Patent ID: 12186272

DESCRIPTION OF REFERENCE SIGNS IN THE DRAWINGS

1: tubular member11: first tubular segment12: second tubular segment13: third tubular segment2: first opening21: inward crimp of the first opening3: second opening31: inward crimp of the second opening4: device cap5: granules or multi-particulates containing active pharmaceutical ingredients6: drug holding part61: orifice7: step structure71: first step71: second step8: fold cluster81: first fold cluster811: fold structure82: second fold cluster9: inner cavity

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following examples of the present invention will be illustrated with reference to the drawings. In the drawings of the description, elements with similar structures or functions will be represented by the same element symbols. It is understood that the drawings are only used to facilitate the description of the embodiments of the present invention, and are not intended to be an exhaustive description of the present invention nor to limit the scope of the present invention.

An oral drug delivery device including a turbulence-creating means having a step structure is prepared in the present invention.FIG.1AtoFIG.2Crespectively show a cross-sectional view of the type I and type II telescopic configuration of the oral drug delivery device according to the present invention. The oral drug delivery device is in a shorten form prior to use (FIG.1AorFIG.2A) and in an elongated form prior to sipping action (FIG.1BorFIG.2B), and granules are suspended during the sipping process (FIG.1CorFIG.2C). The oral drug delivery device shown inFIG.1AtoFIG.2Ccomprises a tubular member1that can be elongated or shorten having a first opening2, a second opening3and a device cap4.FIG.1AtoFIG.2Cillustrate a tubular member composed of three tubular segments11,12, and13, respectively. InFIG.1AtoFIG.1C, in the direction from the first opening2to the second opening3, the inner diameter of the first tubular segment11is the same as that of the third tubular segment13, and the outer diameter of the second tubular segment12is smaller than the inner diameter of the first tubular segment11, so that the first tubular segment11and the third tubular segment13can be elongated (FIG.1BandFIG.1C) or shorten (FIG.1A) axially along the second tubular segment12. InFIG.2AtoFIG.2C, the inner diameter of the first tubular segment11, the outer diameter and inner diameter of the second tubular segment12, and the outer diameter of the third tubular segment13in the direction from the first opening2to the second opening3gradually decrease, however, the edge lines on the same side of the profile of the three tubular segments are parallel to each other, so that the third tubular segment13and the second tubular segment12can be elongated (FIG.2BandFIG.2C) or shorten (FIG.2A) axially along the first tubular segment11.

The drug holding part6is arranged in the inner cavity9of the tubular member1near the first opening2, and the structure when it contains granules or multi-particulates5is showed in the figure. After the drug holding part6is placed in the inner cavity, the end of the first opening2is an inward crimp21, so that the diameter of the opening after inwardly crimped is smaller than the minimum diameter of the structure of the drug holding part6; the end of the second opening3is an inward crimp31, so that the diameter of the opening after inwardly crimped is smaller than the maximum diameter of the structure of the drug holding part6, thereby retaining the drug holding part6in the inner cavity. And a device cap4is arranged outside the second opening3. The drug holding part6is matched with the tubular member1to form a space5that can contain the drug (in the example of the present invention, it appears as granules and multi-particulates structure, and the active ingredient of the drugs is contained in the granules and multi-particulates structure). The drug holding part6comprises a porous structure having a plurality of orifices61, whose diameter is smaller than the granules or multi-particulates5, allowing the passage of drinkable liquids; but when no liquid passes through, the granules or multi-particulates5remain in the inner cavity9of the tubular member1. The oral drug delivery device is elongated to form a step structure7, which is shown inFIG.1AtoFIG.2C, and the step structure is arranged in the position of the inner cavity9between the second opening3and the drug holding part6. The step structure7shown inFIG.1AtoFIG.2Chas a first step71and a second step72, by sipping action, drinkable liquids pass through the steps71and72to create turbulence, thereby enhancing the mixing of drug-containing granules or multi-particulates5with drinkable liquids. It is well known to those skilled in the art that when the number of tubular segments increases, the total number of the step structures also increases accordingly, so the Reynolds number of created turbulences is also greater; in addition, when the height of the step structure increases in the range of the conventional art, the Reynolds number of created turbulences is also greater.

