DE102009006594A1 - Pharmaceutical preparation, useful for the treatment of digestive disorders, cystic fibrosis and pancreatitis, comprises a liquid dosage form of enzymes - Google Patents

Abstract

Pharmaceutical preparation comprises a liquid dosage form of enzymes for the treatment of digestive disorders. An independent claim is also included for the treatment of the pancreatic diseases, comprising using lipase as a stable solution with stabilizers e.g. salts, organic acids, amino acids, detergents or sugars, where the bacterial lipase is not chemically modified. ACTIVITY : Gastrointestinal-Gen; CNS-Gen; Respiratory-Gen; Antiinflammatory. MECHANISM OF ACTION : None given.

Description

Summary of the invention

The The invention relates to pharmaceutical preparations for treatment of pancreatic insufficiency, for example cystic fibrosis or others Pancreatic diseases. In particular, the present invention relates liquid pharmaceutical preparations of digestive enzymes, which have no coating and in the aggressive environment of stomach / duodenum are active. Furthermore These are liquid pharmaceutical preparations stable and can be stored at high temperatures.

Background of the invention

excessive Expression or lack of effective enzymes often results to metabolic or gastrointestinal diseases. imbalance The lipase level can, for example, a variety of digestive disorders cause, including malabsorption of fats. In patients, those with cystic fibrosis, chronic pancreatitis and other pancreatic diseases suffer from malabsorption of fats. Usually observed consequences of malabsorption of fats are abdominal complaints, Steatorrhea (fat loss), lack of essential fatty acids, on fat-soluble vitamins (for example A, D, E and K) and general developmental disorder.

The usual Procedure for the treatment of diseases with lipase insufficiency are orally administered lipase enzymes, mostly based on products of porcine pancreas, degreased, dried and pounded has been. The resulting product consists of several enzymes, such as Lipase, amylases, proteases, esterases etc.

Generally available dosage forms are common enteric-coated film-coated tablets, microtablets, Mikrodragées, capsules, powders and granules. The disadvantage These forms of administration consist in the inconvenience of Administration to the patient, the large tablets or Must swallow capsules. Especially in the case of patients who are unable to swallow tablets like little children, or need the artificial diet, these are Forms of administration are difficult to apply. The pounding The tablets can not have a homogeneous distribution of the enzymes in the chyme ensure and the low solubility of the product can lead to the obstruction of the feeding tubes.

Liquid formulations of digestive enzymes have been described in, for example, EP 0826375 or US 2006/0128587 described. In these patent applications, the enzymes are either stabilized with additives or by modification of the enzymes themselves. In both cases, however, the enzyme solutions must be prepared fresh prior to administration, which is less convenient than a ready-to-use liquid preparation. In addition, the effects of additives on the active substance, efficacy and safety must be considered.

The Treatment based on readily available pancreatin products has several disadvantages. The lipase is considered the lead enzyme. Due to the low specific lipase activity needs an amount of up to 5-10 g per day from the patients be taken. In addition, the pig lipase is in active in a pH range of 5 to 9 and is therefore during of the stomach passage inactive.

In addition, due to the low pH sensitivity, lipase activity must be protected from the acidic pH conditions in the stomach, for example by enteric coating of the tablets. In some medical applications, the accompanying proteolytic or amylolytic enzyme activities are undesirable: the level of amylase is undesirable in children with cystic fibrosis, whereas lipases are therapeutically required. Proteases are contraindicated in patients with acute pancreatitis or active phases of chronic pancreatitis (see US 5,645,832 ). Therefore, the availability of a lipase as a single protein is advantageous. In US 5,645,832 or US 5,489,530 a lipase derived from bacteria has already been described in detail. In addition to providing a purified single protein, the lipase concentration of bacterial lipase is very high so that only small amounts of substance (about 0.2 g) need to be administered. The pH range for the activity of the bacterial lipases is between 3 and 9 and therefore overcomes the limitations of the stability and activity of porcine lipase / pancreatin. This means that the lipolytic action of the bacterial lipases can be used with greater effect in the gastrointestinal tract than the products marketed for the treatment of maldigestion on the market. In addition, the bacterial lipase is a non-animal product that avoids the risk of possible animal source virus contamination.

Description of the invention

The The present invention provides a liquid pharmaceutical Preparation containing a digestive enzyme. The Preparation is used to treat patients with pancreatic insufficiency, For example, cystic fibrosis or other pancreatic diseases.

Surprisingly, it was shown who that lipase is active without coating in the aggressive environment of stomach / duodenum and that the enzyme is stable in aqueous solution for several months at room temperature. In addition, it has been found that bacterial lipase is able to reduce fat diarrhea in cystic fibrosis patients.

The invention is based on a lipase which is produced in bacteria and their production is described in US 5,645,832 expressly described.

The Lipase application has been proven to be effective in treating patients who suffer from pancreatitis or cystic fibrosis. The reduction of fat loss was when used exclusively observed by lipase. No other enzymes, such as proteases, amylases or esterases were present (Example 1).

