Oral drug delivery device

Abstract

The application discloses an oral administration delivery device, which comprises a tubular member, a medicine containing part, a device cap and a turbulence generating part. The tubular member has two open ends and an inner cavity, one of the open ends is a first open end, the other is a second open end, and the inner cavity is connected with the first and second open ends. The turbulence generating part comprises a step structure or a fold structure and is arranged in the inner cavity between the second open end and the medicine containing part. The structure of the medicine containing part and the device cap and the connection relationship between them and the tubular member are as described in the application. The oral administration delivery device can generate turbulence in a normal sipping process, provide sufficient mixing of medicine particles or multiple pills and drinkable liquid, and is telescopic, small in size and convenient to carry.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of medical devices, and more particularly to an oral delivery device. BACKGROUND

[0002] Tablets and capsules are the most convenient and acceptable oral dosage forms. However, some patients, especially children and the elderly, often have difficulty in swallowing large size tablets and capsules. Some patients are reluctant to take such oral medications because of the unacceptable bad taste. Therefore, various drug delivery devices have been proposed which facilitate the swallowing of large tablets and capsules and minimize the perception of the dose of the drug by the patient. The following patents and applications related to sipper devices are incorporated herein by reference.

[0003] EP 0383503 Al describes an improved device for holding and positioning a unit dose of a therapeutic agent in a tube, the device being adapted to deliver the dose through the tube by the normal sipper action of the patient. The device has a screen having a surface area greater than the cross-sectional area of the internal bore of the tube, thereby minimizing the resistance to fluid flow during the sipper action.

[0004] US Patent 6096003 describes a sipper device comprising an elongate tubular member having a deformable closure means (equivalent to a one-way valve, which does not create turbulence) adapted to allow delivery of an active agent upon deformation by the normal sipper action.

[0005] US Patent 6109538 discloses a sipper device comprising an elongate tube having a pair of screens disposed in the lumen of the tube to restrict flavouring objects from passing through the lumen to impart flavour to a drinkable liquid.

[0006] EP 1517628 Bl describes a sipper device consisting of a straw, a movable or fixed plug and a cap for oral administration of a vitamin and / or nutritional preparation which is at least partially soluble in a drinkable liquid.

[0007] US Patent 6210713 Bl describes a sipper device comprising an elongate tubular member having a one-way valve acting as a closure means and also allowing fluid passage by the normal sipper action.

[0008] US Patent 8334003 describes a sipper device comprising an elongate tubular member having a pair of filter means at each end of the tubular member to hold flavouring particles within the filter means to be released into a normal beverage by the normal sipper action.

[0009] US Patent 6,024,721 describes a sipping device which includes an elongated tubular member having a mixing chamber of a diameter greater than the diameter of the tubular member to provide improved mixing of the potable liquid and the active agent in the device. However, this device is difficult to practice and difficult to manufacture. In addition, the incorporation of a mixing chamber of a larger internal diameter than the internal diameter of the tubular member into the sipping device will reduce the flow rate of the potable liquid into the mouth by normal sipping action, thereby increasing the likelihood of a perceived bad taste of the active agent. SUMMARY

[0010] To solve the technical problem of lack of an effective device to facilitate swallowing of medicine in the prior art, the present application provides an oral drug delivery device and a preparation method thereof.

[0011] One of the technical solutions of the present application is to provide an oral drug delivery device, which comprises a tubular member, a medicine containing part, a device cap and a turbulence generating part, wherein the tubular member has two open ends and an internal cavity, one of the open ends is a first open end, the other open end is a second open end, the internal cavity is connected to the first open end and the second open end; the medicine containing part has a hole structure and is maintained in the internal cavity near the first open end and is used to contain particles or multiple pills containing active pharmaceutical ingredients; the hole structure has one or more holes allowing liquid to pass through, the diameter of the hole is smaller than the diameter of the particles or multiple pills containing active pharmaceutical ingredients; the device cap is detachably connected and is arranged outside the second open end; the turbulence generating part has a step structure or a corrugated structure and is arranged in the internal cavity between the second open end and the medicine containing part.

[0012] In use, the device cap is detached from the second open end; the first open end is in contact with a potable liquid; the second open end is placed in the mouth of a patient; the tubular member allows the potable liquid to pass through; the medicine containing part is located inside the tubular member near the first open end (i.e. the liquid end) to keep the particles or multiple pills of medicine. The second open end (i.e. the mouth end) is placed in the mouth and the first open end is in contact with the potable liquid, due to the action of the turbulence generating part, a turbulent flow can be formed in the oral drug delivery device, thereby improving the mixing of the particles or multiple pills containing medicine and the potable liquid.

[0013] In a preferred embodiment, there is provided an oral drug delivery device as described above, wherein the diameter of the first opening is smaller than the smallest diameter of the drug containing member, thereby maintaining the drug containing member in the lumen. In the present invention, since the drug containing member is a cylinder or a frustum-like shape, the diameter of its cross section is not constant. Thus, the drug containing member can be maintained in the lumen of the tubular member without using other fixing means. When the drug containing member is fitted into the tubular member, an inner lumen is formed which can accommodate the drug containing particles and multiple pills. Thus, when sipping, the drinkable liquid can flow through the porous structure of the drug containing member via the first opening, and thus reach the second opening. The diameter of the second opening can be set to be smaller than the largest diameter of the drug containing member, so that when the device cap is not used to close the second opening, even if the drug containing member accidentally passes through the step structure or the fold structure, it can still be maintained in the lumen without falling out.

