WO2020143843A1 - 一种口服给药递送装置 - Google Patents

一种口服给药递送装置 Download PDF

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Publication number
WO2020143843A1
WO2020143843A1 PCT/CN2020/073865 CN2020073865W WO2020143843A1 WO 2020143843 A1 WO2020143843 A1 WO 2020143843A1 CN 2020073865 W CN2020073865 W CN 2020073865W WO 2020143843 A1 WO2020143843 A1 WO 2020143843A1
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WIPO (PCT)
Prior art keywords
opening
tubular member
diameter
delivery device
drug delivery
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PCT/CN2020/073865
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English (en)
French (fr)
Inventor
董良昶
雷杨
吴刚
焦艳
石劲敏
Original Assignee
上海汉都医药科技有限公司
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Application filed by 上海汉都医药科技有限公司 filed Critical 上海汉都医药科技有限公司
Priority to EP20738987.5A priority Critical patent/EP4094746A4/en
Priority to JP2021539676A priority patent/JP2022517574A/ja
Priority to US17/420,618 priority patent/US20220110832A1/en
Publication of WO2020143843A1 publication Critical patent/WO2020143843A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0015—Devices specially adapted for taking medicines
    • A61J7/0061—Swallow helping devices, e.g. tongue shields
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0015—Devices specially adapted for taking medicines
    • A61J7/0038—Straws
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

Definitions

  • the invention relates to the field of medical devices, in particular to an oral drug delivery device.
  • Tablets and capsules are convenient and most acceptable oral dosage forms. But some patients, especially children and the elderly, often have difficulty swallowing large-sized tablets and capsules. Some patients are unwilling to take this oral medication because they feel an unacceptable bad taste. Therefore, various drug delivery devices have been provided that can facilitate the swallowing of large tablets and capsules and minimize the patient's perception of the dose administered.
  • the following patents and applications related to sip devices are incorporated herein by reference.
  • EP0383503 A1 describes an improved device for holding and positioning a unit dose of therapeutic agent in a tube, which device is adapted to deliver liquid through the tube by the normal sipping action of the patient.
  • the device has a screen having a surface area greater than the cross-sectional area of the lumen of the tube, thereby minimizing resistance to fluid flow during the sipping action.
  • U.S. Patent 6,960,003 describes a sipping device that includes an elongated tubular member with a deformable closing device (equivalent to a one-way valve that does not generate turbulence), the closing device is suitable for normal sipping The action allows the delivery of the active agent when deformed.
  • U.S. Patent 6,109,538 discloses a sip device including an elongated tube having a pair of screens disposed in the lumen to restrict the flavoring object, thereby transmitting the fragrance to the drinkable through the lumen liquid.
  • EP1517628 B1 describes a sipping device consisting of a straw, a removable or fixed stopper and a lid for oral administration of vitamins and/or nutritional preparations that are at least partially soluble in drinkable liquids.
  • U.S. Patent 6,210,713 B1 describes a sip device that includes an elongated tubular member with a one-way valve that serves as a closing device and also allows fluid to pass through the one-way valve when passing through a normal sip action .
  • U.S. Patent 8334003 describes a sipping device that includes an elongated tubular member with a pair of filtering devices at each end of the tubular member to retain flavored particles within the filtering device so that the flavoring agent enters the ordinary by normal sipping In the drink.
  • US Patent 6024721 describes a sip device including an elongated tubular member having a mixing chamber with a diameter greater than the diameter of the tubular member to provide drinkable liquid and active agent in the device Improved blending.
  • this device is difficult to practice and difficult to manufacture.
  • incorporating a mixing chamber with an inner diameter larger than the inner diameter of the tubular member into the sipping device will reduce the flow rate of the drinkable liquid into the mouth through normal sipping, thereby increasing the possibility of sensing the bad taste of the active agent.
  • the present invention provides an oral drug delivery device and a preparation method thereof.
  • an oral drug delivery device which includes: a tubular member, a drug containing part, a device cap, and a turbulence generating part, wherein the tubular member has openings at both ends and The inner cavity has a first opening at one end and a second opening at the other end, and the inner cavity communicates with the first opening and the second opening;
  • the medicine accommodating member has a hole-like structure and is maintained at the In the inner cavity, near the first opening, and used to accommodate particles or multi-pills containing active pharmaceutical ingredients;
  • the hole-like structure has one or more holes that allow liquid to pass through, and the diameter of the holes is smaller than that containing The diameter of the active pharmaceutical ingredient particles or multiple pills;
  • the device cap is a detachable connection and is provided outside the second opening;
  • the turbulence generating member has a stepped structure or a fold structure and is provided on the A position in the inner cavity between the second opening and the medicine containing member.