Pure Bacterial lipase can do more specific activities than 3.5 billion U / g. Because of this high lipolytic Activity must give the patient a lower amount of administration (i.e., number of tablets or volume of solution) become.

The The present invention provides the lipase as a liquid pharmaceutical Preparation to the limitations of the common To overcome formulations (tablets) of therapeutic digestive enzymes. Especially in the case of patients who are unable to To swallow tablets, such as small children, or those that are artificial Nutrition, the common administration forms are not or only conditionally applicable.

One liquid pharmaceutical product offers the possibility a convenient dosage of the drug, homogeneous distribution of the Enzymes in the diet and use in artificial nutrition.

It has been shown that lipase is active without coating under pH conditions that mimic the aggressive environment of the stomach when ingested (Example 2). In addition, it has been shown that the bacterial lipase is stable in aqueous solution for at least 3 months even at high temperatures (Example 3). No chemical modification, as in US 2006/0128587 was described was required.

• – Salze
• – organische Säuren
• – Aminosäuren
• – Detergentien
• – Zucker
• – Öle
• – Viskositätsregulierungsmittel.

Included in the invention are formulations which also use stabilizers, such as

• - salts
• - organic acids
• - Amino acids
• - detergents
• - Sugar
• - oils
• - viscosity control agent.

at the liquid formulation can be: solutions, Solution / drops; suspensions; Suspension drops. The invention is based on the advantages of liquid administration forms especially, but not exclusively, for children.

liquid Forms of administration can either be prepared by that the lipase is produced directly as a liquid solution or by dissolving the active ingredient lipase in an aqueous or nonaqueous solvent, by suspending the drug in a suitable environment or by inserting the drug into one of the two phases an oil / water system.

dosage forms like solutions, suspensions and emulsions of lipase useful for a number of reasons. You can be formulated for different routes of administration: Oral intake, insertion into body cavities or external application. The dose can be adjusted by dilution For example, single drops can be made with one Drip device can be administered. The liquid oral Shape can be easily administered to children or people who are unable are, tablets, capsules or any other solid forms of administration to swallow.

The Lipase solution is a homogeneous mixture, the pharmaceutical Includes forms that are water, aromatic waters, aqueous acids, called solutions become.

The Lipase suspension refers to a two-phase system that consists of solid lipase dispersed in a liquid is.

Example 1: Cumulative amount of fat in patient's stool during treatment with placebo or verum - 1 -

Bacterial lipase was tested during a clinical trial in cystic fibrosis patients. As in 1 and the table below, which shows the fat absorption coefficient of patients on placebo and verum, shows significant differences in the amount of fats in the stool of the patients taking Verum as well as the fat absorption coefficient (CFA). The bacterial lipase significantly improves the breakdown of fat during digestion. patient CFA Placebo 1 73% Placebo 2 64% Placebo 3 65% Verum 1 92% Verum 2 96% Verum 3 93%

Example 2: Activity of lipase under conditions of low pH (imitation of the pH in the stomach) 2 -

Bacterial lipase was dissolved and adjusted to the pH of 1.0, 2.0, 3.0, 4.0 and 5.0 are set. Lipase activities were applied of the tributyrin test after 15, 30 min and 1, 2, 4 and 18 hours measured at the test pH (8.0).

It has been found that the pH in the stomach of patients suffering from cystic fibrosis increases to 4 when swallowed. Bacterial lipase shows sufficient activity under these conditions ( 2 ), while the activity of porcine lipase (from pancreatin) is reduced by 85% after 2 hours and by 96% after 4 hours at pH 4 (not shown).

Example 3: Stability of Bacterial Lipase in Aqueous Solution 3 -

Bacterial lipase was dissolved in water and at 4 ° C, room temperature and 40 ° C incubated. The activity became 1, Measured 2, 3, 4, 5, 10 and 14 weeks. No significant loss of activity was detected during this period.

The The invention includes the description with the examples, the claims and the pictures.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - EP 0826375 [0005]
• US 2006/0128587 [0005, 0015]
• US 5645832 [0007, 0007, 0010]
• US 5489530 [0007]

Claims (5)

Pharmaceutical preparation comprising liquid administration form of enzymes for the Treatment of indigestion. Pharmaceutical preparation according to claim 1, where the digestive disorder is a pancreatic disease is - cystic fibrosis - pancreatitis. Pharmaceutical preparation according to claim 1, wherein the liquid administration form is a solution is a suspension or an emulsion. Pharmaceutical preparation according to claim 1, wherein the enzyme is a bacterial lipase - from the kind of Burkholderia - of the species Pseudomonas - from Burkholderia plantarii. Treatment of the above diseases by application of lipase as a stable solution - Treatment the above diseases by using lipase as a solution with stabilizers such as salts, organic acids, amino acids, Detergents, Sugars, - being the bacterial lipase is not chemically modified - orally administered Lipase in liquid form.