[0014] In a preferred embodiment, there is provided an oral drug delivery device as described above, wherein the tubular member has at least two tube segments which are sealingly connected and can be axially stretched or contracted along the tubular member, and the tubular member in the stretched state forms a turbulence generating member having at least one step structure. The turbulence generating member can have a step structure due to, for example, the difference in the inner diameter of the adjacent tube segments in the cross-sectional direction. More specifically, the thickness of the step is determined by the thickness of the tube segment with the smaller inner diameter among the two tube segments which are sealingly connected in a telescopic manner. In a practical range, the more the number of step structures, the greater the Reynolds number of the turbulence generated; and in a reasonable range, the greater the thickness of the step structure, the greater the Reynolds number of the turbulence generated. In the present invention, the tube segments of the oral drug delivery device which are sealingly connected in a telescopic manner are similar to the sleeve structure of a telescope, and thus are also referred to as a telescope-like structure or a telescope-like telescopic sleeve structure. The axial stretching or contraction of the tubular member can be a telescopic stretching or contraction, or any other stretching or contraction mode achieved by, for example, rotation.

[0015] In a preferred embodiment, there is provided an oral drug delivery device as described above, wherein the number of tube segments is 2-5; preferably 2-4; and most preferably 3.

[0016] In a more preferred embodiment, there is provided an oral drug delivery device as described above, wherein, when the number of tube segments is 3: the inner diameter of the first tube segment and the inner diameter of the third tube segment are the same, the outer diameter of the second tube segment is smaller than the inner diameter of the first tube segment, and each tube segment is axially stretchable or contractible along other tube segments; or the inner diameter of the first tube segment, the outer diameter and the inner diameter of the second tube segment, and the outer diameter of the third tube segment gradually decrease from the first opening to the second opening, and each tube segment is axially stretchable or contractible along other tube segments. Since the edges of the cross section of each tube segment are parallel to each other, the adjacent tube segments can be stretched or contracted in the axial direction.

[0017] When the number of tube segments is 4: the inner diameter of the first tube segment and the inner diameter of the third tube segment are the same, the inner diameter of the second tube segment and the inner diameter of the fourth tube segment are the same, wherein the inner diameter of the second tube segment is smaller than the inner diameter of the first tube segment, and each tube segment is axially stretchable or contractible along other tube segments; or the inner diameter of the first tube segment to the fourth tube segment gradually decrease from the first opening to the second opening, and each tube segment is axially stretchable or contractible along other tube segments. Since the edges of the cross section of each tube segment are parallel to each other, the adjacent tube segments can be stretched or contracted in the axial direction. The case of the number of tube segments being greater than 4 can be analogized from the above.

[0018] In a more preferred embodiment, there is provided an oral drug delivery device as described above, wherein the tubular member has at least one pleat structure, the pleat structure has one pair of wings and one turning end; the pleat structure is axially stretchable or contractible along the tubular member and forms a turbulent flow generating component when stretched. The turning end is the bending site of the pleat from one wing to the other wing. In the cross section, the turning end is usually a point, so one pair of wings and one turning end usually form an angular structure. The angle can be acute, right or obtuse.

[0019] When the tubular member contains a plurality of continuous pleat structures, i.e. forms a pleat group structure, the pleat group structure is similar to an accordion structure, so in the present application, the pleat group is also referred to as an accordion structure or an accordion-like pleat group. In a more preferred embodiment, there is provided an oral drug delivery device as described above, wherein a plurality of continuous pleat structures form a pleat group structure, the number of pleat group structures is 1-5; preferably 2-3.

[0020] In a preferred embodiment, there is provided an oral drug delivery device as described above, wherein the inner lumen cross-sectional diameter at the crimped section is smaller than the inner lumen cross-sectional diameter at the junction of the tubular member and the crimped section, and the minimum inner lumen cross-sectional diameter at the crimped section is not less than one fifth of the inner lumen cross-sectional diameter of the tubular member. The protrusion formed by the turning end of the crimped section towards the tubular member axis in this case can make the oral drug delivery device form a turbulence generating means in the contracted state.

[0021] In a preferred embodiment, there is provided an oral drug delivery device as described above, wherein the tubular member has a maximum outer diameter of 4.0-15.0 mm and a minimum inner diameter of 2.0-14.8 mm; and / or the length of the tubular member is 5-30 cm in the contracted state and 10-50 cm in the stretched state.

[0022] The active pharmaceutical ingredient can be prepared into granules or pellets with other excipients by a process. If the taste of the drug incorporated into the granules or pellets is not good, it can be necessary to coat them with a taste masking composition. The pellets can also be coated separately with an enteric coating or a sustained release coating or both an enteric coating and a sustained release coating for sustained or delayed release or enteric / sustained release. Thus, in a preferred embodiment, there is provided an oral drug delivery device as described above, wherein, when the drug containing part comprises granules or pellets containing an active pharmaceutical ingredient, the granules or pellets have a diameter of 50-5000 μιη, preferably 75-2000 μιη, more preferably 100-1000 μιη; and the active pharmaceutical ingredient comprises one or more of the following: dabigatran etexilate or a pharmaceutically acceptable salt thereof, levodopa / carbidopa, montelukast, lansoprazole, omeprazole, amoxicillin, clarithromycin, acetaminophen, dextromethorphan, doxylamine, pseudoephedrine and diphenhydramine.

