v/v) 1M HEPES (hydroxyethyl propylidene ethane sulphonic acid) solution adjusted to pH 7.0.
- the pH 7.5 medium was prepared using HBSS containing 50 mM TRIZMATM, and adjusted to pH 7.5.
- the pH 8.0 medium was prepared using HBSS containing 50 mM TRIZMATM, and adjusted to pH 8.0.
- the pH 8.5 medium was prepared using HBSS containing 50 mM Tricine, and adjusted to pH 8.5. The results also indicate that this phenomenon is observed with 0.1 M bicarbonate at pH 8.0, but not with HBSS alone at pH 7.0.
- Pigs large white x large white/landrace, male, 65kg were employed for the study and were surgically prepared ten days before commencement by implantation, under anaesthesia, of two catheters in the dorsal aorta via the median saphenous arteries. A cannula of approximately 1.6-2mm internal diameter was implanted in the jejunum. Animals were provided with water ad lib, fasted overnight, and fed twice daily in the morning and evening. On days of treatment, the morning feed was withheld until after the taking of the last blood sample.
- sCT salmon calcitonin
- Each of the treatments consisted of 625iu of sCT dissolved in 2ml of phosphate-buffered saline at pH 7.5, either alone (-o-) , together with 25mg of sodium chenodeoxy cholate (- ⁇ -) , together with 50mg of sodium chenodeoxy cholate (- ⁇ -) , or with 50mg of sodium chenodeoxy cholate where the pH was subsequently brought down to 6.5 with hydrochloric acid (-x-) .
- Pigs prepared in an identical manner to that described in Example 3 were employed. Blood samples taken were analysed for glucose using standard enzyme-based methodology.
- Bovine insulin 2.4 Bovine insulin 2.4 Chenodeoxy- Chenodeoxy- cholic acid 16. .7 cholic acid 16.7
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nutrition Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ291863A NZ291863A (en) | 1994-08-31 | 1995-08-25 | Medicament containing a bile salt and a buffer for increased bioavailability of an active material |
KR1019970701088A KR970705406A (en) | 1994-08-31 | 1995-08-25 | PHARMACEUTICAL COMPOSITIONS CONTAINING A BILE SALT AND A BUFFER FOR INCREASED BIOAVAILABILITY OF AN ACTIVE COMPOUND |
JP8508551A JPH10504835A (en) | 1994-08-31 | 1995-08-25 | Pharmaceutical composition comprising a bile salt and a buffer that enhances the bioavailability of the active compound |
EP95929955A EP0769960A1 (en) | 1994-08-31 | 1995-08-25 | Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound |
AU33510/95A AU705123B2 (en) | 1994-08-31 | 1995-08-25 | Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound |
MXPA/A/1997/001455A MXPA97001455A (en) | 1994-08-31 | 1997-02-26 | Pharmaceutical compositions containing a salvage and a regulator to increase the biodisponibility of a compound act |
FI970825A FI970825A0 (en) | 1994-08-31 | 1997-02-27 | Pharmaceutical compositions containing a bile salt and a buffer for increased biological benefit of an active compound |
NO970894A NO970894D0 (en) | 1994-08-31 | 1997-02-27 | Pharmaceutical preparations containing a bile salt and buffer for increased bioavailability of an active compound |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9417524A GB9417524D0 (en) | 1994-08-31 | 1994-08-31 | Pharmaceutical compositions |
GB9417524.7 | 1994-08-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996006635A1 true WO1996006635A1 (en) | 1996-03-07 |
Family
ID=10760623
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1995/002015 WO1996006635A1 (en) | 1994-08-31 | 1995-08-25 | Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound |
Country Status (13)
Country | Link |
---|---|
US (1) | US5853748A (en) |
EP (1) | EP0769960A1 (en) |
JP (1) | JPH10504835A (en) |
KR (1) | KR970705406A (en) |
AU (1) | AU705123B2 (en) |
CA (1) | CA2198721A1 (en) |
FI (1) | FI970825A0 (en) |
GB (1) | GB9417524D0 (en) |
IL (1) | IL115097A0 (en) |
