MXPA96003556A - Medical application of bromela - Google Patents
Medical application of bromelaInfo
- Publication number
- MXPA96003556A MXPA96003556A MXPA/A/1996/003556A MX9603556A MXPA96003556A MX PA96003556 A MXPA96003556 A MX PA96003556A MX 9603556 A MX9603556 A MX 9603556A MX PA96003556 A MXPA96003556 A MX PA96003556A
- Authority
- MX
- Mexico
- Prior art keywords
- bromelain
- cholesterol
- bile
- bile acid
- treatment
- Prior art date
Links
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Abstract
The application relates to the use of bromelain in the treatment of hypercholesterolemia and similar diseases. Bromelain is able to act as an antagonist of the biliary acid receptor and, therefore, to prevent the reabsorption of bile acids by the gastrointestinal tract
Description
MEDICAL APPLICATION OF BROMELAINA
The present invention relates to the use of the enzyme mixture known as bromelain in the treatment of conditions that require a reduction or other modification in the volume of bile acid. In particular, the invention relates to the treatment and prophylaxis of hyperlipidemia, especially hypercholesterolemia. Coronary heart disease is one of the leading causes of death in the Western World, and results from the accumulation of atherosclerotic plaques within the main arteries that supply oxygen and nutrients to the heart. Atherosclerosis progresses for decades without clinical effect, gradually constricting the arterial lumen. Coronary Artery Disease is defined as less than 75 percent occlusion of the arterial lumen; Coronary Heart Disease is defined as more than 75 percent occlusion. Symptoms occur when a vessel becomes completely blocked; angina (acute chest pain) or myocardial infarction (heart attack), or sometimes sudden death. A number of major risk factors have been identified for Coronary Artery Disease and Coronary Heart Disease: age, male sex, hypertension, cigarette smoking, lack of exercise, stress, diet, diabetes, style of life and high serum cholesterol (hypercholesterolemia, particularly where cholesterol is carried by low density lipoprotein cholesterol). Cholesterol is an important component of cell membranes, steroid hormones, and bile acids. Approximately two thirds of the daily cholesterol requirement is met by endogenous synthesis by the liver, with the remainder being provided by the diet. Cholesterol is an insoluble lipophilic material that requires encapsulation in lipoproteins before it can be transported in the blood. The major types of lipoproteins are chylous icrones, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and high density lipoprotein (HDL). The liver secretes cholesterol into the blood as very low density lipoprotein, which is converted to intermediate density lipoprotein, which in turn is converted to low density lipoprotein. Low-density lipoprotein forms approximately two thirds of the cholesterol carried in the blood, where it is transported back to the liver with the help of high-density lipoprotein. Many cells exhibit low density lipoprotein receptors on their surface, making possible the recovery and extraction of low density lipoprotein cholesterol for the synthesis of cellular components. However, it is the liver that is responsible for the extraction of most of the low density lipoprotein cholesterol, where it can be secreted into the blood, or alternatively into the bile (either as bile acids or as free cholesterol) . Chylomicrons are made by gastrointestinal cells from lipids, including cholesterol, absorbed from the diet, secreted into the lymph, and subsequently enter the systemic blood supply, where the peripheral tissues break down and utilize the lipid components.