[0023] In a preferred embodiment, the oral drug delivery device comprises granules or pellets, wherein the granules or pellets comprise 9-48 wt% of dabigatran etexilate mesylate, 9-44 wt% of 0-30 wt% of Kolliphor P407, 0-23 wt% of Kolliphor P188, 0-58 wt% of lactose monohydrate, 0-32 wt% of mannitol, 0-20 wt% of croscarmellose sodium, 0-5 wt% of silicon dioxide and 0-3 wt% of magnesium stearate. Preferably, the granules or pellets comprise 10.4-17.2 wt% of dabigatran etexilate mesylate, 24.3-35.7 wt% of 13.1 wt% Kolliphor P407 or 19.0 wt% Kolliphor P188, 0-52.2 wt% lactose monohydrate, 0-17.9 wt% mannitol, 0-9.7 wt% croscarmellose sodium and 0-0.5 wt% magnesium stearate.

[0024] In a particular embodiment, the oral drug delivery device comprises a plurality of pellets comprising 10.4 wt% of dabigatran etexilate mesylate, 2.6 wt% of 13.1 wt% Kolliphor P407, 52.2 wt% sucrose pellet cores and 21.7 wt% Soluplus powder. The plurality of pellets preferably is a dosage of 50 mg and 75 mg of active pharmaceutical ingredient.

[0025] In a particular embodiment, the oral drug delivery device comprises a plurality of pellets comprising 10.4 wt% of dabigatran etexilate mesylate, 2.6 wt% of 17.9 wt% mannitol, 19.0 wt% Kolliphor P188, 9.7 wt% croscarmellose sodium and 0.5 wt% magnesium stearate. The plurality of pellets preferably is a dosage of 50 mg and 75 mg of active pharmaceutical ingredient.

[0026] In a preferred particular embodiment, the oral drug delivery device comprises a plurality of pellets and a plurality of pellets, the plurality of pellets or the plurality of pellets comprising 42.3-70.41 wt% levodopa, 0-45.7 wt% carbidopa monohydrate, 1.9-3.81 wt% sodium laurylsulfate, 4.8-19.03 wt% filler (e.g. one or more of microcrystalline cellulose, hydroxypropyl cellulose and mannitol), 1.9-4.8 wt% binder (e.g. one or more of methyl cellulose, hypromellose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, povidone and gelatin). Preferably, the plurality of pellets further comprises a coating film, the coating film comprising cellulose acetate and copovidone, the cellulose acetate being 50-90 wt% of the coating film; the copovidone being 10-50 wt% of the coating film.

[0027] In a preferred embodiment, the oral drug delivery device comprises granules and multiple pellets, the granules are immediate release granules, the multiple pellets are sustained release multiple pellets, the granules comprise 42.3 wt% levodopa, 45.7 wt% carbidopa monohydrate, 1.9 wt% sodium lauryl sulfate, 4.8 wt% hydroxypropyl methylcellulose (HPMC) E5, 4.8 wt% croscarmellose sodium and 0.5 wt% magnesium stearate; and / or, the multiple pellets comprise 70.41 wt% levodopa, 19.03 wt% microcrystalline cellulose, 3.81 wt% sodium lauryl sulfate, 1.90 wt% Povidone K29 / 32, 4.12 wt% cellulose acetate 39.8 and 0.73 wt% Copovidon (Kollidone VA64). Preferably, the sustained release multiple pellets are coated with an enteric coating composition at a coating level of 5.1-10.9 wt%, preferably 7.7%. More preferably, the sustained release multiple pellets are coated with an enteric coating composition at a coating level of 3-10 wt%.

[0028] In a preferred embodiment, the oral drug delivery device comprises granules, the granules comprise 0.83 wt% montelukast sodium, 93.67 wt% mannitol, 5.00 wt% hydroxypropyl cellulose and 0.50 wt% magnesium stearate. The granules are preferably 500 mg (4 mg montelukast), 625 mg (5 mg montelukast), 1250 mg (10 mg montelukast) and 500 mg (10 mg montelukast).

[0029] In a preferred embodiment, the oral drug delivery device comprises granules and multiple pellets, the granules are amoxicillin granules and clarithromycin granules, the multiple pellets are lansoprazole delayed release multiple pellets, the fill weight of the lansoprazole delayed release multiple pellets, amoxicillin granules and clarithromycin granules are 480 mg, 1334 mg and 840 mg respectively. The lansoprazole delayed release multiple pellets comprise a core and an enteric coating, the core comprises 6.3 wt% lansoprazole, 31.3 wt% sugar spheres, 11.3 wt% corn starch, 12.1 wt% sucrose, 1.3 wt% low-substituted hydroxypropyl cellulose, 0.8 wt% hydroxypropyl cellulose and 6.3 wt% magnesium carbonate, the enteric coating comprises 13.1 wt% Eudragit L-30D solid content, 4.0 wt% talc, 1.3 wt% PEG 6000, 0.7 wt% Tween 80 and 1.8 wt% titanium dioxide. The amoxicillin granules comprise 75.0 wt% amoxicillin trihydrate, 24.5 wt% microcrystalline cellulose and 0.5 wt% magnesium stearate. The clarithromycin granules comprise 59.5 wt% clarithromycin, 30.0 wt% microcrystalline cellulose, 5.0 wt% croscarmellose sodium, 5.0 wt% Povidone and 0.5 wt% magnesium stearate.