NO (1) | NO970894D0 (en) |
NZ (1) | NZ291863A (en) |
WO (1) | WO1996006635A1 (en) |
ZA (1) | ZA957247B (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1003516A1 (en) * | 1998-06-18 | 2000-05-31 | The George Washington University | Methods of administering camptothecin compounds for the treatment of cancer with reduced side effects |
US6197746B1 (en) | 1998-05-19 | 2001-03-06 | Repligen Corporation | Method of using secretin for treating autism |
US6498143B1 (en) | 1997-05-19 | 2002-12-24 | Repligen Corporation | Method for assisting in differential diagnosis and treatment of autistic syndromes |
US7153930B1 (en) | 1999-07-30 | 2006-12-26 | James Duncan Morrison | Peptide transport |
US7923025B2 (en) | 2002-01-16 | 2011-04-12 | Astellas Pharma Inc. | Pharmaceutical composition for oral use with improved absorption |
EP2361091A1 (en) * | 2008-10-01 | 2011-08-31 | Axcess Limited | Bile acids and biguanides as protease inhibitors for preserving the integrity of peptides in the gut |
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 |
Families Citing this family (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2294988C (en) | 1997-07-01 | 2015-11-24 | Isis Pharmaceuticals Inc. | Compositions and methods for the delivery of oligonucleotides via the alimentary canal |
US6221378B1 (en) | 1998-02-10 | 2001-04-24 | Generex Pharmaceuticals Incorporated | Mixed micellar delivery system and method of preparation |
US7070799B1 (en) * | 1998-02-10 | 2006-07-04 | Generex Pharmaceuticals, Inc. | Method for administering insulin to the buccal region |
US20030118645A1 (en) * | 1998-04-29 | 2003-06-26 | Pather S. Indiran | Pharmaceutical compositions for rectal and vaginal administration |
US20030091629A1 (en) | 1998-03-27 | 2003-05-15 | Cima Labs Inc. | Sublingual buccal effervescent |
US6974590B2 (en) | 1998-03-27 | 2005-12-13 | Cima Labs Inc. | Sublingual buccal effervescent |
JP2003524586A (en) * | 1998-05-21 | 2003-08-19 | アイシス・ファーマシューティカルス・インコーポレーテッド | Compositions and methods for parenteral administration of oligonucleotides |
TW570805B (en) * | 1998-09-01 | 2004-01-11 | Hoffmann La Roche | Water-soluble pharmaceutical composition in an ionic complex |
US6294153B1 (en) | 1998-12-21 | 2001-09-25 | Generex Pharmaceuticals, Inc. | Aerosol pharmaceutical formulation for pulmonary and nasal delivery |
US6761903B2 (en) | 1999-06-30 | 2004-07-13 | Lipocine, Inc. | Clear oil-containing pharmaceutical compositions containing a therapeutic agent |
US6350432B1 (en) | 1999-03-19 | 2002-02-26 | Generex Pharmaceuticals Incorporated | Pressurized container having an aerosolized pharmaceutical composition |
US6458383B2 (en) | 1999-08-17 | 2002-10-01 | Lipocine, Inc. | Pharmaceutical dosage form for oral administration of hydrophilic drugs, particularly low molecular weight heparin |
US20030235629A1 (en) * | 1999-11-06 | 2003-12-25 | Janmarie Hornack | Dietary supplement containing alkaline electrolyte buffers |
US9357797B2 (en) | 1999-11-06 | 2016-06-07 | Janmarie Hornack | Dietary supplement containing alkaline electrolyte buffers |
US20030003537A1 (en) * | 2001-04-30 | 2003-01-02 | Ventana Medical Systems, Inc. | Method and composition of matter for enhancing staining of microorganisms |
US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
US6858580B2 (en) * | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6713452B2 (en) * | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US20030068356A1 (en) * | 2001-07-10 | 2003-04-10 | Pather S. Indiran | Sequential drug delivery systems |
US6913903B2 (en) | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US7312192B2 (en) | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US7166571B2 (en) | 2001-09-07 | 2007-01-23 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
GB0217056D0 (en) * | 2002-07-23 | 2002-08-28 | Ass Octel | Use |