The resulting chylomicron remains are returned to the liver. Elevated levels of low density lipoproteins in the blood can be reduced in a number of ways, with a concomitant decrease in the risk of developing disorders associated with atherosclerosis. Normal serum cholesterol levels are defined below 200 milligrams / deciliter, those of mild hypercholesterolemia that require modification to the diet as of 200-220 milligrams / deciliter, of moderate hypercholesterolemia as of 220-260 milligrams / deciliter, and as severe hypercholesterolemia, which requires drugs and dietary intervention, such as more than 260 milligrams / deciliter. T. Gordon W.P. Castelli, M.C. Hjortland, W.B. Kannel and T.R. Dawber (1984), Predicting Coronary Heart Disease in Middle-Aged and Older Persons. The Framingham Study: Journal of the American Medical Association (1977); 238, 497. National Institute of Health Consensus Development Conference State in Lowering Blood Cholesterol, December 10-12 (1984). When hypercholesterolemia is detected, a series of possible treatments can be considered: (i) Diet. For mild and moderate hypercholesterolemia, the initial therapy recommended is not drugs, but diet. Dietary modification includes reduced consumption of foods high in cholesterol and in saturated fat, such as eggs, dairy products and red meat. (ii) Drugs. In patients with severe osteoclemia or moderate hypercholesterolemia who are resistant to changes in diet, then treatment with drugs may be considered. These include:
Cholestyramine is a bile acid sequestrant or binding agent, which interrupts the recycling of cholesterol, in the form of bile acids, back to the liver. Bile acids, which are synthesized from cholesterol by the liver, are normally actively conserved in the enterohepatic circulation. Cholestyramine, following oral administration, binds with bile acids in the duodenum, forming an insoluble complex that is subsequently excreted from the body in the faeces. The interruption of the enterohepatic circulation results in the up-regulation of the synthesis of bile acid from cholesterol in the liver. This higher requirement of cholesterol has its source partially in the newly synthesized hepatic cholesterol, and the rest by means of the greater recovery of low density lipoprotein cholesterol from the blood. The best hepatic recovery of low density lipoprotein cholesterol results in a global low in blood cholesterol concentrations. Patients receiving cholestyramine typically experience a 13 percent decrease in serum cholesterol, a 20 percent reduction in low density lipoprotein cholesterol, and a 24 percent reduction in deaths associated with coronary heart disease. Effective cholestyramine treatment has a number of drawbacks related to its unpleasant administration; it is presented as unit dosage packages containing 4 grams of granules that are mixed with water or fruit juice. Up to 9 unit dosage packs (average of 3 to 6) may be required in single or divided doses daily for extended periods, which results in poor patient compliance (typically 30% stop taking the medication). The granules of colistiramina have the appearance of small plastic granules, and it is reported that they have the texture of liquefied sandpaper. There is a high incidence of gastrointestinal discomfort associated with treatment with colistiramine, and there is also an increased risk of bleeding over long-term therapy, and a number of important interactions of the drug with digitalis, antibiotics and diuretics. Dietary supplements of vitamins A, D and K are required over long-term treatment. Colistiramine is also expensive to manufacture, which is reflected in its high cost of treatment. ls HMGCoA reductase inhibitors Examples of HMGCoA reductase inhibitors include pravastatin and simvastatin. These drugs act by inhibiting endogenous cholesterol synthesis,
mainly in the liver, by competitive inhibition of the enzyme limiting the speed in the
, 'biosynthesis of cholesterol. Large reductions in plasma cholesterol levels can be achieved up to
40 percent with this type of therapy. 20 Restricting the endogenously synthesized cholesterol supply means that the liver can only obtain cholesterol for the manufacture of cellular components, secretions and bile acids from the blood. This results in a massive up-regulation of the activity of the low density lipoprotein receptor, causing a subsequent reduction in serum cholesterol and low density lipoprotein cholesterol levels. Reductions in serum low-density lipoprotein cholesterol levels are associated with an increase in "protective" high-density lipoprotein cholesterol levels in serum. The most common side effect of HMGCoA reductase inhibitors is gastrointestinal discomfort, others include fatigue, itching, elevated hepatic transminase levels, and headache. More recently, large detailed studies have questioned the long-term effectiveness of HMGCoA reductase inhibitors in reducing death rates. Statistical analysis has shown that any benefit is obscured by an unexplained increase in the incidence of violent death (murder, suicide and accidents). * «* Treatments with other drugs Other examples of drugs used to treat hypercholesterolemia include the isobutyric acid derivative and the nicotinic acid derivatives. The isobutyric acid derivatives include bezafibrate, clofibrate, fenofibrate and gemfibrozil. These drugs effectively reduce plasma triglycerides and very low density lipoproteins, raise high density lipoproteins, and lower low density lipoprotein cholesterol by up to 18 percent. The isobutyric acid derivatives cause about 10 percent incidence of side effects (which are mainly gastrointestinal or central nervous system). Animal studies have shown tumors and stone formation with these compounds. The nicotinic acid derivatives lower both triglyceride levels and serum cholesterol. They inhibit lipolysis in adipose tissues, decrease the esterification of triglycerides in the liver, and increase the activity of lipoprotein lipase. The resulting drop in very low density lipoprotein levels is followed by a decrease in intermediate density lipoproteins and low density lipoproteins, which can be up to 20 percent, and a
,, * increase in high density lipoprotein levels.