An oral drug delivery device including a turbulence-creating means with a fold structure is also prepared in the present invention.FIG.3AtoFIG.3Cshow a cross-sectional view of the accordion-type fold cluster configuration of the oral drug delivery device according to the present invention. The device is in a shorten form prior to use (FIG.3A) and in an elongated form prior to sipping action (FIG.3B), and granules are suspended during the sipping process (FIG.3C). The oral drug delivery device shown inFIG.3AtoFIG.3Ccomprises tubular member1that can be elongated with an inner cavity9and a plurality of fold cluster configurations, two fold cluster configurations81and82are shown inFIG.3AtoFIG.3C. Each fold cluster configuration has a plurality of fold structures811. The oral drug delivery device comprises a first opening2, a second opening3and a device cap4. Contained in the inner cavity9of the tubular member are granules or multi-particulates containing active pharmaceutical ingredients5and a drug holding part6. After the drug holding part6is placed in the inner cavity, the end of the first opening2is inwardly crimped, so that the diameter of the opening after inwardly crimped is smaller than the minimum diameter of the drug holding part6; the end of the second opening3is inwardly crimped31, so that the diameter of the opening after inwardly crimped is smaller than the maximum diameter of the structure of the drug holding part6, thereby retaining the drug holding part6in the inner cavity. In addition, a device cap4is arranged outside the second opening3. The drug holding part6shown inFIG.3AtoFIG.3Cis a porous structure, which has a plurality of orifices61and is positioned in the inner cavity9of the tubular member near the first opening2. The drug holding part6is matched with the tubular member1to form a space that can contain the drug granules or multi-particulates containing active pharmaceutical ingredients5. The diameter of orifices61of the porous structure is smaller than that of the granules or multi-particulates5, thereby allowing the passage of drinkable liquids; but when there is no liquid passed through, the granules or multi-particulates5remain in the inner cavity9of the tubular member1. When the oral drug delivery device is in an elongated form, drinkable liquids flow through the fold structure811to create turbulence through the sipping action, thereby enhancing the mixing of granules or multi-particulates containing active pharmaceutical ingredients5with drinkable liquids. It is well known to those skilled in the art that when the number of fold clusters increases, the total number of the fold structure also increases accordingly, so the Reynolds number of created turbulences is also greater; in addition, when the height of the protrusion of the fold structure toward the inner cavity increases in the range of the conventional art, the Reynolds number of created turbulences is also greater.

It is well known to those skilled in the art that after the drug holding part6is placed in the inner cavity9through the first opening2end, the device cap4can be directly disposed outside the second opening3. At this time, because the device cap is connected to the second opening hermetically, even if the end of the second opening3is not inwardly crimped, due to the existence of the step structure or the fold structure, the drug holding part6will not reach the outside of the second opening3through the cavity9, thereby retaining the drug holding part6in the inner cavity9. At this time, if the end of the second opening3is inwardly crimped, the diameter of the opening after inwardly crimped is smaller than the maximum diameter of the drug holding part, which can further ensure that the drug holding part6will not be sipped into the patient's mouth, leading to medical accidents during the use of the oral drug delivery device.

FIG.4AtoFIG.4Bschematically shows the plug flow and turbulence created by the oral drug delivery device including a turbulence-creating means with a step structure or a fold structure according to the present invention.

In the present invention, the tubular member1of the oral drug delivery device generally has an outer diameter between 4.0 mm and 15.0 mm. The inner cavity9of the tubular member1has a diameter usually between 2.0 mm and 14.8 mm. The length of the tubular member1is between 5 cm and 15 cm in its prepared form, and between 10 cm and 30 cm in its elongated form.