GB0308732D0 (en) * | 2003-04-15 | 2003-05-21 | Axcess Ltd | Absorption enhancers |
GB0308734D0 (en) * | 2003-04-15 | 2003-05-21 | Axcess Ltd | Uptake of macromolecules |
US7858121B2 (en) * | 2003-12-31 | 2010-12-28 | Cima Labs, Inc. | Effervescent oral fentanyl dosage form and methods of administering fentanyl |
BRPI0418213A (en) | 2003-12-31 | 2007-04-27 | Cima Labs Inc | dosage form and method for treating pain in a patient in need thereof |
JP2007517054A (en) * | 2003-12-31 | 2007-06-28 | シーマ・ラブス、インコーポレイテッド | Generally linear effervescent oral fentanyl dosage forms and methods of administration |
US20070219131A1 (en) * | 2004-04-15 | 2007-09-20 | Ben-Sasson Shmuel A | Compositions capable of facilitating penetration across a biological barrier |
MXPA06011871A (en) * | 2004-04-15 | 2007-10-08 | Chiasma Inc | Compositions capable of facilitating penetration across a biological barrier. |
NZ553263A (en) | 2004-07-19 | 2010-06-25 | Biocon Ltd | Insulin-oligomer conjugates, formulations and uses thereof |
ES2546016T3 (en) * | 2005-10-13 | 2015-09-17 | Biocon Limited | Procedure for the preparation of insulin conjugates |
KR100700948B1 (en) * | 2006-05-25 | 2007-03-28 | 삼성전자주식회사 | Apparatus and method for data transmission utilizing multi-channel of wireless lan in mobile communication system |
WO2009050738A2 (en) | 2007-10-16 | 2009-04-23 | Biocon Limited | An orally administerable solid pharmaceutical composition and a process thereof |
FR2925333B1 (en) * | 2007-12-19 | 2012-04-13 | Farid Bennis | PHARMACEUTICAL COMPOSITIONS COMPRISING AT LEAST ONE PROTEIN ACTIVE INGREDIENT PROTECTS DIGESTIVE ENZYMES |
WO2010032140A2 (en) | 2008-09-17 | 2010-03-25 | Chiasma Inc. | Pharmaceutical compositions and related methods of delivery |
US11304960B2 (en) | 2009-01-08 | 2022-04-19 | Chandrashekar Giliyar | Steroidal compositions |
US9358241B2 (en) | 2010-11-30 | 2016-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9034858B2 (en) | 2010-11-30 | 2015-05-19 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US20180153904A1 (en) | 2010-11-30 | 2018-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US20120148675A1 (en) | 2010-12-10 | 2012-06-14 | Basawaraj Chickmath | Testosterone undecanoate compositions |
MX2016017063A (en) | 2014-06-27 | 2018-01-12 | Medytox Inc | Methods and compositions of bile acids and salts for reduction of fat. |
WO2016033549A2 (en) | 2014-08-28 | 2016-03-03 | Lipocine Inc. | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
WO2016033556A1 (en) | 2014-08-28 | 2016-03-03 | Lipocine Inc. | BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS |
MA41462A (en) | 2015-02-03 | 2021-05-12 | Chiasma Inc | METHOD OF TREATMENT OF DISEASES |
US20180147215A1 (en) | 2016-11-28 | 2018-05-31 | Lipocine Inc. | Oral testosterone undecanoate therapy |
US11141457B1 (en) | 2020-12-28 | 2021-10-12 | Amryt Endo, Inc. | Oral octreotide therapy and contraceptive methods |
GB2625490A (en) * | 2021-01-27 | 2024-06-19 | D&D Pharmatech Inc | Pharmaceutical composition comprising large physiologically active substance and excipient |
CN118019522A (en) * | 2021-09-07 | 2024-05-10 | D&D制药技术股份有限公司 | Pharmaceutical composition comprising a large physiologically active substance and an excipient |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0127535A2 (en) * | 1983-05-23 | 1984-12-05 | Hadassah Medical Organization | Pharmaceutical compositions containing insulin |
JPH04149126A (en) * | 1990-10-09 | 1992-05-22 | Mitsubishi Kasei Corp | Pharmaceutical composition for transmucous administration |
EP0509335A1 (en) * | 1991-04-12 | 1992-10-21 | ALFA WASSERMANN S.p.A. | Gastroresistant pharmaceutical formulations for oral administration containing bile acids |