Nicotinic acid produces an intense wash and headache that can be reduced by slowly titrating the dose. Gastrointestinal disorders are also common with this medication. The potential for unpleasant side effects, the high cost, or the questionable efficacy of existing treatments for hypercholesterolemia, ensures that there is still a considerable opportunity for improvement in this therapeutic area. Ideally, the treatment should have few, if any, side effects, low risk of toxicity and, due to the extended periods necessary to control this condition, the treatment should be convenient and well tolerated (for example, once a day). , once a week) . The cost of treatment should also be low. The present invention relates to the control of hypercholesterolemia and other conditions mediated by bile acids by a modification of the volume of bile acid. Bile acids (or bile salts - the nature and exact proportion of the species present will depend on the pH of the environment, and thus, the terms are used interchangeably) are a group of naturally occurring detergents, which form a major component of bile. As mentioned briefly in the above, bile acids are synthesized in the liver from cholesterol by hydroxylation and other modifications, and represent the end products of cholesterol metabolism. In its role as an exocrine gland, the liver secretes bile; the secretion of bile acids that provide the osmotic impulse force for a greater proportion of bile flow. In some species, the bile suffers storage and concentration in the gallbladder until the food is consumed, over which, the contraction and emptying of the gallbladder takes place in response to the gastrointestinal hormone cholescistokinin. The bile acids subsequently enter the duodenum, where they perform their main role as surfactants; improving the digestion and absorption of dietary lipids and lipid-soluble vitamins. Bile acids also increase the action of pancreatic lipases. After performing its role in digestion, the bile acids are eagerly stored in the body: they are efficiently reabsorbed by a process mediated by an active receptor from the terminal ileum, and are returned to the liver via the hepatic portal vein, and they undergo another extraction improved by the receiver before the resecretion towards the bile. The almost continuous flow of bile acids is located topographically and is limited to the liver, the biliary tree, the intestine, the enterocytes and the hepatic portal venous system and, therefore, comprises the enterohepatic circulation. The enterohepatic circulation works not only to preserve the valuable bile acid detergent molecules, by allowing its repeated use many times, but also allows the bile acids to maintain continuous homeostatic control over a variety of metabolic events. Bile acids have an essential role in the requirement for the synthesis and transport of a variety of lipids within and between cells, tissues and organs, which find bile acids during their enterohepatic circulation. The volume of human bile acid contains approximately 3 grams of bile acids that are typically recycled 4 to 12 times a day. Faecal excretion accounts for 0.2 to 0.6 grams per day, this amount being formed by synthesis from cholesterol in the liver. The efficient reabsorption of bile acids from the digestive tract is the result of both active and passive transport mechanisms; More than 95 percent of bile acids are removed by these processes. The active transport system resides in the terminal ileum, and carries a number of similarities with the active liver transporter that removes bile acids from the hepatic portal blood supply. The ileal bile acid transporter demonstrates saturation kinetics, competitive inhibition, and depends on the presence of sodium ions. The sodium gradient necessary to boost the recovery of bile acid is thought to be provided by the Na + / K + -ATPase present on the basolateral membrane of the ileocytes. Recovery of bile acid involves a bile acid / Na + cotransporter of the apical membrane and an anion-bile acid exchange system in the basolateral membrane. The evidence would suggest that the absorption of bile acid occurs through a protein, with a molecular weight of 99 kDa, which is found in the ileum but is absent from the jejunum, with a specific bile acid binding site. Alternatively, the absorption of bile acid through the small intestine and colon can be presented by ionic and non-ionic diffusion. Although it seems that in reality only non-ionic diffusion forms a significant proportion (90 percent) of the total. The main determinant of the absorption path of a bile acid is its hydrophilicity: relative hydrophobicity, which is determined by the structure. In general, more hydrophobic bile acids, such as deoxycholic and chenodeoxycholic acid, have a greater tendency to be absorbed through passive diffusion, while more hydrophilic bile acids, such as cholic acid, are more likely to be absorbed by means of the active transporter. In vivo, most bile acids are amidated with either glycine or taurine, and this has the effect of lowering their pKa (dissociation constant), thereby increasing their tendency to ionize at the gastrointestinal pH, thus necessitating of its absorption through the active bile acid transporter. As mentioned above, it is possible that the ileal bile acid transporter is a transmembrane protein, bile acid being bound to the site that protrudes into the gastrointestinal lumen. Accordingly, it can be envisaged that an agent that interacts with, or that inactivates the lumenal part of the receptor, prevents bile acid transport from occurring. An example of an agent that could inhibit the bile acid receptor is a chemically modified bile acid that combines irreversibly with
