Taste masked pharmaceutical liquid formulations

The present invention relates to oral pharmaceutical liquid preparations which are effective in masking the unpleasant taste of pharmaceutical or nutritional additives with bitter, metallic or otherwise undesirable taste characteristics. More particularly, the invention relates to liquid suspensions of enteric polymer coated with reversible polymer dosage forms which mask the unpleasant taste of the active ingredient. Liquid suspensions may be swallowed without experiencing a bitter taste in the mouth, but the coated center is immediately bioavailable when exposed to pH levels found in the stomach.

Medicines can be administered to a patient in many forms, with oral administration being the most common. The drugs can be administered to the patient orally, as liquid solutions, emulsions, or suspensions, or in solid form such as capsules or tablets. Babies, children, the elderly, and many others cannot swallow whole pills and capsules. Thus, in cases where the administered dose cannot be manufactured as a very small tablet or capsule, it is desirable to make the medicament liquid or chewable.

Many active ingredients, such as antibiotics, have a strong, unpleasant taste. When the medicament is manufactured in the form of a tablet or capsule to be swallowed whole, the taste of the active ingredient is usually not critical as the capsule prevents the active ingredient from coming into contact with the mouth and the tablet may be coated to prevent the active ingredient from contacting the mouth for a short time while the tablet is in place. present in the mouth.

On the contrary, masking the unpleasant taste of an active ingredient is an extremely important factor in the formulation of liquid and chewable pharmaceuticals. The appetizing nature of the liquid or chewable dosage form is a critical factor in ensuring patient compliance.

In some cases, the unpleasant taste of the active drug in a liquid or chewable preparation can be overcome by adding flavor and sweetening ingredients to improve taste and appetite. However, when the active drug exhibits a particularly strong or bitter taste, as is the case with many antibiotics, simply adding such flavors ingredients and sweeteners are insufficient to improve taste and palatability. Accordingly, various taste-masking coating compositions have been used in the formulation of liquid suspension and chewable tablet dosage forms. US Patent No. 5,599,556 discloses liquid formulations in which the active ingredient is coated with a single outer polymeric coating derived from the prolamine proteins of cereal grains and a plasticizer. The coatings are designed to rapidly degrade once the composition leaves the oral cavity.

US Patent No. 5,489,436 discloses chewable tablets made from a coated drug wherein the coating is a "reversible enteric coating" designed to be soluble at the lower pH of the stomach but relatively insoluble in water at the higher pH of the oral cavity. The coatings consist of a polymer mixture of dimethylaminoethyl methacrylate and neutral methacrylic acid ester and cellulose ester.

While the above-mentioned reversible enteric coating has been disclosed in connection with chewable tablets as a method of masking the taste of oral formulations, its use in a liquid formulation has not been disclosed where the taste-masking coating will have to survive in an aqueous environment for an extended period of time. There is therefore a need for a taste-masking formulation suitable for an aqueous liquid suspension which is stable and retains its taste-masking properties in the aqueous medium for an extended period of time, yet exhibits immediate bioavailability upon ingestion and swallowing.

Summary of the invention

The present invention relates to a liquid composition for oral administration comprising a pharmaceutically active drug coated with a taste masking effective amount of a polymer blend of (a) dimethylaminoethyl methacrylate and neutral methacrylic acid ester (MM / MAE) and (b) cellulose ester, in an aqueous carrier, where the weight ratio of the polymer is the cellulose ester to MM / MAE is about 40:60 to about 90:10, preferably about 60:40. The liquid composition employs a "reversible enteric coating" that is soluble under the acidic pH of the stomach, generally about 1.0 to 4.0, but relatively insoluble under the non-acidic pH of the oral cavity. Coatings allow for rapid drug release and absorption which is generally desirable for liquid dosage forms.