The preferred materials for manufacturing the tubular member1, the drug holding part6and the device cap4are polypropylene and polyolefin family polymers conventional in the art.

The active pharmaceutical ingredients (API) covered by the present invention include, but are not limited to, dabigatran etexilate or pharmaceutically acceptable salt thereof, levodopa/carbidopa, montelukast, lansoprazole, omeprazole, amoxicillin, clarithromycin, acetaminophen, dextromethorphan, doxylamine, pseudoephedrine and diphenhydramine.

In an embodiment, an oral drug delivery device comprises dabigatran etexilate methylate (DEM) with enhanced solubility in the form of granules, which is prepared by using a hot melt granulation process.

In another embodiment, an oral drug delivery device comprises dabigatran etexilate methylate (DEM) with enhanced solubility in the form of multi-particulates, the DEM is prepared by using a spraying process.

In another embodiment, an oral drug delivery device comprises an extended-release levodopa/carbidopa formulation in the form of multi-particulates, which is prepared by using extrusion, spheronization, and coating processes.

In another embodiment of the present invention, an oral administration delivery device comprises montelukast granules, which are prepared by conventional granulation process, including wet granulation, fluidized bed granulation, dry granulation, and the like.

In another embodiment of the present invention, an oral administration delivery device comprises lansoprazole in the form of multi-particulates and amoxicillin and clarithromycin in the form of granules, the multi-particulates are prepared by spraying and coating processes, and the granules are prepared by conventional granulation process, including wet granulation, fluidized bed granulation, dry granulation, and the like.

In another embodiment of the present invention, an oral administration delivery device comprises omeprazole in the form of multi-particulates and amoxicillin and clarithromycin in the form of granules, the multi-particulates are prepared by spraying and coating processes, and the granules are prepared by conventional granulation process, including wet granulation, fluidized bed granulation, dry granulation, and the like.

In another embodiment of the present invention, an oral administration delivery device comprises cold drug granules prepared by conventional granulation process, including wet granulation, fluidized bed granulation, dry granulation, and the like.

One of the oral drug delivery devices in the present invention is an oral drug delivery device including a turbulence-creating means with a stepped structure. One configuration of the device may be manufactured by the following manufacturing steps. First, a three-part tubular member (type I or type II, seeFIG.1AandFIG.2A) is manufactured by the traditional method of manufacturing straws.

Next, the drug holding part6is inserted into the first opening2end of the tubular member1. Then, the end is inwardly crimped so that the drug holding part6can be retained in the inner cavity9of the tubular member1. After that, the granules or multi-particulates containing active pharmaceutical ingredients5are filled into the tubular member1through the second opening3end of the tubular member1. Finally, the filled tubular member1is enclosed by the device cap4and wrapped with an aluminum pouch (not shown in figures).

Another oral drug delivery device in the present invention is an oral drug delivery device including a turbulence-creating means with a fold structure. The device may be manufactured by the following manufacturing steps. First, the tubular member1with three sets of accordion-type fold configurations8is manufactured by the traditional process of manufacturing straws. Next, the drug holding part6is inserted into the first opening2end of the tubular member1. Then, the end of the first opening2is inwardly crimped so that the drug holding part6can be retained in the inner cavity9of the tubular member1. After that, the granules or multi-particulates containing active pharmaceutical ingredients5are filled into the tubular member1through the second opening3end of the tubular member1. Finally, the filled tubular member1is enclosed by the device cap4and wrapped with an aluminum pouch (not shown in figures).

The present invention is further explained by specific embodiments below, but the present invention is not limited to the scope of the described embodiments. In the following examples, the experimental methods not specified in the following embodiments shall be selected in accordance with the conventional methods and conditions or in accordance with the product specifications.

