PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION COMPRISING LACTASE AND PROCESS FOR PRODUCING SAME

Abstract

The present invention falls within the fields of nutrition and pharmacy, being related to an orally disintegrating tablet comprising the lactase enzyme in combination with pharmaceutically acceptable excipients, and to a process for preparing same. The tablet of the present invention, as a result of disintegrating in a reduced amount of time, can be orally administered, making it easier to swallow and dispensing with the simultaneous consumption of liquid, and can also be mixed with lactose-rich foods, inducing enzyme activity outside of the organism.

Claims

1. A pharmaceutical composition for oral administration, wherein it is an orally disintegrating tablet comprising lactase enzyme in combination with pharmaceutically acceptable excipients.

2. The pharmaceutical composition, according to claim 1, wherein the pharmaceutically acceptable excipients comprises at least a disintegrating agent, a lubricant, a flavoring, a sweetener, and a diluent.

3. The pharmaceutical composition, according to claim 2, wherein the disintegrating agent is chosen from crospovidone, croscarmellose, glycated starch, polacrilin potassium, hydroxypropyl cellulose, microcrystalline cellulose, or combinations thereof.

4. The pharmaceutical composition, according to claim 2, wherein the lubricant is chosen from magnesium stearate, sodium stearyl fumarate, stearic acid, sodium citrate or combinations thereof.

5. The pharmaceutical composition, according to claim 2, wherein the diluent is chosen from several polyols (maltitol, mannitol and xylitol), microcrystalline cellulose, starch, talc, maltodextrin, sucrose, and dextrose or combinations thereof.

6. The pharmaceutical composition, according to claim 1, wherein it shows total disintegration in up to 1 minute and friability lower than 1.5%.

7. The pharmaceutical composition, according to claim 1, wherein it is mixed in lactose-rich foods.

8. A process to produce a pharmaceutical composition, according claim 1, wherein it comprises the steps of mixing of lactase with blend of diluents, disintegrating agents, and sweeteners, and next step of pressing.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0061] This description aims to investigate the inventive concept details, providing examples to facilitate cognition/understanding of the same and providing precise technical data about some ways to achieve the inventive concept of the invention. The detailed description also aims to avoid the third parties repetition, extensive experimentation, financial, time and intellectual activity expenses that inventors/filling performed to solve the technical problems which are settled herein.

[0062] In order to avoid doubts regarding interpretation, any feature described in an aspect of the present invention may be used in other aspect of the invention. The word comprising means including, but not necessarily consisting in or composed by. In other words, the steps or options listed should not be exhaustive. It is noted that the examples provided in the following description aim to clarify the invention, and should not be understood per se as limiting the scope of the invention.

[0063] This project is related to an orally disintegrating composition comprising lactase, and a process for preparing the same.

[0064] In a first aspect, the present invention defines a pharmaceutical composition for oral administration being an orally disintegrating tablet comprising the lactase enzyme in combination with pharmaceutically acceptable excipients.

[0065] In a concretization of pharmaceutical composition, the pharmaceutically acceptable excipients comprise at least a disintegrating, a lubricant, a flavoring, a sweetener and a diluent.

[0066] In a concretization of pharmaceutical composition, disintegrating agent is chosen among crospovidone, croscarmellose, glycated starch, polacrilin potassium, hydroxypropyl cellulose, microcrystalline cellulose or combinations thereof.

[0067] In a concretization of pharmaceutical composition, lubricant is chosen among magnesium stearate, sodium stearyl fumarate, stearic acid, sodium citrate or combinations thereof.

[0068] In a concretization of pharmaceutical composition, diluent is chosen among several polyols (e.g. maltitol, mannitol and xylitol), microcrystalline cellulose, starch, talc, maltodextrin, sucrose and dextrose or combinations thereof.

[0069] In a concretization, the pharmaceutical composition shows total disintegration in up to 1 minute and friability lower than 1.5%.

[0070] In a concretization, the pharmaceutical composition is mixed in lactose-rich foods.

[0071] In a second aspect, the present invention defines a process for producing the said pharmaceutical composition comprising the step of lactase mixturing with blend of diluents, disintegrating agents, and sweeteners, and next step of compression.