PL 197 812 B1

In preferred active embodiments, the drug useful in the taste-masking liquid formulations of the present invention is antibiotics, especially levofloxacin, ofloxacin and related quinolone antibiotics, such as other known antibiotics which have an unpleasant taste and are formulated for oral administration as liquids such as cephalosporins. , macrolide antibiotics, penicillins and the like. Other active drugs that can be advantageously used in the liquid compositions of the invention, include pain relievers such as tramadol or codeine, anti-inflammatory drugs such as ibuprofen, naproxen, and other NSAIDs. Other active agents with which the liquid compositions of the invention can be used include gastrointestinal, antihistamines, decongestants, antidepressants, antipsychotics, antivirals, oncolytic drugs, vaccines, antiepileptics (e.g., topiramate), antiasthmatic drugs, anticonvulsants, and the like.

According to the invention, the active drug particles are generally spray-coated with a polymeric coating either directly or after granulation, and then the coated particles are mixed with other pharmaceutically acceptable additives such as sweeteners, flavors and the like in an aqueous liquid carrier for oral administration.

The invention also relates to a method of masking the taste of medicaments for oral administration using the coating compositions of the invention.

Detailed description

The invention relates in particular to taste-masked liquid preparations for oral administration, comprising a pharmaceutically active drug having an unpleasant taste, which is coated with a reversible enteric coating. Reversible enteric coatings are coatings that are not water-soluble at the non-acidic pH of the mouth, but soluble at the acidic pH of the stomach. Coatings provide a protective layer which masks the unpleasant taste characteristics of the active ingredient in the mouth due to its poor solubility, but is readily soluble in the stomach and thus provides immediate release of the active drug in the stomach. Reversible enteric coatings enclose the active ingredient and thus effectively and permanently mask the taste of the active drug.

According to the invention, there is provided an orally absorbable liquid composition comprising a particulate pharmaceutically active agent contained in a liquid suspension having a pH greater than about 6.0, each molecule containing a pharmaceutically active agent core, optionally associated with inactive pharmaceutical adjuvants; a core coated with a taste-masking effective amount of a polymer blend of (a) dimethylaminoethyl methacrylate and neutral methacrylic acid ester (MM / MAE) and (b) cellulose ester, in an aqueous carrier wherein the weight ratio of cellulose ester polymer to MM / MAE is about 60:40 to about 70:30, preferably about 60:40. In a preferred embodiment, the formulation is prepared as a dry powder which is reconstituted with water to provide the liquid compositions of the invention.

Details of the polymer blend used for coatings and coating techniques are described in US Patent 5,489,436, hereby incorporated by reference for this application. In general, cellulose acetate, the solubility of which is independent of pH, and the MM / MAE component, whose solubility is pH-dependent, are mixed in a ratio that provides the desired diffusion characteristics. The diffusion and solubility of the coating depends on the ratio of the two components and the physicochemical properties of the drug to be coated. For liquid formulations according to the present invention, the inventors have found that the optimal CE: MM / MAE ratio especially when the active agent is the quinolone antibiotic levofloxacin is about 60:40 to 70:30, respectively. This ratio provides the desired diffusion characteristics, that is, adequate taste masking when present in the mouth, but immediate disintegration and diffusion of the active ingredient when present in the acidic pH of the stomach. The diffusion characteristics so obtained ensure the proper immediate bioavailability of the active ingredient, as is generally desired in liquid preparations.

If necessary, the particles of the active ingredient are first granulated before coating, especially if the particles are of irregular shapes and sizes. Preferably, the coated particles will range from about 3 to about 500 µm. The optimal thickness of the coating material applied to the particles will depend on the physicochemical characteristics of the active ingredient, but is generally from about 40% to about 120% of the applied layer. The most preferred level of coating is between about 50% to about 120% by weight of the coating based on the weight of the encapsulated component particles

PL 197 812 B1 active. For levofloxacin, the preferred level of coating is from about 90% to about 120%, most preferably about 111%, of the initial particle weight.

The components of the polymer coating are as disclosed in US Patent No. 5,489,436. A variety of cellulose esters can be used in the polymer coating. The preferred cellulose esters are cellulose acetate, cellulose butyrate and cellulose triacetate, with cellulose acetate being most preferred. A preferred MM / MAE is a polymer blend under the trade name EU-DRAGIT® E-100, available from Rohm Pharma. It is a copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters with an average molecular weight of 150,000. Other optional additives such as polyvinylpyrrolidone or 2-vinylpyridine (V) / styrene (S) copolymer can be added to the polymer coating blend.