EXAMPLE 1

Multi-particulates containing dabigatran etexilate mesylate (DEM) were prepared by spraying the solid solution/dispersion composition onto sugar pellets. The composition comprises, in weight percentage, 40% of dabigatran etexilate mesylate (DEM), 10% of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol-grafted copolymer, Soluplus, and 50% of polyoxyethylene polyoxypropylene ether block copolymer, Kolliphor P407. First, these solid components were dissolved in 92% ethanol to prepare a coating solution with 24.2% of solid content. Then, 714.8 g of the coating solution containing 173.0 g of solid components was sprayed onto 346.0 g of pre-dried sugar cores by using a fluidized bed granulator with Wurster insert under appropriate air inlet pressure and at 38-40° C. of air inlet temperature. During the coating process, the spraying speed and atomization pressure were adjusted to keep the product temperature at 28-30° C. After the coating solution was exhausted, the coated pills were dried in a fluidized bed until the water content was below 1.7%. The target weight ratio of the drug layer to the sucrose core was 0.5:1.0. Additional Soluplus granules (180 mg) were added in the form of powder (<80 mesh). The Soluplus powder used in this experiment was obtained by grinding Soluplus granules, followed by sieving them with an 80-mesh sieve.

The DEM comprising multi-particulates (552.4 mg for 50 mg dose and 648.6 mg for 75 mg dose) and Soluplus powder (120 mg for 50 mg dose and 180 mg for 75 mg dose) were filled into the inwardly crimped first opening2end of the tubular member1through the second opening3end. Finally, the filled tubular member was enclosed by a device cap and wrapped with an aluminum pouch (not shown in figures). The compositions of the multi-particulates fill formulation in the device were listed in the Table 1.

TABLE 1The compositions of the multi-particulates fill formulation in Example 1wt/piece, mgwt/piece, mgCompositionswt %(50 mg dose)(75 mg dose)Dabigatran etexilate mesylate10.457.786.5(DEM)*Soluplus2.614.421.6Kolliphor P40713.172.1108.1Sucrose core52.2288.2432.4Soluplus powder21.7120.0180.0Total content100.0552.4828.6*57.7 mg and 86.5 mg DEM are equivalent to 50 mg and 75 mg of its free base, respectively.

A two-stage method with 45 minutes at the gastric phase (pH 2.0) and 10 minutes at the intestinal phase (pH 6.8) was used to measure the dissolution profile of the fill formulation. As shown inFIG.5, compared with the commercial product Pradaxa®, the fill formulation in this example showed a more rapid dissolution at low pH and less precipitation at pH 6.8. The error bars represented the standard deviation of n=3.

EXAMPLE 2

In this example, a DEM comprising granular formulation was prepared by a hot melt granulation process. The compositions of the hot melt DEM formulation were listed in the Table 2.

TABLE 2The compositions of hot melt DEM formulationmg/piecemg/piece,Compositionswt %(50 mg dose)(75 mg dose)Dabigatran etexilate mesylate17.257.786.5(DEM)Soluplus ®35.7120.0180.0Mannitol17.960.090.0Kolliphor P18819.064.096.0Cross-linked9.732.749.1carboxymethylcellulosesodiumMagnesium stearate0.51.72.5Total content100.0336.1504.1*57.7 mg and 86.5 mg DEM are equivalent to 50 mg and 75 mg of its free base, respectively.

The hot melt granulation process is briefly described as follows. First, Soluplus® was ground and passed through an 80-mesh sieve, and Kolliphor P188 was ground and passed through a 40-mesh sieve, and then the sieved Soluplus® powder was mixed with other excipients except magnesium stearate in a high-shear granulator with a thermal jacket at the temperature of 65-75° C. until formation of consistent and homogeneous granules were formed. Next, the hot melt granules were passed through a 20-mesh sieve and then blended with magnesium stearate.