[0072] Lactase enzyme, or -D-Galactosidase, is a tetramer composed by A and B chains pursuant to family 1 of glucohydrolazes and it is in brush-border of mammal small bowel. Its local action occurs through its catalyst activity on hydrolyzes of lactose disaccharide -1,4 bond exclusively found in milk and milky products, having as products D-galactose and free glucose. This hydrolysis allows glucose and galactose monomers be absorbed by bowel membrane and in such way they may be used by body as energy source. Thus, lactase is an enzyme aiding lactose digestion present in milk-derived foods.

[0073] Lactase is also produced by plants, yeasts, bacteria and fungus. Several microbial sources may be used aiming to synthesize lactose. Industrially, obtained lactase is usually originated from fungus (Aspergillus oryzae, Aspergillus flavus and Aspergillus niger), bacteria (Escherichia coli and Lactobacillus bulgaricus) or yeasts (Saccharomyces fragilis, Torula cremoris and Torula utilis).

[0074] Lactose is a disaccharide formed by one glucose and one galactose molecule, exclusively found in mammal's milk. Lactase is the responsible enzyme for hydrolyzing lactose, allowing its absorption in monosaccharide form. Children usually have high lactase concentrations. However, after weaning, in many cases occurs a genetically programmed decrease in lactase synthesis, resulting in enzyme activity loss in adults. In these cases, disaccharide remains in intestinal lumen and is fermented by microflora, resulting in discomfort, pain, swelling abdominal, flatulence and diarrhea. Such situation is called primary lactose intolerance, or even non-persistent lactase.

[0075] The present product is presented in orally disintegrating tablet form, providing between 5000 and 15000 units FCC: 1 unit FCC is defined as the enzyme amount releasing o-nitrophenol compound at rate of 1 mol/min of lactase enzyme in unit portion, under conditions set forth by Food Chemicals Codex (FCC). It is recommended consume 1 tablet before the milk-originated products consumption or according to physician or nutritionist guidelines.

[0076] The product is presented in orally disintegrating tablet form so there is no need to drink water, facilitating the product use by the consumer, becoming this presentation novel for the product.

[0077] The amounts may vary among different subjects, and they may be adjusted depending on amount of consumed milk derivatives in each meal or according to physician or nutritionist guideline.

[0078] Regarding to safety of lactase consumption, it should be attention to the fact that the same contains enzyme-intrinsic proprieties, composed by natural and digestible amino acids, like any other naturally found protein in foods.

[0079] Regarding the producer microorganism, Aspergillus niger is used for commercially producing of several enzymes employed in foods and its safety is also well established, which is also the case of donor specimen of gene encoding lactase production, Aspergillus oryzae.

[0080] Therefore, the present invention is composed mainly by lactase enzyme in combination with adequate excipients, such as emulsifiers, lubricants, sweeteners, and a diluent.

[0081] Disintegrating agents which may be used in the present invention are crospovidone, croscarmellose, glycated starch, polacrilin potassium, hydroxypropyl cellulose (HPC) and microcrystalline cellulose. These excipients may be present in amount from 70.70 to 106.26 mg, corresponding to 14.13% and 21.25% by weight of final tablet, respectively.

[0082] Lubricants that may be used in the present invention are magnesium stearate, sodium stearyl fumarate, stearic acid and sodium citrate. These excipients may be present in concentration from 4.25 to 5.75 mg, corresponding to 0.85% up to 1.15% by weight of final tablet, respectively.

[0083] There are several flavoring agents that may be used in the present invention and they are divided between flavourings and sweeteners, which are included in formulation to promote a pleasant taste during oral disintegration. They are vanilla taste, chocolate taste, strawberry taste, grape taste, caramel taste, orange taste, lemon taste, apricot taste, cherry taste, mint taste, peppermint taste, apple taste, banana taste, sucralose, acessulfame, stevia, aspartame, glucose, several polyols, agave, cyclamate and saccharine. These excipients may be present in amount from 1.53 to 2.07 mg, corresponding to 0.306 up to 0.414% by weight of final tablet, respectively, for flavourings; and 0.17 to 0.23 mg, corresponding to 0.034% up to 0.046% by weight of final tablet, respectively, for sweeteners.

[0084] Diluents that may be used in the present invention are several polyols (e.g. maltitol, mannitol and xylitol), microcrystalline cellulose, starch, talc, maltodextrin, sucrose and dextrose. These excipients may be present in amount from 193.33 to 261.56 mg, corresponding to 38.6% up to 52.32% by weight of final tablet, respectively.