DE4234537A1 (en) * | 1992-10-14 | 1994-04-21 | Hoechst Ag | A compound a polymeric bile acid and insulin - useful in the prodn. of a medicament for diabetes mellitus, for nasal admin. |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8909022D0 (en) * | 1989-04-20 | 1989-06-07 | Cortecs Ltd | Pharmaceutical compositions |
GB9013448D0 (en) * | 1990-06-15 | 1990-08-08 | Sandoz Ltd | Pharmaceutical resorption-improved somatostatin compositions,their preparation and use |
-
1994
- 1994-08-31 GB GB9417524A patent/GB9417524D0/en active Pending
-
1995
- 1995-08-25 NZ NZ291863A patent/NZ291863A/en unknown
- 1995-08-25 JP JP8508551A patent/JPH10504835A/en active Pending
- 1995-08-25 WO PCT/GB1995/002015 patent/WO1996006635A1/en not_active Application Discontinuation
- 1995-08-25 EP EP95929955A patent/EP0769960A1/en not_active Withdrawn
- 1995-08-25 AU AU33510/95A patent/AU705123B2/en not_active Ceased
- 1995-08-25 CA CA002198721A patent/CA2198721A1/en not_active Abandoned
- 1995-08-25 KR KR1019970701088A patent/KR970705406A/en not_active Application Discontinuation
- 1995-08-29 ZA ZA957247A patent/ZA957247B/en unknown
- 1995-08-29 IL IL11509795A patent/IL115097A0/en unknown
-
1997
- 1997-02-24 US US08/804,508 patent/US5853748A/en not_active Expired - Lifetime
- 1997-02-27 FI FI970825A patent/FI970825A0/en unknown
- 1997-02-27 NO NO970894A patent/NO970894D0/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0127535A2 (en) * | 1983-05-23 | 1984-12-05 | Hadassah Medical Organization | Pharmaceutical compositions containing insulin |
JPH04149126A (en) * | 1990-10-09 | 1992-05-22 | Mitsubishi Kasei Corp | Pharmaceutical composition for transmucous administration |
EP0509335A1 (en) * | 1991-04-12 | 1992-10-21 | ALFA WASSERMANN S.p.A. | Gastroresistant pharmaceutical formulations for oral administration containing bile acids |
DE4234537A1 (en) * | 1992-10-14 | 1994-04-21 | Hoechst Ag | A compound a polymeric bile acid and insulin - useful in the prodn. of a medicament for diabetes mellitus, for nasal admin. |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Section Ch Week 9227, Derwent World Patents Index; Class B04, AN 92-223421 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6498143B1 (en) | 1997-05-19 | 2002-12-24 | Repligen Corporation | Method for assisting in differential diagnosis and treatment of autistic syndromes |
US6790825B2 (en) | 1997-05-19 | 2004-09-14 | Repligen Corporation | Method of using secretin and compositions made therefrom for the treatment of autism and other neurological, behavioral and immunological disorders |
US7091182B2 (en) | 1997-05-19 | 2006-08-15 | Repligen Corporation | Method for assisting in differential diagnosis and treatment of autistic syndromes |
US6197746B1 (en) | 1998-05-19 | 2001-03-06 | Repligen Corporation | Method of using secretin for treating autism |
EP1003516A1 (en) * | 1998-06-18 | 2000-05-31 | The George Washington University | Methods of administering camptothecin compounds for the treatment of cancer with reduced side effects |
EP1003516A4 (en) * | 1998-06-18 | 2006-07-12 | Univ George Washington | Methods of administering camptothecin compounds for the treatment of cancer with reduced side effects |
US7153930B1 (en) | 1999-07-30 | 2006-12-26 | James Duncan Morrison | Peptide transport |
US7923025B2 (en) | 2002-01-16 | 2011-04-12 | Astellas Pharma Inc. | Pharmaceutical composition for oral use with improved absorption |
EP2361091A1 (en) * | 2008-10-01 | 2011-08-31 | Axcess Limited | Bile acids and biguanides as protease inhibitors for preserving the integrity of peptides in the gut |
EP2361091A4 (en) * | 2008-10-01 | 2012-05-23 | Axcess Ltd | Bile acids and biguanides as protease inhibitors for preserving the integrity of peptides in the gut |
EP2873420A1 (en) * | 2008-10-01 | 2015-05-20 | Axcess Limited | Bile acids and biguanides as protease inhibitors for preserving the integrity of peptides in the gut |