; the binding site of the bile acid receptor, or an agent that removes the bile acid binding sites from the surface of the gastrointestinal cells (see, for example, Wess et al., J .. Med. Chem., 37: 873 -875 (1994)). Inactivation of the ileal bile acid receptor would possibly result in a greater loss of bile acids in the faeces, an increase in the synthesis of hepatic bile acid, and a concomitant upward regulation of
- .. the activity of the hepatic low density lipoprotein receptor. The upregulation of the activity of the low density lipoprotein receptor in the liver would have the beneficial effect of reducing the levels of low density lipoprotein cholesterol in serum. Accordingly, an agent capable of increasing the activity of the hepatic low density lipoprotein receptor would be useful in the treatment of hypercholesterolemic patients, particularly those affected by the side effects of other treatments. Now we have made the surprising discovery that bromelain is capable of decreasing the efficiency of bile acid reabsorption by the gastrointestinal tract. Accordingly, in a first aspect of the present invention, the use of bromelain in the preparation of an agent to reduce or prevent the reabsorption of bile acid by the gastrointestinal tract is provided. As a result of its effect on the reabsorption of bile acids by the gastrointestinal tract, bromelain will be beneficial for patients suffering from hyperlipidemia, particularly hypercholesterolemia. In addition, bromelain is able to reduce the enterohepatic circulation of bile acids and, therefore, to benefit patients suffering from cholestatic liver disease or liver failure. Under these conditions, recycling a normal bile acid volume through a damaged liver can further damage the remaining liver function. The invention will also be useful in a method for the treatment of a patient suffering from a condition mediated by the volume size of bile acid, the method comprising administering to a patient suffering from this condition, an effective amount of bromelain. It is believed that the mechanism of action of bromelain in the present invention is to antagonize the ileal bile acid receptors, although the effectiveness of the enzymes of the present invention is not affected by the precision of this theory. This mechanism of action also does not require that bromelain be absorbed intact from the gastrointestinal tract. Bromelain is the collective name for the propiolytic enzymatic composition found in the tissues of the Bromeliaceae plant. Bromelain is a mixture of different fractions derived from the stem of the pineapple (Ananas comosus). It contains at least proteolytic enzymes, but also non-proteolytic enzymes, including an acid phosphatase and a peroxidase. It can also contain amylase and cellulase activity. In addition, there are other different components present, in particular, organically bound calcium. The proteolytic enzymes
/ ,. known bromelain and papain share a high degree of homology of the amino acid sequence around the active center, and evidence suggests that bromelain and papain use the same catalytic mechanism. However, bromelain differs from papain by having a different specificity of dissociation. In addition, the known proteolytic enzymes of bromelain are glycoproteins, while papain is a simple protein. Bromelain is reviewed by Taussig and Batkin (J. Ethno Pharmacol, 22 191-203 (1988)).
As early as the fifteenth century, bromelain has been used with a digestive aid, as a cleansing agent to improve the texture of the skin, and to treat wounds to promote its healing. Recently, a vast accumulation of knowledge about its pharmacological and biological effects, have resulted in bromelain being available for clinical use in man. In particular, bromelain is used as an aid in the treatment of soft tissue inflammation and in edema associated with trauma and surgery. Bromelain is available in different countries under the trademarks ANANASE FORTE, ANANASE, EXTRAÑASE, PR0TE0LIS, RESOLVIT, ROGORIN, BROMASE and TRAUMANASE. In clinical use over a period of more than 30 years, there have been few reports of significant undesirable effects. Documents discussing other medical applications of bromelain include International Patent Application Number PCT / GB93 / 01374, which describes the use of proteolytic enzymes, including bromelain, in the treatment of diarrhea in humans. However, there is no reference in the application to the treatment of different conditions of diarrhea, and certainly there is no reference to