[0085] Friability of tablets should be lower than 1.0%, i.e., the mass loss of each tablet when subjected to mechanical tension should not be equal or lower than 5 mg.

[0086] As the object of the invention is an orally disintegrating tablet, the disintegrating time should be equal or lower than 1 minute.

[0087] Table 2 below summarizes all components of the present invention and its optimal amounts.

TABLE-US-00002 TABLE 2 ORALLY DISINTEGRATING TABLETS CONCENTRATION FUNCTION COMPONENTS AMOUNT/VOLUME PERCENTAGE Enzyme lactase from 10.000 to 500.000 76.50 to 103.50 mg 15.3% to 20.7% ALU**/g Disintegrating crospovidone, croscarmellose, 70.70 to 106.26 mg 14.13% to 21.25% agents glycated starch, polacrilin potassium, hydroxypropyl cellulose (HPC), microcrystalline cellulose. Lubricants Magnesium stearate, sodium 4.25 to 5.75 mg 0.85% to 1.15% stearyl fumarate, stearic acid, sodium citrate Flavourings Vanilla taste, chocolate taste, 1.53 to 2.07 mg 0.306% to 0.414% strawberry taste, grape taste, caramel taste, orange taste, lemon taste, apricot taste, cherry taste, mint taste, peppermint taste, apple taste, banana taste Sweeteners Sucralose, acesulfame, stevia, 0.17 to 0.23 mg 0.034% to 0.046% aspartame, glucose, several polyols, agave, cyclamate, saccharine Diluents several polyols (mannitol, 193.33 to 261.56 mg 38.6% to 52.32% xylitol, sorbitol, eritritol, isomalt, lactitol, maltitol), microcrystalline cellulose, starch, talc, maltodextrin, sucrose and dextrose

[0088] The producing process uses usual equipment for preparing solid pharmaceutical forms, for example:

[0089] Vibrating sieves, pharmaceutical mixers (V Mixer, Doble-Cone Mixer, BIN Mixer and/or Turbula Mixer shaker mixer) and rotating-type pharmaceutical compressor.

[0090] The invention is illustrated in more details by the following examples.

EXAMPLES

Preferential Realizations

[0091] The examples shown here are intended only illustrate one of several ways to implement this invention, however, without limiting the scope thereof.

Example 1

[0092] In order to prepare orally disintegrating tablets, according to Example 1, lactase (9,000 FCC) was mixed with polyols mix, for 10 minutes in V mixer. Sodium stearyl fumarate was added to previously prepared mixture and mixed for 2 minutes. The ready-to-compress mixture was compressed in tablets employing different compaction presses in a pharmaceutical rotating compressor.

TABLE-US-00003 TABLE 3 # MATERIAL Concentration formulation % 1 LACTASE Eq. a 9,000 FCC 18.00 2 POLYOLS MIX (Maltitol, 400.00 mg 80.00 xylitol and mannitol) 3 SODIUM STEARYL FUMARATE 10.00 mg 2.00

Example 2

[0093] In preparation, according to Example 2, lactase (9,000 FCC) was mixed with mannitol, microcrystalline cellulose, and flavoring for 15 minutes in V mixer. Sodium stearic acid was added in sequence and mixed for 5 minutes. The ready-to-compress mixture was pressed in tablets employing a pharmaceutical rotating compressor.

TABLE-US-00004 TABLE 4 # MATERIAL Concentration formulation % 1 LACTASE Eq. a 9,000 FCC 18.00 2 MANNITOL 200.00 mg 40.00 3 MICROCRYSTALLINE 198.20 mg 39.64 CELLULOSE 4 VANILLA TASTE 1.80 mg 0.36 5 MICRONIZED STEARIC ACID 10.00 mg 2.00

Example 3

[0094] In Example 3, lactase (9,000 FCC) was mixed with mannitol, L-HPC, vanilla taste, and croscarmellose, for 15 minutes in BIN-type mixer. Magnesium stearate was sieved, followed added, and mixed for 3 minutes. The ready-to-compress mixture was pressed in tablets employing a pharmaceutical rotating compressor.