  • the tubular member allows the drinkable The liquid passes through; the medicine containing part is located inside the tubular member close to the first open end (ie, the liquid end) to keep the medicine in the form of particles or multiple pills.
  • the second open end ie, the mouth end
  • the first open end contacts the drinkable liquid. Due to the action of the turbulence generating member, turbulence can be formed in the oral drug delivery device, thereby improving the drug-containing particles Or more pills mixed with drinkable liquid.
  • an oral drug delivery device as described above is provided, wherein the diameter of the first opening is smaller than the minimum diameter of the drug receiving member, thereby maintaining the drug receiving member In the inner cavity.
  • the medicine accommodating member is in the shape of a cylinder or a truncated cone, its cross-sectional diameter is not the same.
  • the medicine containing part can be maintained in the inner cavity of the tubular member without using other fixing devices.
  • an inner cavity capable of accommodating particles and multiple pills containing medicine is formed.
  • the drinkable liquid flows through the hole-like structure of the medicine containing member through the first opening, thereby reaching the second opening.
  • the diameter of the second opening may be set to be smaller than the maximum diameter of the medicine accommodating part, so that when the device cap is not used to close and connect the second opening, even if the medicine accommodating part accidentally passes through the step structure or wrinkle
  • the internal structure can also be maintained in the inner cavity without falling out.
  • an oral drug delivery device as described above is provided, wherein the tubular member has at least two tube sections, and the tube sections are sealedly connected and can be along the axis of the tubular member Stretching or shrinking; when the tubular member is in a stretched state, a turbulence generating part having at least one step structure is formed.
  • the turbulence generating member may have a stepped structure due to, for example, different inner diameters of the adjacent pipe sections in the cross-sectional direction. More specifically, the thickness of the step is determined by the thickness of the pipe segment with the smaller inner diameter among the two adjacent pipe segments that are telescopically nested.
  • the telescopically nested tube section of the oral drug delivery device is similar to the telescope sleeve structure, so it is also referred to as a telescope-type structure or telescope-type telescopic sleeve structure.
  • the stretching or contracting along the axial direction of the tubular member may be a sleeve type stretching or contracting, or any other manner of stretching or contracting achieved by, for example, rotation.
  • an oral drug delivery device as described above is provided, wherein the number of the tube sections is 2-5; preferably 2-4; most preferably 3.
  • an oral drug delivery device as described above is provided, wherein, when the number of the tube segments is 3: the direction from the first opening to the second opening
  • the inner diameter of the first pipe section on the top is the same as the inner diameter of the third pipe section, the outer diameter of the second pipe section is smaller than the inner diameter of the first pipe section, and each pipe section can be stretched or contracted along the axial direction of other pipe sections;
  • the inner diameter of the first pipe section, the outer diameter, the inner diameter of the second pipe section, and the outer diameter of the third pipe section in the direction from the first opening to the second opening gradually decrease, and each pipe section can be axially stretched along the other pipe sections Or shrink. Since the edges of the three pipe sections on the cross section are parallel to each other, the adjacent pipe sections can be stretched or shrunk in the axial direction.
  • the inner diameter of the first pipe section from the first opening to the second opening is the same as the inner diameter of the third pipe section, and the inner diameter of the second pipe section is the same as that of the fourth pipe section
  • the inner diameter is the same, wherein the inner diameter of the second pipe section is smaller than that of the first pipe section, and each pipe section can be axially stretched or contracted along the other pipe sections; or, it extends from the first opening to the second opening
  • the inner diameters of the first to fourth pipe sections of the upper section gradually decrease, and each pipe section can be axially stretched or contracted along the other pipe sections. Since the edges of each pipe section on the cross section are parallel to each other, adjacent pipe sections can be stretched or shrunk in the axial direction. The case where the number of pipe sections is greater than 4 can be deduced by analogy.
  • an oral drug delivery device as described above is provided, wherein the tubular member has at least one fold structure, and the fold structure has a pair of wings and one Turning end; the fold structure can be stretched or contracted along the axial direction of the tubular member, and forms a turbulence generating part during the stretching.