blocking the reabsorption of bile acid by the gastrointestinal tract, or to the decrease of blood lipid levels. U.S. Patent Application Number 9313188, refers to the use of a single component of the bromelain mixture. The paper discusses the use of stem bromelain in the mediation of cyclic nucleotide trajectories. However, it does not suggest that stem bromelain, or indeed any other component of bromelain, may be useful in preventing the reabsorption of bile acids. Although any route of administration can be employed, bromelain will generally be administered orally, since it is intended to operate in the gastrointestinal tract. It can be administered in the form of tablets, syrups, elixirs or hard or soft gelatin capsules, which can be enteric coated. The preferred application system for bromelain in the present invention would be of controlled release, to ensure at least the partial removal of the bile acid receptors from the enterocytes located in the terminal ileum. It would be desirable to have a combination of gastric protection (to prevent degradation of bromelain in the stomach), and a delay in the release of the bromelain protease to the terminal ileum. The delayed release of bromelain would help ensure that other receptors present in the small intestine used for digestion and absorption of nutrients remain intact. The delayed release of bromelain can be achieved by a number of formulation strategies, alone or in combination. Another formulation strategy that can be employed is to formulate bromelain with a thermosetting solid (at physiological temperatures). The application of rapid or sustained release of bromelain can be achieved by administration with one or more polyglycolized glycerides or other suitable and physiologically compatible compounds having a phase transition temperature (melting point) greater than 37 ° C. Suitable glycerides include di- and triglycerides, such as many of the GELUCIRE compounds, which are hydrogenated fatty acid esters available from Gattefosse. (The word GELUCIRE is a registered trademark). Other registered trademarks of suitable glycerides include LABRAFIL and PRECIROL. Care must be taken to select formulation systems that do not require heating to a degree that causes thermal decomposition of the enzyme: in general, the temperature should be kept below about 60 ° C. Specific examples of the example GELUCIRE compounds, and their equivalents include: GELUCIRE 50/02; GELUCIRE 46/07; GELUCIRE 48/09; GELUCIRE 50/13; and GELUCIRE 53/10. The first two digits in the numerical portion of the GELUCIRE name represent the liquid / solid phase transition temperature in degrees centigrade, and the second two digits represent the hydrophilic / lipophilic balance (HLB). The type of GELUCIRE used (or mixture of GELUCIRES) should be selected to give the appropriate release characteristics desired, which can be a quick or sustained release, or a combination of release profiles. There may be different formulation aids present. For example, a surfactant, such as one or more of those discussed below in greater detail, may be included in the sustained or rapid release formulations. The surfactants can be used to modify the release characteristics of bromelain from a formulation. Particularly one that contains glycerides. Another auxiliary of this ratio that may be present is a fluidizing and / or thickening agent, such as colloidal silicon dioxide, for example, the preparation available under the registered trademark AEROSIL (eg, AEROSIL 200). Colloidal silicon dioxide can also be used to modify the release rate of bromelain, from formulations based on thermobranching-deceiving agents, such as GELUCIRES. An additional approach to the formulation of components for sustained release is to use a thixotropic material. These materials behave like fluids when they are stressed by tearing forces (such as can be induced by agitation or pumping), but they become gels without flow when the tearing force is removed. Like the thermobranching vehicles described above, the thixotropic carriers are suitable for the hard gelatin encapsulation technology. Suitable thixotropic carriers include colloidal silicon dioxide (such as the AEROSIL 200 preparation, previously referenced), and ethyl cellulose. Other components that may be present include gel promoters and dispersion aids. Glycols, such as polyethylene glycol (e.g., PEG 400) are useful gel promoters in thixotropic formulations, and also assist dispersion. Nonionic surfactants, such as polyethoxylated, optionally hydrogenated castor oil, for example, having hydrophilic / lipophilic balance values in the range of 12 to 14, or 14 to 16, can be used. The gel composition can be varied within of very broad limits while having an acceptable performance. It can also be an advantage to formulate part of the active ingredients for sustained release and part for non-sustained release. This can be achieved by incorporating part of the enzyme in a matrix containing sustained release GELUCIRES described above, and part of the enzyme in GELUCIRES that can disperse more rapidly, such as: GELUCIRE 35/10; GELUCIRE 33/01; GELUCIRE 