[0030] In a preferred embodiment, the oral drug delivery device contains granules and multiple pellets, the granules are amoxicillin granules and clarithromycin granules, the multiple pellets are omeprazole delayed release multiple pellets, the filling weight of the omeprazole delayed release multiple pellets, amoxicillin granules and clarithromycin granules are 320 mg, 1334 mg and 840 mg respectively. The omeprazole delayed release multiple pellets comprise a core and an enteric coating, the core contains 6.3 wt% omeprazole, 31.3 wt% sugar pellets, 11.3 wt% corn starch, 12.1 wt% sucrose, 11.3 wt% low-substituted hydroxypropylcellulose, 0.8 wt% hydroxypropylcellulose and 6.3 wt% magnesium carbonate, the enteric coating contains 13.1 wt% Eudragit L-30D solid content, 4.0 wt% talc, 1.3 wt% PEG6000, 0.7 wt% Tween 80 and 1.8 wt% titanium dioxide. The amoxicillin granules contain 75.0 wt% amoxicillin trihydrate, 24.5 wt% microcrystalline cellulose and 0.5 wt% magnesium stearate. The clarithromycin granules contain 59.5 wt% clarithromycin, 30.0 wt% microcrystalline cellulose, 5.0 wt% croscarmellose sodium, 5.0 wt% Povidone and 0.5 wt% magnesium stearate.

[0031] In a preferred embodiment, the oral drug delivery device contains granules, the active pharmaceutical ingredients of the granules are acetaminophen, dextromethorphan, doxylamine, pseudoephedrine and diphenhydramine, the dose range of the active pharmaceutical ingredients are 250-1000 mg, 10-30 mg, 6.25-12.5 mg, 20-30 mg and 12.5-25 mg respectively.

[0032] The drinkable liquid can be used to carry the drug-containing granules or multiple pellets through the tubular portion of the device by normal sipping. The liquid is preferably any drinkable liquid, including but not limited to water, lemonade, fruit-free juice, milk, soda, coffee and tea.

[0033] One of the technical solutions of the present application is to provide a method for preparing an oral drug delivery device, which comprises the following steps:

[0034] 1) preparing the turbulence generating component and assembling it with the tubular member;

[0035] 2) preparing the drug containing component and maintaining it in the inner cavity, near the first opening;

[0036] 3) setting the device cap at the second opening.

[0037] Preferably, the method further comprises the step of filling the drug before the step 3).

[0038] The above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present application.

[0039] The reagents and raw materials used in the present application are commercially available.

[0040] The positive progress effect of the present application is that the oral administration delivery device of the present application provides sufficient mixing of the drug-containing granules or pellets with the drinkable liquid for normal sipping action; and the device of the present application is telescopic, reducing the size, facilitating portability. In addition, the drug-containing granules or pellets with active ingredient dabigatran etexilate show significantly faster dissolution at acidic pH and less precipitation at neutral pH. At the same time, the preparation method of the oral administration delivery device of the present application is simple, and the use effect is good. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 is a schematic diagram of the oral administration delivery device with a step structure of the turbulence generating component, type I: a. retracted state, b. stretched state + before sipping, c. stretched state + while sipping;

[0042] Figure 2 is a schematic diagram of the oral administration delivery device with a step structure of the turbulence generating component, type II: a. retracted state, b. stretched state + before sipping, c. stretched state + while sipping;

[0043] Figure 3 is a schematic diagram of the oral administration delivery device with a step structure of the turbulence generating component, type II: a. retracted state, b. stretched state + before sipping, c. stretched state + while sipping;

[0044] Figure 4 is a schematic diagram of the oral administration delivery device with a step structure of the turbulence generating component, type II: a. retracted state, b. stretched state + before sipping, c. stretched state + while sipping;

[0045] Figure 5 is a dissolution curve of the granules described in Example 1.

[0046] Figure 6 is a dissolution curve of the pellets described in Example 2.

[0047] BRIEF DESCRIPTION OF DRAWINGS

[0048] 1: tubular member

[0049] 11: first tube section

[0050] 12: second tube section

[0051] 13: third tube section

[0052] 2: First opening

[0053] 21: First Opening Internal Twist

[0054] 3: Second opening

[0055] 31: Second Opening Inward Twist

[0056] 4: Device cap

[0057] 5: Granules or pills containing active pharmaceutical ingredients

[0058] 6: Drug containment components

[0059] 61: Kong

[0060] 7: Stepped structure

[0061] 71: Step 1

[0062] 72: The second step

[0063] 8: Pleated Group

[0064] 81: First fold group

[0065] 811: Folds

[0066] 82: Group 2 folds

[0067] 9: Inner cavity Detailed Implementation

[0068] Various embodiments of the present invention will be described with reference to the accompanying drawings. In the drawings, elements having similar structures or functions will be represented by the same element symbols. It is understood that the drawings are only for illustrating various embodiments of the present invention and are not intended to be exhaustive or to limit the scope of the invention.

[0069] This invention provides an oral drug delivery device with a turbulence-generating component having a stepped structure. Figure 1 and 2 Cross-sectional views of telescope-type structures type I and type II of the oral drug delivery device according to the present invention are shown respectively. The oral drug delivery device is in a retracted state before use. Figure 1 (a or 2a), is in a stretched state before sucking ( Figure 1 b or 2b), which are in the form of suspended particles during inhalation ( Figure 1 c or 2c). Figure 1 and 2 The oral drug delivery device shown includes a stretchable or retractable tubular member 1 having a first opening 2, a second opening 3, and a device cap 4. Figure 1 and2 A tubular member consisting of three tube segments 11, 12, 13 is exemplified. Figure 1 In one embodiment, the inner diameter of the first tube segment 11 and the inner diameter of the third tube segment 13 are the same in the direction from the first opening 2 to the second opening 3, and the outer diameter of the second tube segment 12 is smaller than the inner diameter of the first tube segment 11, so that the first tube segment 11 and the third tube segment 13 can be axially stretched ( Figure 1 b and 1c) or shrunk ( Figure 1 a) along the second tube segment 12. Figure 2 In one embodiment, the inner diameter of the first tube segment 11, the outer diameter of the second tube segment 12, and the outer diameter of the third tube segment 13 gradually decrease in the direction from the first opening 2 to the second opening 3, but the side lines of the three tube segments on the same side of the cross section are parallel to each other, so that the third tube segment 13 and the second tube segment 12 can be axially stretched ( Figure 2 b and 2c) or shrunk ( Figure 2 a) along the first tube segment 11.