The hot melt DEM granular preparations (336.1 mg for 50 mg dose, 504.1 mg for 75 mg dose) were filled into the inwardly crimped first opening2end of the tubular member through the second opening3end. Finally, the filled tubular member was enclosed by a device cap and wrapped in an aluminum pouch (not shown in figures). A two-stage method, 45 mins at the gastric stage (pH 2.0) followed by the intestinal stage (pH 6.8), was used to measure the dissolution profile of the fill formulation. As shown inFIG.6, compared with Pradaxa®, the fill formulation in this example showed significantly faster dissolution at acidic pH and much less precipitation at the neutral pH. The error bars represent the standard deviation of n=3.

EXAMPLE 3

In this example, a fill formulation was composed of immediate-release levodopa/carbidopa granules and levodopa extended-release multi-particulates. The compositions of the fill formulation were listed in Table 3. The immediate-release granules were prepared by conventional wet granulation process, and extended-release multi-particulates were prepared by extrusion/spheronization/spray coating process. The coating level of the extended-release multi-particulates was 5.1% by weight, with 90% of levodopa released at approximately 3.9 hours.

TABLE 3The compositions of the levodopa/carbidopa formulationin Example 3Compositionswt %mg/pieceImmediate-release granulesLevodopa42.350.0Carbidopa monohydrate*45.754.0Sodium dodecyl sulfate1.92.4Hydroxypropyl methylcellulose (HPMC) E54.85.6Cross-linked carboxymethylcellulose sodium4.85.6Magnesium stearate0.50.6Total content100.0118.2Extended-release multi-particulatesLevodopa70.41200.0Microcrystalline cellulose19.0354.1Sodium dodecyl sulfate3.8110.8Povidone K29/321.905.4Cellulose acetate 39.84.1211.7Copovidon (Kollidone VA64)0.732.1Total content100.00284.1*54 mg of carbidopa monohydrate is equivalent to 50 mg of carbidopa.

EXAMPLE 4

Under the coating level of 7.7% and 10.9% instead of 5.1%, the preparation process and fill formulation of the extended-release multi-particulates in Example 3 were repeated in this example, with 90% of levodopa released at approximately 6.6 hours and 9.3 hours, respectively.

EXAMPLE 5

In this example, the extended-release multi-particulates described in Examples 3 and 4 were coated with conventional enteric-soluble compositions in the art at a coating level of 3-10%.

EXAMPLE 6

In this example, the fill formulation was in the form of granules comprising montelukast sodium, mannitol, hydroxypropyl cellulose and magnesium stearate. The immediate-release granules were prepared by a wet granulation process using a high-shear granulator.

The compositions of the fill formulation were listed in Table 4.

TABLE 4The compositions of montelukast fill formulationCompositionsmg/piecewt %Montelukast sodium *4.20.83Mannitol468.493.67Hydroxypropyl cellulose25.05.00Magnesium stearate2.50.50Total content500.0100.00* 4.2 mg of montelukast sodium is equivalent to 4 mg of montelukast.

The montelukast granular formulations (500 mg) were filled into the inwardly crimped first opening2end of the tubular member through the second opening3end. Finally, the filled tubular member was enclosed by a device cap and wrapped with an aluminum pouch (not shown in figures).

Montelukast sodium in the fill formulation can be rapidly dissolved in an aqueous medium, with 85% of the drug dissolved in less than 30 minutes.

EXAMPLE 7

In this example, the procedures of Example 6 were repeated for providing a same fill formulation. In this example, the filling weight was 625 mg instead. Each filled device comprised 5 mg of montelukast.

EXAMPLE 8

In this example, the procedures of Example 6 were repeated for providing a same fill formulation. In this example, the filling weight was 1250 mg instead. Each filled device comprised 10 mg of montelukast.

EXAMPLE 9

In this example, the procedures of Example 6 were repeated for providing a fill formulation, the compositions of which were listed in Table 5. In this example, the fill weight was 500 mg. Each filled device comprised 10 mg of montelukast.