US9913850B2 (en) | 2008-10-01 | 2018-03-13 | Axcess Limited | Bile acids and biguanides as protease inhibitors for preserving the integrity of peptides in the gut |
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 |
Also Published As
Publication number | Publication date |
---|---|
AU3351095A (en) | 1996-03-22 |
NO970894L (en) | 1997-02-27 |
ZA957247B (en) | 1997-02-28 |
EP0769960A1 (en) | 1997-05-02 |
MX9701455A (en) | 1998-05-31 |
FI970825A (en) | 1997-02-27 |
GB9417524D0 (en) | 1994-10-19 |
IL115097A0 (en) | 1996-01-19 |
CA2198721A1 (en) | 1996-03-07 |
NZ291863A (en) | 1998-12-23 |
AU705123B2 (en) | 1999-05-13 |
FI970825A0 (en) | 1997-02-27 |
JPH10504835A (en) | 1998-05-12 |
KR970705406A (en) | 1997-10-09 |
NO970894D0 (en) | 1997-02-27 |
US5853748A (en) | 1998-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5853748A (en) | Pharmaceutical compositions | |
AU2002244020B2 (en) | Methods of treating diabetes mellitus | |
EP0128831B1 (en) | Drug administration | |
US9345715B2 (en) | Methods of treating diabetes or obesity using bile acids, bile salts, and mimics thereof | |
KR100848344B1 (en) | Preparation of aqueous clear solution dosage forms with bile acids | |
US20090192075A1 (en) | Amylin Formulations | |
ZA200406332B (en) | ACC inhibitors. | |
AU2002244020A1 (en) | Methods of treating diabetes mellitus | |
CA2642847A1 (en) | Dissolution aids for oral peptide delivery comprising a biguanide | |
Gómez-Pérez et al. | Insulin therapy: current alternatives | |
AU2008345474A1 (en) | Pharmaceutical compositions containing at least one proteinaceous active ingredient protected against digestive enzymes | |
US20110046058A1 (en) | Compositions for enteral absorption and sustained action of leptin-related peptides useful in the treatment of obesity and leptin-modulated disease | |
KR20220131946A (en) | cell uptake | |
AU2010280418B2 (en) | Orally administerable pharmaceutical preparation containing insulin | |
MXPA97001455A (en) | Pharmaceutical compositions containing a salvage and a regulator to increase the biodisponibility of a compound act | |
JP2013501043A5 (en) | ||
CN116407614A (en) | Stable preparation of novel tri-agonist innovative biological medicine | |
JP2007506683A (en) | Human growth hormone agent and its preparation and use | |
JP2024525779A (en) | Oral dosage form compositions containing GLP-1 analogues - Patents.com | |
CN118370728A (en) | GLP-1RA drug-loaded nano-particle and preparation method thereof | |
KR0133998B1 (en) | Pharmaceutical composition for treating gastrointestinal | |
CN116635023A (en) | Ionic liquid preparation for treating diabetes | |
CN1163573A (en) | Pharmaceutical compositions containing bile salt and buffer for increased bioavailability of active compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 95194834.2 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TT UA UG US UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
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 | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1995929955 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 291863 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1019970701088 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08804508 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/1997/001455 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2198721 Country of ref document: CA Ref document number: 2198721 Country of ref document: CA Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 970825 Country of ref document: FI |
|
WWP | Wipo information: published in national office |
Ref document number: 1995929955 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1019970701088 Country of ref document: KR |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1995929955 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1019970701088 Country of ref document: KR |