[0070] The drug containing part 6 is arranged in the inner cavity 9 of the tubular member 1 near the first opening 2, and the configuration thereof when containing granules or multiple pills 5 is shown in the figure. After placing the drug containing part 6 in the inner cavity, the end of the first opening 2 is internally indented 21, so that the opening diameter after the indentation is smaller than the minimum diameter of the structure of the drug containing part 6; the end of the second opening 3 is internally indented 31, so that the opening diameter after the indentation is smaller than the maximum diameter of the structure of the drug containing part 6, thereby maintaining the drug containing part 6 in the inner cavity. An upper device cap 4 is arranged outside the second opening 3. The drug containing part 6 cooperates with the tubular member 1 to form a space that can contain drugs (in the examples of the present application, in the form of granules and multiple pills, and the active ingredients of the drugs are contained in the granules or multiple pills) 5. The drug containing part 6 is a hole structure, and the hole structure contains a plurality of holes 61, the diameter of the holes 61 is smaller than the diameter of the granules or multiple pills 5, and can allow the passage of drinkable liquid; but when there is no liquid passing through, the granules and multiple pills 5 remain in the inner cavity 9 of the tubular member 1. The oral drug delivery device is stretched to form a stepped structure 7, Figure 1 and 2 The stepped structure 7 is shown in one embodiment, and the stepped structure is arranged at the position of the inner cavity 9 between the second opening 3 and the drug containing part 6. Figure 1 and 2The step structures 7 of the example have a first step 71 and a second step 72. By the action of sipping, the drinkable liquid passes through the steps 71 and 72 to generate turbulence, thereby enhancing the mixing of the drug-containing particles or pellets 5 with the drinkable liquid. It is known to those skilled in the art that when the number of pipe sections increases, the total number of step structures also increases accordingly, and therefore the Reynolds number for generating turbulence is greater; furthermore, when the thickness of the step structures increases within the range of the art, the Reynolds number for generating turbulence is greater.

[0071] The present application also provides an oral drug delivery device with a turbulence-generating member having a pleat structure. Figure 3 A cross-sectional view of the accordion pleat group structure of an oral drug delivery device according to the present application is shown. The device is in a collapsed state before use Figure 3 a), in a stretched state before sipping Figure 3 b), and in a particle-suspended form during sipping Figure 3 c). Figure 3 The oral drug delivery device shown comprises a stretchable tubular member 1 having an internal cavity 9 and a plurality of pleat group structures, in Figure 3 two pleat group structures 81 and 82 are shown. Each pleat group structure has a plurality of pleat structures 811. The oral drug delivery device has a first opening 2, a second opening 3 and a device cap 4. Contained within the internal cavity 9 of the tubular member are drug-containing particles or pellets 5 comprising an active pharmaceutical ingredient and a drug-holding member 6. After the drug-holding member 6 is placed in the internal cavity, the end of the first opening 2 is internally constricted 2 so that the diameter of the constricted opening is smaller than the smallest diameter of the drug-holding member 6; the end of the second opening 3 is internally constricted 31 so that the diameter of the constricted opening is smaller than the largest diameter of the drug-holding member 6 structure, thereby maintaining the drug-holding member 6 in the internal cavity. The device cap 4 is then placed over the second opening 3. Figure 3 The drug-holding member 6 shown in is a hole structure having a plurality of holes 61 and located in the internal cavity 9 of the tubular member near the first opening 2. The drug-holding member 6 cooperates with the tubular member 1 to form a space for accommodating the drug-containing particles or pellets 5 comprising an active pharmaceutical ingredient. The hole diameter 61 of the hole structure is smaller than the diameter of the particles or pellets 5, allowing the passage of drinkable liquid but retaining the particles or pellets 5 in the internal cavity 9 of the tubular member 1 when no liquid is passing through. When the oral drug delivery device is in a stretched state, by the action of sipping, the drinkable liquid flows through the pleat structures 811 to generate turbulence, thereby enhancing the mixing of the drug-containing particles or pellets 5 comprising an active pharmaceutical ingredient with the drinkable liquid. It is known to those skilled in the art that when the number of pleat groups increases, the total number of pleat structures also increases accordingly, and therefore the Reynolds number for generating turbulence is greater; furthermore, when the height of the pleat structures protruding into the internal cavity increases within the range of the art, the Reynolds number for generating turbulence is greater.

[0072] As is known to those skilled in the art, once the drug containing component 6 is placed in the lumen 9 from the first opening 2 end, the device cap 4 can be placed directly outside the second opening 3. At this point, due to the sealing connection of the device cap with the second opening, the end of the second opening 3, even if not invaginated, due to the presence of the step structure or the pleat structure, the drug containing component 6 cannot pass through the lumen 9 to the outside of the second opening 3, and the drug containing component 6 can be maintained in the lumen 9. At this point, if the end of the second opening 3 is invaginated, such that the diameter of the invaginated opening is less than the maximum diameter of the drug containing component, this can further ensure that during use of the oral drug delivery device, the drug containing component 6 cannot be inhaled into the patient's mouth and cause a medical accident.

[0073] Figure 4 The plug flow and turbulent flow generated by the oral drug delivery device having a step structure or a pleat structure of the turbulent flow generating component according to the present application is schematically shown.