TABLE 5The compositions of montelukast formulation in Example 9Compositionsmg/piecewt %Montelukast sodium *10.42.08Mannitol462.192.42Hydroxypropyl cellulose25.05.00Magnesium stearate2.50.50Total content500.0100.00* 10.4 mg of montelukast sodium is equivalent to 10 mg of montelukast.

EXAMPLE 10

In this example, the filler was composed of three formulations, the first being lansoprazole delayed-release multi-particulates, the second being amoxicillin granules, and the third being clarithromycin granules. The compositions of the filler were listed in Table 6. In this example, the fill weight of lansoprazole delayed-release multi-particulates, amoxicillin granules, and clarithromycin granules was 480 mg, 1334 mg, and 840 mg, respectively. Each filled device comprises 30 mg of lansoprazole, 1000 mg of amoxicillin and 500 mg of clarithromycin.

TABLE 6The compositions of the fill formulation in Example 10Compositionsmg/piecewt %Lansoprazole delayed-release multi-particulates:Core:Lansoprazole30.06.3Sugar pellets150.031.3Corn starch54.011.3Sucrose58.012.1Low-substituted hydroxypropyl cellulose54.011.3Hydroxypropyl cellulose4.00.8Magnesium carbonate30.06.3Enteric coating:Eudragit L-30D solid component62.813.1Talcum powder19.24.0PEG 60006.41.3Tween 803.20.7Titanium dioxide8.41.8Total content480.0100.0Amoxicillin granules:Amoxicillin trihydrate100075.0Microcrystalline cellulose32724.5Magnesium stearate70.5Total content1334100.0Clarithromycin granules:Clarithromycin50059.5Microcrystalline cellulose25230.0Cross-linked carboxymethylcellulose sodium425.0Povidone425.0Magnesium stearate40.5Total content840100.00

EXAMPLE 11

In this example, the filler was composed of three formulations, the first being omeprazole delayed-release multi-particulates, the second being amoxicillin granules, and the third being clarithromycin granules. The compositions of the filler were listed in Table 7. In this example, the fill weight of omeprazole delayed-release multi-particulates, amoxicillin granules, and clarithromycin granules is 320 mg, 1334 mg, and 840 mg, respectively. Each filled device included 20 mg of omeprazole, 1000 mg of amoxicillin and 500 mg of clarithromycin.

TABLE 7The compositions of the fill formulation in Example 11Compositionsmg/piecewt %Omeprazole delayed-release multi-particulates:Core:Omeprazole20.06.3Sugar pellets100.031.3Corn starch36.011.3Sucrose38.712.1Low-substituted hydroxypropyl cellulose36.011.3Hydroxypropyl cellulose2.70.8Magnesium carbonate20.06.3Enteric coating:Eudragit L-30D solid component41.913.1Talcum powder12.84.0PEG 60004.31.3Tween 802.10.7Titanium dioxide5.61.8Total content320.0100.0Amoxicillin granules:Amoxicillin trihydrate100075.0Microcrystalline cellulose32724.5Magnesium stearate70.5Total content1334100.0Clarithromycin granules:Clarithromycin50059.5Microcrystalline cellulose25230.0Cross-linked carboxymethylcellulose sodium425.0Povidone425.0Magnesium stearate40.5Total content840100.00

EXAMPLE 12

In this example, the fill formulation in the form of granules comprised each individual drug or a combination of the following cold drugs: acetaminophen, dextromethorphan, doxylamine, pseudoephedrine and diphenhydramine. The immediate-release granules can be prepared by a wet granulation process using a high-shear granulator. The dosage ranges of these APIs were listed in Table 8.

TABLE 8The dosage ranges of the cold drugs in Example 12DosageActive pharmaceuticalrangepreparation (drug)(mg)Acetaminophen250-1000Dextromethorphan10-30Doxylamine6.25-12.5Pseudoephedrine20-30Diphenhydramine12.5-25