37/02; and GELUCIRE 44/14. GELUCIRE 44/14 is particularly useful, due to its solubility in water. These materials can be filled into hard or soft gelatin capsules. It is not necessary that any other ingredient is present. However, in some cases suitable antioxidants may be added, and these include d-alpha-tocopherol, dl-alpha-tocopherol, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA). Antioxidants can be used either alone or in combination. Another optional ingredient is a surfactant, as mentioned briefly in the above. Suitable surfactants are ionic or non-ionic, but in general do not include bile acids or their salts. Nonionic surfactants are preferred. A suitable hydrophilic / lipophilic balance scale for the surfactant, if present, is broadly from 0 to 20, preferably from
6 to 18, and typically 10 to 18. Examples of suitable surfactants, which may be used alone or in combination, include the polyoxyethylene sorbitan fatty esters (eg, polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20). ), polyoxyethylene stearates (eg, polyoxyl-40-stearate) and polyoxyethylene, optionally hydrogenated castor oil derivatives, such as CREMOPHOR RH40 and EL products. The word CREMOPHOR is a registered trademark. It is generally preferred that the pharmaceutical formulations according to the invention be substantially non-aqueous, in the sense that water is not added. There may be some water present in the ingredients used. However, water-free formulations do not need to be preferred for all applications. The formulations according to the invention can be enteric coated or otherwise protected to ensure a better survival of the pharmaceutically active compound through the stomach. Any convenient enteric protection method can be employed. Capsules containing the formulation can be coated with an enteric coating, such as hydroxypropylmethyl cellulose phthalate, or by the commercial coating process of Phar a-Vinci A / S, based on the use of the methacrylic acid copolymer in a adequate solvent. The dosage of bromelain will depend on the individual needs of the patient being treated. The dosage of bromelain is conveniently measured in BTU (bromelain tyrosine units), CDU (casein digestion units), GDU (gelatin digestion units), or MCU (milk coagulation units). BTUs, CDUs and GDUs are as defined in the literature as follows: BTU A tyrosine unit of bromelain is the amount of enzyme that releases a micromole of tyrosine per minute under the conditions of the assay (eg, after digestion of a hemoglobin substrate denatured with acid at a pH of 5 and at 30 ° C). CDU The amount of enzyme that releases a microgram of tyrosine after one minute of digestion at 37 ° C from a standard casein substrate at a pH of 7.0. GDU Enzymatic activity that releases a milligram (10 ~ 3 grams) of amino nitrogen from a standard gelatin solution after 20 minutes of digestion at 45 ° C and at a pH of 4.5. 1100 BTU / g = 750 CDU / mg = 1200 GDU / g.
Although the precise dosage will be under the control of the physician, daily dosages of 50 to 4000 GDU / day, and preferably 100 to 1000 GDU / day, may be appropriate. The daily dose can be given in one or more aliquots per day, for example, once, twice, three or four times a day. Alternatively, treatment may only be required once or twice a week for certain conditions.
The invention will now be illustrated by the following examples:
EXAMPLE 1 The formulation used is an example of a heat-refining vehicle. Typically, these materials melt upon heating, thus allowing the use of conventional mixing and pumping technology for fluid filling. Amount of Material Capsule power: 275 GDU / capsule.
mq / capsule (%) weight / weight Bromelain 90.00 mg 27.3 GELUCIRE 35/10 225.0 mg 68.2 AEROSIL 200 15.0 g 4.5
330. 0 mg 100.0 The GELUCIRE 35/10 was melted by heating to around 40 ° C. Bromelain and AEROSIL 200 were added until they were completely dispersed. A total of 330 milligrams of the formulation was filled into hard gelatin capsules size "1" while hot, and then allowed to solidify with cooling. The capsules can be subsequently sealed using a gelatin band. Enteric Coating To prevent premature release of bromelain from the delayed release formulation described above, an enteric coating can be applied to the hard gelatin capsule, for example, using the commercial process of Pharma Vinci A / S (Denmark). The enteric coating is applied to the capsules in an aqueous ethanolic solution by spray coating on a Combi-coata.
EXAMPLE 2 Effect of bromelain on fecal excretion of bile acids. Two formulations of bromelain were prepared to be tested in healthy human volunteers. The formulations were as follows: A: One size 1 hard gelatin capsule containing 276 units of bromelain gelatin digestion; B: A size 0 hard gelatin capsule, containing 1104 units of bromelain gelatin digestion. The hard gelatin capsules were enterically coated and, therefore, designed to release a bolus of bromelain after leaving the acidic environment of the stomach. The study was conducted over a period of 5 days. An initial period free of 2-day treatment was followed by a 3-day post-dose surveillance interval.