[0074] In the present application, the tubular member 1 of the oral drug delivery device generally has an outer diameter between 4.0 mm and 15.0 mm. The lumen 9 of the tubular member 1 has a diameter generally between 2.0 mm and 14.8 mm. The length of the tubular member 1 is between 5 cm and 15 cm in its ready form and between 10 cm and 30 cm in its elongated form.

[0075] The preferred materials for manufacturing the tubular member 1, the drug containing component 6 and the device cap 4 are polypropylene and polymers of the polyolefin family, which are conventional in the art.

[0076] The active pharmaceutical ingredients (APIs) encompassed by the present application include, but are not limited to, dabigatran etexilate or a pharmaceutically acceptable salt thereof, levodopa / carbidopa, montelukast, lansoprazole, omeprazole, amoxicillin, clarithromycin, acetaminophen, dextromethorphan, doxylamine, pseudoephedrine and diphenhydramine.

[0077] In one embodiment, the oral drug delivery device comprises solubility enhanced dabigatran etexilate methanesulfonate (DEM) in granular form, which is prepared by utilizing a hot melt granulation process.

[0078] In another embodiment, the oral drug delivery device comprises solubility enhanced dabigatran etexilate methanesulfonate (DEM) in multiparticulate form, which is prepared by utilizing a spray coating process.

[0079] In another embodiment, the oral drug delivery device comprises a sustained release levodopa / carbidopa formulation in multiparticulate form, which is prepared by utilizing an extrusion, spheronization and coating process.

[0080] In another embodiment of the present application, the oral drug delivery device contains granules of montelukast which are prepared by conventional granulation methods including wet granulation, fluid bed granulation, dry granulation, etc.

[0081] In another embodiment of the present application, the oral drug delivery device contains granules of montelukast which are prepared by conventional granulation methods including wet granulation, fluid bed granulation, dry granulation, etc.

[0082] In another embodiment of the present application, the oral drug delivery device contains granules of montelukast which are prepared by conventional granulation methods including wet granulation, fluid bed granulation, dry granulation, etc.

[0083] In another embodiment of the present application, the oral drug delivery device contains granules of montelukast which are prepared by conventional granulation methods including wet granulation, fluid bed granulation, dry granulation, etc.

[0084] One of the oral drug delivery devices in the present application is an oral drug delivery device with a stepped structure of the turbulence-generating component. One configuration of the device can be manufactured by the following manufacturing steps. First, a tubular member (type I or type II, see Figure 1 a and Figure 2 a) by conventional methods of manufacturing straws. Second, the drug containing component 6 is inserted into the first opening 2 end of the tubular member 1. Next, the end of the first opening 2 is inwardly flared so that the drug containing component 6 can be held within the lumen 9 of the tubular member 1. Then, the granules or pellets 5 containing the active pharmaceutical ingredient are filled into the tubular member 1 through the second opening 3 end of the tubular member 1. Finally, the filled tubular member 1 is closed by the device cap 4 and wrapped with an aluminum bag (not shown).

[0085] Another oral drug delivery device in the present application is an oral drug delivery device with a pleated structure of the turbulence-generating component. The device can be manufactured by the following manufacturing steps. First, a tubular member 1 with 3 groups of accordion-like pleated groups 8 is manufactured by conventional processes of manufacturing straws. Second, the drug containing component 6 is inserted into the first opening 2 end of the tubular member 1. Next, the end of the first opening 2 is inwardly flared so that the drug containing component 6 can be held within the lumen 9 of the tubular member 1. Then, the granules or pellets 5 containing the active pharmaceutical ingredient are filled into the tubular member 1 through the second opening 3 end of the tubular member 1. Finally, the filled tubular member 1 is closed by the device cap 4 and wrapped with an aluminum bag (not shown).

[0086] The application is further illustrated by the following examples without thereby limiting the application to the examples described. The experimental procedures in the following examples, where no specific conditions are mentioned, are carried out according to standard procedures and conditions, or according to the instructions of the commercial suppliers.

[0087] Example 1

[0088] Multi-pellets comprising dabigatran etexilate mesylate (DEM) were prepared by spraying a solid solution / dispersion composition onto sugar pellets. The composition comprised 40% dabigatran etexilate mesylate (DEM), 10% polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Soluplus and 50% polyoxyethylene-polyoxypropylene ether block copolymer Kolliphor P407 by weight percentage. First, the solid ingredients were dissolved in 92% ethanol to make a coating solution with a solid content of 24.2%. Then, using a fluid bed granulator with a Wurster insert, 714.8 g of the coating solution comprising 173.0 g of the solid components were sprayed onto 346.0 g of pre-dried sugar cores at a suitable inlet air pressure and an inlet air temperature of 38-40°C. During the coating process, the spraying rate and the atomization pressure were adjusted to maintain the product temperature at 28-30°C. After the coating solution was exhausted, the coated pellets were dried in the fluid bed until the moisture content was below 1.7%. The target weight ratio of the drug layer to the sucrose pellet core was 0.5:1.0. Additional Soluplus granules (180 mg) were added as a powder (<80 mesh). The Soluplus powder used in this experiment was obtained by grinding Soluplus granules and subsequently sieving with an 80 mesh sieve.

[0089] The multi-pellets comprising DEM (552.4 mg for 50 mg dose, 648.6 mg for 75 mg dose) and the Soluplus powder (120 mg for 50 mg dose, 180 mg for 75 mg dose) were filled into the tubular member 1 through the second opening 3 into the indented first opening 2. Finally, the filled tubular member was closed with the device cap and wrapped with an aluminum bag (not shown). Table 1 lists the composition of the multi-pellet fill in the device.

[0090] Table 1. Composition of multi-pellet fill in Example 1

[0091]

[0092]

[0093] *57.7 mg and 86.5 mg of DEM correspond to 50 mg and 75 mg of free base, respectively.