The preparation of the formulation can be accomplished by a number of coating techniques known in the art, including fluidized bed coating, conventional top spray coating, and wet granulation. Preferably, a coated fluid bed coating with a Wurster column insert is used for the application. In this procedure, the particles of the active ingredient to be coated are suspended in an apparatus which creates an upward flow of air through which the particles move. The stream passes through the region of the finely atomized coating material which coats the passing particles, whereupon the coated particles fall through the Wurster column and downstream in a fluidized countercurrent with the heated fluidizing gas stream and dried. The particles can be re-streamed for further coating.

Generally, the polymer coating material is dissolved in an organic solvent to form a solution for use in a fluidized bed coating process. A variety of organic solvents can be used, preferably acetone or an acetone-methanol mixture. The solvent is removed in the drying process and is therefore not present in the final composition. The total polymer concentration in the coating solutions may generally range from about 5 to about 20% by weight, preferably about 12% by weight.

After the dried coated particles are obtained, they are mixed with other pharmaceutically acceptable adjuvants such as flavoring, sweetening, thickening, coloring and the like to form the compositions of the invention for oral administration of a liquid. Suitable flavoring agents include fruit, mint, licorice or bubble gum. Sweetening agents may e.g. be mostly sweeteners such as sucrose or polyols (e.g. malitol, sorbitol) and / or intense sweeteners such as saccharin, aspartame or acesulfame K. The preparation can be prepared as a liquid or as a powder to be reconstituted with water by a pharmacist prior to release.

It is also desirable to include an alkalizing agent in the aqueous liquid slurry to maintain the integrity of the reversible taste-masking coating. Alkalizing agents that can be used in the present invention are agents that are alkaline in an aqueous solution and can raise and maintain the pH of the aqueous suspension above about 5. The alkalizing agent can be selected from any of the following: alkali metal hydroxides, phosphates, carbonates and bicarbonates such as sodium bicarbonate; magnesium hydroxide; magnesium oxide; magnesium phosphate; magnesium carbonate; magnesium bicarbonate; magnesium glycinate; magnesium silicates; magnesium aluminum silicate; basic clays such as bentonite; zeolites; calcium oxide; calcium hydroxide; calcium phosphates; magaldrat; hydrotalcite; sodium aluminum dihydroxy carbonate; ammonium hydroxide; ammonium bicarbonate; ammonium carbonate; ethanolamines; diethanolamine; triethanolamine; tetrasodium ethylenediaminetetraacetate, their hydrates and the like.

In the case of levofloxacin, sodium bicarbonate is preferred.

One or more of such alkalizing agents may be used in an amount necessary to raise the pH of the slurry above 5.0.

The taste masking formulations of the present invention have been found to meet the special requirements imposed on liquid formulations. According to the invention, its object is a formulation that is stable, i.e. the taste-masking properties persist in the "foreign" aqueous environment after reconstitution for at least the duration of treatment (in the case of antibiotics 7-14 days), while still providing an appropriate masking taste when administering the product. .

In order to further illustrate the present invention and the advantages thereof, specific examples have been prepared, it being understood that these examples are only intended to illustrate the invention and are not intended to limit the scope of the present invention.

PL 197 812 B1

Example 1

Preparation of a taste-masking composition of levofloxacin for oral administration of a liquid. Pharmaceutically active core particles of a coating solution of polymers, as described in Table 1 below, are prepared by adding the polymers to acetone.

Table 1:

Quantitative composition of levofloxacin coated beads

<td>Ingredient</td><td>% wt / wt</td>

<td>Levofloxacin</td><td> 9,836</td>

<td>Eudragit E100</td><td> 4,328</td>

<td>Cellulose acetate NF (CA 398-10)</td><td> 6,328</td>

<td>Acetone, ^NF®</td><td> 79,344</td>

<td>Together:</td><td> 100,0</td>

^andAcetone is removed during the process and does not appear in the final product

The coating was made in a Glatt GPCG-3 fluid bed coater with a Wurster insert. The weight ratio of cellulose acetate polymer to Eudragit E100 in the taste-masking coating for the two batches was 60:40 and 70:30 for Charges 1 and 2, respectively. The actual amount of coating, calculated from the strength test, was 111% and 93% of the original, respectively. The coating parameters and the sieve analysis for the two batches are summarized in Tables 2 and 3.