The medication was administered after an overnight fast with 250 milliliters of water. The food was allowed 3 hours after the dose. The fecal samples for each 24-hour period were pooled, weighed and homogenized in a sterile mixer. Then a sample of approximately 50 grams of the homogenate was taken, and it was frozen at -70 ° C until analyzed. The analysis of the faecal samples was carried out by the following method: 1. After thawing, the fecal samples were dried by freezing overnight, and the samples were milled until a fine homogeneous mixture was obtained. 2. Soxhiet extractions were performed overnight (approximately 16 hours) on 500 milligrams of stools dried by freezing with 50 milliliters of 50 percent (volume / volume) of chloroform: methanol. 3. An aliquot (10 milliliters) of this extract was evaporated to dry at 50 ° C under a stream of air, and re-dissolved in 500 microliters of methanol for the determination of bile acid. 4. The bile acid content of the samples was determined by a specific enzymatic assay based on the 3-α-hydroxysteroid dehydrogenase described by Coleman et al., Biochem. Y . , 178, 201-208 (1979). Results The medication was well tolerated in all cases without side effects.
TABLE I: Effect of bromelain on fecal excretion of bile acids.
The values represent the average daily faecal loss of bile acids in milligrams / day in the periods before the dose and after the dose.
The average daily bile acid production in the periods before the dose and after the dose was calculated and shown in Table 1. An increase in the average fecal bile acid production after bromelain administration of 165 was observed. percent and 315 percent for the dose of 276 GDU and 1104 GDU, respectively. An additional observation was the color change of the volume after the dose, reflecting the distinctive red-brown color of bromelain. This observation correlates well with the observed increases in fecal bile acid production. Conclusions The increased fecal excretion of bile acids observed in volunteers after receiving bromelain suggests that, under suitable conditions, the gastrointestinal biliary acid receptor can be inactivated by proteolytic degradation.
EXAMPLE 3 Effect of bromelain on plasma cholesterol and triglyceride levels in healthy volunteers. Following the observation that bromelain increases the fecal excretion of bile acids, detailed in Example 2, an additional study was carried out to investigate whether this phenomenon resulted in a reduction in plasma cholesterol levels, which is important in reducing the risk of developing Coronary Artery Disease. Twenty-one healthy male volunteers received either a placebo or an enteric-coated bromelain formulation, containing approximately 500 units of enzyme gelatin digestion, for 10 consecutive days. Plasma cholesterol and triglyceride levels were determined by standard hospital laboratory test methods, before starting the treatment and at the end of the study period. Results The results of this study show that treatment with bromelain for ten days reduced plasma cholesterol levels by an average of 17 percent, and plasma triglyceride levels by 31 percent. The reductions observed in the control groups during this period were less than 10 percent in the case of both plasma cholesterol and plasma triglycerides (see Table 2 below).
TABLE 2: Effect of treatment with bromelain on triglyceride and plasma cholesterol levels.
The values are the averages + sem of 10 or 11 observations.
Conclusions The treatment of healthy volunteers for 10 days with an enteric-coated bromelain product reduces plasma triglyceride and cholesterol levels, which are important risk factors in the development of Coronary Artery Disease.
Claims (7)
1. The use of bromelain in the preparation of an agent to reduce or prevent the reabsorption of bile acid by the gastrointestinal tract.
2. The use of bromelain in the preparation of an agent for the treatment or prophylaxis of conditions mediated by the volume of bile acid.
3. The use as claimed in claim 2, for the treatment or prophylaxis of hyperlipidemia, for example, hypercholesterolemia.
4. The use as claimed in claim 2, for the treatment or prophylaxis of cholestatic liver disease or liver failure.
5. The use as claimed in any of claims 1 to 4, wherein the bromelain is formulated for oral application.
6. The use as claimed in any of claims 1 to 5, wherein the bromelain is in a delayed release formulation.
7. The use as claimed in any of claims 1 to 6, wherein the bromelain is enterically protected.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9403344.6 | 1994-02-22 | ||
PCT/GB1995/000352 WO1995022348A1 (en) | 1994-02-22 | 1995-02-21 | Medical application of bromelain |
Publications (2)
Publication Number | Publication Date |
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MXPA96003556A true MXPA96003556A (en) | 1998-01-01 |
MX9603556A MX9603556A (en) | 1998-01-31 |
Family
ID=39164894
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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MX9603556A MX9603556A (en) | 1995-02-21 | 1995-02-21 | Medical application of bromelain. |
Country Status (1)
Country | Link |
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MX (1) | MX9603556A (en) |
-
1995
- 1995-02-21 MX MX9603556A patent/MX9603556A/en unknown
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