[0094] The dissolution profile of the filled formulation was measured using a two-stage method, 45 minutes in the gastric phase (pH 2.0) followed by the intestinal phase (pH 6.8). As shown in Figure 5 compared to the commercial product The filled formulation in this example showed faster dissolution at low pH and less precipitation at pH 6.8 compared to the commercial product. Error bars represent standard deviation for n=3.

[0095] Example 2

[0096] In this example, granular formulations containing DEM were prepared by a hot melt granulation process. Table 2 lists the composition of the hot melt DEM formulations.

[0097] Table 2. Composition of hot melt DEM formulations

[0098]

[0099] * 57.7 mg and 86.5 mg of DEM correspond to 50 mg and 75 mg of free base, respectively.

[0100] The hot melt granulation process is outlined as follows. First, the Kolliphor P188 was milled and passed through an 80 mesh sieve, and the milled powder was mixed with the other excipients, except magnesium stearate, in a hot jacketed high shear granulator at 65-75 °C until a consistent and uniform granulation was formed. Next, the hot melt granulation was passed through a 20 mesh sieve and then mixed with magnesium stearate.

[0101] The hot melt DEM granular formulation (336.1 mg for 50 mg dose and 504.1 mg for 75 mg dose) was filled into the tubular member 1 with the open end 3 into the indented end 2. Finally, the filled tubular member was closed with a device cap and wrapped with an aluminum bag (not shown). The dissolution profile of the filled formulation was measured using a two-stage method, 45 minutes in the gastric phase (pH 2.0) followed by the intestinal phase (pH 6.8). As shown in Figure 6 compared to the commercial product The filled formulation in this example showed significantly faster dissolution at acidic pH and less precipitation at neutral pH compared to the commercial product. Error bars represent standard deviation for n=3.

[0102] Example 3

[0103] In this example, the fill formulation consists of immediate release levodopa / carbidopa granules and levodopa extended release multiple pellets. Table 3 lists the composition of the fill formulation. The immediate release granules are prepared using a conventional wet granulation process, while the extended release multiple pellets are prepared using an extrusion / spheronization / spray coating process. The extended release multiple pellets are coated at a level of 5.1% by weight, with 90% of the levodopa being released after approximately 3.9 hours.

[0104] Table 3. Composition of levodopa / carbidopa formulation in Example 3

[0105]

[0106]

[0107] * 54 mg carbidopa monohydrate is equivalent to 50 mg carbidopa.

[0108] Example 4

[0109] The preparation process and composition of the extended release multiple pellets in Example 3 are repeated in this example at coating levels of 7.7% and 10.9% instead of 5.1%, with 90% of the levodopa being released at approximately 6.6 hours and 9.3 hours, respectively.

[0110] Example 5

[0111] In this example, the extended release multiple pellets described in Examples 3 and 4 are coated with an enteric composition at a coating level of 3-10%.

[0112] Example 6

[0113] In this example, the fill formulation is in the form of granules, comprising montelukast sodium, mannitol, hydroxypropyl cellulose, and magnesium stearate. The immediate release granules are prepared by a wet granulation process using a high shear granulator.

[0114] Table 4 lists the composition of the fill formulation.

[0115] Table 4. Composition of montelukast formulation

[0116] Component mg / tablet wt% Montelukast sodium 4.2 0.83 Mannitol 468.4 93.67 Hydroxypropyl cellulose 25.0 5.00 Magnesium stearate 2.5 0.50 Total content 500.0 100.00

[0117] * 4.2 mg montelukast sodium is equivalent to 4 mg montelukast.

[0118] The montelukast granule formulation (500 mg) is filled into the tubular member 1 through the second opening 3 into the indented first opening 2. Finally, the filled tubular member is closed with a device cap and wrapped with an aluminum bag (not shown).

[0119] The montelukast sodium in the fill formulation can be rapidly dissolved in aqueous media, with 85% of the drug being dissolved in no more than 30 minutes.

[0120] Example 7

[0121] The procedure of Example 6 was repeated in this example to provide the same filled formulation. In this example, the fill weight was changed to 625 mg. Each filling device contained 5 mg montelukast.

[0122] Example 8

[0123] The procedure of Example 6 was repeated in this example to provide the same filled formulation. In this example, the fill weight was changed to 1250 mg. Each filling device contained 10 mg montelukast.

[0124] Example 9

[0125] The procedure of Example 6 was repeated in this example to provide a filled formulation whose composition is listed in Table 5. In this example, the fill weight was 500 mg. Each filling device contained 10 mg montelukast.

[0126] Table 5. Composition of montelukast formulation in Example 9

[0127]

[0128]

[0129] *10.4 mg montelukast sodium is equivalent to 10 mg montelukast.

[0130] Example 10

[0131] In this example, the fill consisted of three formulations, the first being a delayed release ranitidine multi-pellet, the second being amoxicillin granules, and the third being clarithromycin granules. The fill composition is listed in Table 6. In this example, the fill weights of the delayed release ranitidine multi-pellet, amoxicillin granules, and clarithromycin granules were 480 mg, 1334 mg, and 840 mg, respectively. Each filling device contained 30 mg ranitidine, 1000 mg amoxicillin, and 500 mg clarithromycin.

[0132] Table 6. Composition of filled formulation in Example 10

[0133]

[0134]

[0135] Example 11

[0136] In this example, the fill comprises three formulations, the first being a delayed release omeprazole multi-pellet, the second being amoxicillin granules, and the third being clarithromycin granules. The fill composition is listed in Table 7. In this example, the fill weight of the omeprazole delayed release multi-pellet, amoxicillin granules, and clarithromycin granules are 320 mg, 1334 mg, and 840 mg, respectively. Each filling device comprises 20 mg of omeprazole, 1000 mg of amoxicillin, and 500 mg of clarithromycin.