Table 2:

Coating parameters of two batches of coated levofloxacin beads prepared using a Glatt GPCG-3 coater with a 7 Wurster column

<td rowspan="2">Batch</td><td rowspan="2">Batch size (kg)</td><td colspan="3">Temperature when spraying</td><td rowspan="2">Fluidizing air (%)</td><td rowspan="2">Nozzle size (mm)</td><td rowspan="2">Atomizing air (bar)</td><td rowspan="2">Baffle height (inch)</td><td rowspan="2">Spray rate (g / min)</td><td rowspan="2">Spray time (min)</td><td rowspan="2">Drying time (min)</td><td rowspan="2">Temp. drying the product</td><td rowspan="2">Total performance capacity (%)</td>

<td>Inlet ("C)</td><td>Product ("C)</td><td>Departure fC)</td>

<td> 1</td><td> 1,2</td><td> 62-64</td><td> 25-40</td><td> 26-31</td><td> 12</td><td> 1,2</td><td> 3</td><td> 1</td><td> 16,8-25,7</td><td> 183</td><td> 30</td><td>30-42 ”C</td><td> 88,5</td>

<td> 2</td><td> 1,1</td><td> 57-64</td><td> 30-33</td><td> 26-32</td><td> 12</td><td> 1,2</td><td> 3</td><td> 1</td><td> 16,6-25,3</td><td> 159</td><td> 30</td><td>30-36 "C</td><td> 87,4</td>

Table 3

Sieve analysis of coated levofloxacin

<td>Batch</td><td> 1</td><td> 2</td>

<td>Mesh size</td><td> (%)</td><td> (%)</td>

<td> &gt; 40</td><td> 0,44</td><td> 0,43</td>

<td> 40-60</td><td> 5, 61</td><td> 2,81</td>

<td> 60-80</td><td> 18,36</td><td> 14, 68</td>

<td> 80-100</td><td> 14,81</td><td> 15,01</td>

<td> 100-140</td><td> 35,29</td><td> 44,14</td>

<td> 140-200</td><td> 19,59</td><td> 16,73</td>

<td> &lt; 200</td><td> 5,91</td><td> 6,20</td>

<td>Together</td><td> 100,0</td><td> 100,0</td>

PL 197 812 B1

After coating the levofloxacin particles, the coated particles are mixed with the adjuvants shown in Table 4 below to form a liquid oral administration composition suitable for pediatric use.

Table 4

Quantitative composition of levofloxacin powder for reconstitution 125 and 250 mg / 5 ml after reconstitution

<td>Ingredient</td><td>g / 5 ml</td><td>g / 5 ml</td>

<td>Levofloxacin</td><td> 0^,125^and</td><td> 0^,250^and</td>

<td>E.^atdragit E100 0^and</td><td> 0^,05^and</td><td> 0^,10^and</td>

<td>Cellulose acetate, NF (CA 398-10)</td><td> 0^,075^and</td><td> 0^,15^and</td>

<td>Sodium Bicarbonate, USP</td><td> 0,02</td><td> 0,02</td>

<td>Microcrystalline Cellulose + Carboxymethyl Cellulose, NF (Avicel RC591)</td><td> 0,275</td><td> 0,275</td>

<td>Sucrose, NF (Baker's Special Granulated)</td><td> 2,5</td><td> 2,5</td>

<td>N&amp;A Bubblegum Flavor</td><td> 0,001</td><td> -</td>

<td>N &amp; A Fruit Punch Flavor</td><td> -</td><td> 0,0075</td>

<td>FD&amp;C Red # 40 0.00015 0.002</td><td> 0,00015</td><td> 0,002</td>

<td>Water qs to</td><td> 5^,0 ^ml^b</td><td> 5^,0 ^ml^b</td>

^and based on the theoretical 100% initial coating level.