TABLE-US-00005 TABLE 5 # MATERIAL Concentration formulation % 1 LACTASE Eq. a 9,000 FCC 18.00 2 MANNITOL 280.00 mg 56.00 3 L-HPC 89.00 mg 17.80 4 VANILLA TASTE 1.80 mg 0.36 5 CROSCARMELLOSE 29.20 mg 5.84 6 MAGNESIUM STEARATE 10 mg 2.00

Example 4

[0095] In Example 4, lactase (9,000 FCC) was mixed with mannitol, sylicated cellulose, sucralose, vanilla taste and crospovidone, for 15 minutes in V mixer. Magnesium stearate was sieved, followed added and mixed for 3 minutes. The ready-to-compress mixture was pressed in tablets employing a pharmaceutical rotating compressor.

TABLE-US-00006 TABLE 6 # MATERIAL Concentration formulation % 1 LACTASE 9,000 FCC 18.00 2 MANNITOL 180.00 mg 36.00 3 SYLICATED CELLULOSE 198.16 mg 39.63 4 SUCRALOSE 0.04 mg 0.008 5 VANILLA TASTE 1.80 mg 0.36 6 CROSPOVIDONE 20.00 mg 4.00 7 MAGNESIUM STEARATE 10.00 mg 2.00

Example 5

[0096] Tablets obtained from previous examples are subjected to analysis related to process and quality control. As the object of said invention is fast disintegrating tablets, disintegrating time is a critical quality parameter; however, this parameter is closely linked to friability, hardness and average weight of tablets.

[0097] The method of each analysis applicable to orally disintegrating lactase tablets is described above.

Friability:

[0098] Friability is performed in Friability Meter, apparatus consisting in rotating cylinder, rotating about its axis at a speed of 25 rotations per minute. The test establishes abrasion-resistance of tablets, when they are subjected to mechanic action and it is applied only to non-coated tablets. The test consisted in weighting exactly a certain number of tablets, submit them to apparatus function, and retrieve them after 100 rotations are completed. Twenty tablets were weighted and inserted in apparatus. The speed was adjusted to 25 rotations per minute and the apparatus time to 4 minutes. After this term, any powder residue was removed from tablets surface and they were weighted again. In accordance with Brazilian Pharmacopoeia (2010), none tablet may present any cracks, chip, rupture or breaks ate the end of test. Tablet with loss equal or lower than 1.5% of its weight are considered acceptable. If the result is doubtful or if its loss is higher than specified limit, test should be repeated for two times more, considering average result of three determinations on assessment. Friability test was performed in friability meter ERWEKA, model TAR120.

Hardness:

[0099] Hardness test is applicable mainly to non-coated tablets, allowing to determine tablet resistance to crushing or rupturing under radial pressure, through apparatus called durometer. Analysis was performed as described in Brazilian Pharmacopoeia (2010), wherein 10 tablets were submitted, solely, to action of apparatus measuring diametrically applied force required for crushing it. The result is expressed as the average of values obtained in determinations. Hardness was determined using a durometer of brand ERWEKA, model TBH125.

Average Weight:

[0100] Brazilian Pharmacopoeia reports that trial performed to establish average weight consists in individually weighting 20 tablets, in analytical scale, and divide total weight by amount of weighted units, obtaining average weight. To be in accordance with the acceptable parameters, average weight should not have more than two units out of specified limits, and no one may be above or under the indicated percentage, for 500 mg tablets the acceptable range is 5.0%. The analysis was performed according to Brazilian Pharmacopoeia description (F. Bras. 5 ed., 2010).

Disintegration:

[0101] The disintegration test aims to submit six tablets to conditions similar those found in human body. It is performed through disintegrating apparatus that consist of a baskets and tubes system, container suited to immersion liquid (distilled water) and thermostat to maintain the liquid at 37 C. Samples were input and submitted to a moving system, ascending and descending, intending to produce the same effects which tablets are undergone following consumption and through the mouth, stomach, and bowel. Optimal time cutoff for disintegrating is 30 minutes for immediate-release tablets (F. Bras. 5 ed., 2010), however, for orally disintegrating tablets is recommended the disintegrating time lower than 1.0 minute. Disintegrating test was performed in a disintegrator ERWEKA, model CT322.

Results:

[0102] The obtained results average of analysis of orally disintegrating lactase tablets is shown below.

TABLE-US-00007 TABLE 7 SAMPLES RESULTS SD CV Friability (Weight Loss - %) 0.1% Mean Hardness (Kgf) 9.265 Kgf 1.25 0.13 Average weight (mg) 501.91 mg 8.93 0.018 Disintegration (s) 48

[0103] Those well versed in the art will value the knowledge here, and may reproduce the invention in the manner provided and other variants, covered within the scope of appended claims.