[0137] Table 7. Fill formulation composition in Example 11

[0138]

[0139]

[0140] Example 12

[0141] In this example, the fill formulation in granular form comprises each individual drug or their combination, including the following cold medicine drugs: acetaminophen, dextromethorphan, doxylamine, pseudoephedrine, and diphenhydramine. The immediate release granules can be prepared by a wet granulation process using a high shear granulator. Table 8 lists the dose ranges for these drug substances.

[0142] Table 8. Dose ranges for cold medicine drugs in Example 12

[0143] Active pharmaceutical ingredient (drug) Dose range (mg) Acetaminophen 250-1000 Dextromethorphan 10-30 Doxylamine 6.25-12.5 Pseudoephedrine 20-30 Diphenhydramine 12.5-25

Claims

1. An oral drug delivery device, characterized in that, It comprises: a tubular member, a drug containing part, a device cap and a turbulence generating part, wherein the tubular member has two open ends and an inner cavity, one open end is a first open end, the other open end is a second open end, the inner cavity is communicated with the first open end and the second open end; the drug containing part has a hole structure and is maintained in the inner cavity near the first open end and is used for containing particles or multiple pills containing active pharmaceutical ingredients; the hole structure has one or more holes allowing liquid to pass through, the diameter of the hole is smaller than the diameter of the particles or multiple pills containing active pharmaceutical ingredients; the device cap is detachably connected and is arranged outside the second open end; the turbulence generating part has a step structure or a fold structure and is arranged in the inner cavity between the second open end and the drug containing part; wherein when the turbulence generating part has a step structure, the tubular member has at least two tube segments, the tube segments are sealingly connected and can be axially stretched or contracted along the tubular member; the tubular member in the stretched state forms a turbulence generating part with at least one step structure; when the number of tube segments is three: the inner diameter of the first tube segment and the inner diameter of the third tube segment in the direction from the first open end to the second open end are the same, the outer diameter of the second tube segment is smaller than the inner diameter of the first tube segment, and each tube segment can be axially stretched or contracted along other tube segments; or, the inner diameter of the first tube segment, the outer diameter and the inner diameter of the second tube segment and the outer diameter of the third tube segment gradually decrease in the direction from the first open end to the second open end, and each tube segment can be axially stretched or contracted along other tube segments; when the number of tube segments is four: the inner diameter of the first tube segment and the inner diameter of the third tube segment in the direction from the first open end to the second open end are the same, the inner diameter of the second tube segment and the inner diameter of the fourth tube segment are the same, wherein the inner diameter of the second tube segment is smaller than the first tube segment, and each tube segment can be axially stretched or contracted along other tube segments; or, the inner diameter of the first tube segment to the fourth tube segment gradually decreases in the direction from the first open end to the second open end, and each tube segment can be axially stretched or contracted along other tube segments; wherein when the turbulence generating part has a fold structure, the tubular member has at least one fold structure, the fold structure has a pair of wing parts and a turning end; the fold structure can be axially stretched or contracted along the tubular member, and forms a turbulence generating part when stretched; the inner cavity cross-sectional diameter at the fold structure is smaller than the inner cavity cross-sectional diameter at the connection between the tubular member and the fold structure, and the minimum inner diameter of the inner cavity cross-section at the fold structure is not less than one fifth of the inner cavity cross-sectional diameter of the tubular member.

2. The oral drug delivery device of claim 1, wherein, wherein the diameter of the first open end is smaller than the minimum diameter of the drug containing part.

3. The oral drug delivery device of claim 2, wherein, the diameter of the second open end is smaller than the maximum diameter of the drug containing part.

4. The oral drug delivery device of claim 1, wherein, wherein a plurality of continuous fold structures form a fold group structure, the number of fold group structures is 1-5.

5. The oral drug delivery device of claim 4, wherein, the number of fold group structures is 2-3.

6. The oral drug delivery device according to any of claims 1-5, characterized in that, wherein The tubular member has a maximum outer diameter of 4.0-15.0 mm and a minimum inner diameter of 2.0-14.8 mm; the length of the tubular member is 5-30 cm in the contracted state and 10-50 cm in the stretched state.

7. The oral drug delivery device according to any of claims 1-5, wherein When the drug containing component has granules or pellets containing an active pharmaceutical ingredient, the diameter of the granules and pellets is 50-5000 µm; the active pharmaceutical ingredient contained in the granules and pellets includes, but is not limited to, one or more of the following: dabigatran etexilate or a pharmaceutically acceptable salt thereof, levodopa / carbidopa, montelukast, lansoprazole, omeprazole, amoxicillin, clarithromycin, acetaminophen, dextromethorphan, doxylamine, pseudoephedrine, and diphenhydramine.

8. The oral drug delivery device of claim 7, wherein, When the drug containing component has granules or pellets containing an active pharmaceutical ingredient, the diameter of the granules and pellets is 75-2000 µm.

9. The oral drug delivery device of claim 8, wherein, The diameter of the granules and pellets is 100-1000 µm.

10. A method of preparing an oral drug delivery device according to any one of claims 1-9, characterized in that, The steps include: 1) preparing the turbulence generating component and assembling it with the tubular member; 2) preparing the drug containing component and maintaining it in the inner cavity, near the first opening; 3) providing a device cap at the second opening.

11. The method of oral administration of a delivery device according to claim 10, characterized in that, The steps further include a step of loading the drug before step 3).

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