The actual amount depends on the test strength of the coated levofloxacin beads used in the batch. ^b The water is added by the pharmacist before dispensing.

Example 2

Dissolution Studies of Taste-Masking Levofloxacin Composition for Oral Liquid Administration

Levofloxacin particles with a reversible enteric coating, prepared as described in Example 1, were tested using a dissolution apparatus. Dissolution studies were performed at pH 1, 2, 3 and 7.5 with two batches of coated levofloxacin beads prepared as described in Example 1. The results summarized in Table 5 show that very little active ingredient is released at pH 7.5, whereas rapid release was observed at pH 1.2.

Table 5

Dissolving the preparation to mask the taste

<td rowspan="2">Batch no</td><td rowspan="2">Theoretical coating (% initial)</td><td rowspan="2">Dose form</td><td rowspan="2">Center dissolving (900 ml)</td><td rowspan="2">pH</td><td rowspan="2">Dose / capacity^(mg)</td><td colspan="7">Percentage of the formulation dissolved after</td>

<td>10 min</td><td>20 min</td><td>30 minutes</td><td>45 min</td><td>60 min</td><td>90 min</td><td>120 min</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td> 10</td><td> 11</td><td> 12</td><td> 13</td>

<td> 1</td><td>88 (111% of the actual</td><td>Coated balls equivalent to 250 mg of levofloxacin</td><td>0.1NHCl 900ml + 0.1% Tween20</td><td> 1,2</td><td> 250</td><td> 93,75</td><td> 95,07</td><td> 95,07</td><td> 95,25</td><td> 95,70</td><td> 94,53</td><td> 95,00</td>

<td> 1</td><td>88 (111% of the actual</td><td>Coated balls equivalent to 250 mg of levofloxacin</td><td>0.05M KH2POa buffer / citric acid 900 ml + 0.1% tweed 20</td><td> 3,0</td><td> 25-</td><td> 47.72</td><td> 80.77</td><td> 94.-2</td><td> 98.84</td><td> 99.59</td><td> 99.74</td><td> 99.65</td>

<td> 1</td><td>88 (111% of the actual</td><td>Coated balls equivalent to 250 mg of levofloxacin</td><td>0.05M KH2POa / NaOH buffer 900 ml + 0.1% tweed 20</td><td> 7,5</td><td> 250</td><td> 2.71</td><td> 3.23</td><td> 3.42</td><td> 3.68</td><td> 3.92</td><td> 4.28</td><td> 4.81</td>

PL 197 812 B1 cont. table 5

<td> ,</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td>IN</td><td>H.</td><td> ,2</td><td> ,3</td>

<td> 2</td><td>76 (93% aascaywistsj</td><td>PuwlsUsns UslUi aównuwsens 250 mg of lswufluUsscyna</td><td>0JN HCl 900 ml + 0J% tweed 20</td><td>L2</td><td> 250</td><td> 90,64</td><td> 99,43</td><td>W0.83</td><td> 99,77</td><td> ,00,64</td><td> 99,40</td><td> ,0,,25</td>

<td> 2</td><td>76 (93% aascaywistsj</td><td>PuwlsUsns UslUi aównuwsens 250 mg of lswufluUsscyna</td><td>0.05M bsfua KH2PO4 / Uwss cytaynuwa 900 ml + 0J% tweed 20</td><td> 3,0</td><td> 250</td><td> ,8,66</td><td> 27,32</td><td> 35,38</td><td> 46,98</td><td> 56,94</td><td> 75,98</td><td> 89,0,</td>

<td> 2</td><td>76 (93% aascaywistsj</td><td>PuwlsUsns UslUi aównuwsens 250 mg of lswufluUsscyna</td><td>0.05M bsfua KH2PO4 / NsOH 900 ml + 0J% tweed 20</td><td> 7,5</td><td> 250</td><td> 3,22</td><td> 3,7,</td><td> 4,06</td><td> 4,8,</td><td> 5,30</td><td> 6,20</td><td> 7,08</td>

Patent claims