  • the turning end is a bending part of the fold portion from one wing portion to another wing portion. In the cross section, the turning end is usually a point, so a pair of wings and a turning end usually form a corner structure.
  • the one angle may be an acute angle, a right angle or an obtuse angle.
  • the fold group structure is similar to an accordion type structure, so in the present invention, the fold group is also referred to as an accordion type structure or an accordion-like fold group .
  • an oral drug delivery device as described above is provided, wherein a plurality of continuous fold structure forms a fold group structure, the number of the fold group structure is 1-5 ; Preferably 2-3.
  • an oral drug delivery device as described above is provided, wherein the cross-sectional diameter of the lumen at the fold structure is smaller than the connection point with the tubular member and the fold structure
  • the diameter of the inner cavity of the pleated structure, and the minimum inner diameter of the inner cavity of the fold structure is not less than one fifth of the diameter of the inner cavity of the tubular member.
  • an oral drug delivery device as described above is provided, wherein the maximum outer diameter of the tubular member is 4.0-15.0 mm and the minimum inner diameter is 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.
  • the active pharmaceutical ingredient can be prepared into granules or multiple pills with other excipients through a certain process. If the drugs incorporated in the granules or multiple pills have a bad taste, it may be necessary to coat them with a taste-masking composition. Multi-pills can also be coated with enteric coating or slow-release coating or enteric coating and slow-release coating respectively for slow-release or delayed-release or enteric/slow-release. Therefore, in a more preferred embodiment, an oral drug delivery device as described above is provided.
  • the medicine containing part has particles or multiple pills containing an active pharmaceutical ingredient, the particles and multiple pills
  • the diameter is 50-5000 ⁇ m, preferably 75-2000 ⁇ m, more preferably 100-1000 ⁇ m
  • the active pharmaceutical ingredients include but are 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 benzene Halamine.
  • the oral administration delivery device contains granules or multiple pills, the granules or multiple pills containing 9-48 wt% dabigatran etexilate mesylate, 9-44 wt% Soluplus , 0-30wt% Kolliphor P407, 0-23wt% Kolliphor P188, 0-58wt% lactose monohydrate, 0-32wt% mannitol, 0-20wt% croscarmellose sodium, 0 -5wt% silica and 0-3wt% magnesium stearate.
  • the granules or pellets contain 10.4-17.2wt% dabigatran etexilate mesylate, 24.3-35.7wt% Soluplus , 13.1wt% Kolliphor P407 or 19.0wt% Kolliphor P188, 0-52.2wt% lactose monohydrate, 0-17.9wt% mannitol, 0-9.7wt% croscarmellose sodium and 0-0.5wt% magnesium stearate.
  • the oral administration delivery device contains multiple pills containing 10.4 wt% dabigatran etexilate mesylate, 2.6 wt% Soluplus , 13.1wt% Kolliphor P407, 52.2wt% sucrose pellet core and 21.7wt% Soluplus powder.
  • the multiple pills are preferably in doses of 50 mg and 75 mg of active pharmaceutical ingredient.
  • the oral drug delivery device contains particles, the particles containing 17.2 wt% dabigatran mesylate, 35.7% wt Soluplus , 17.9wt% mannitol, 19.0wt% Kolliphor P188, 9.7wt% croscarmellose sodium and 0.5wt% magnesium stearate.
  • the granules are preferably in doses of 50 mg and 75 mg of active pharmaceutical ingredient.
  • the oral drug delivery device contains granules and multiple pills, the granules or multiple pills contain 42.3-70.41wt% levodopa, 0-45.7wt% carbidopa Hydrate, 1.9-3.81wt% sodium lauryl sulfate, 4.8-19.03wt% filler (such as one or more of microcrystalline cellulose, hydroxypropyl cellulose and mannitol), 1.9-4.8wt % Binder (eg, one or more of methyl cellulose, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, and gelatin).
  • 42.3-70.41wt% levodopa 0-45.7wt% carbidopa Hydrate
  • 1.9-3.81wt% sodium lauryl sulfate such as one or more of microcrystalline cellulose, hydroxypropyl cellulose and mannitol
  • Binder eg, one or more of methyl cellulose,
  • the multi-pills further comprise a coating film, the coating film contains cellulose acetate and copovidone, the cellulose acetate is 50-90 wt% of the coating film; the copovidone is The coating film is 10-50 wt%.
  • the oral drug delivery device contains particles and multiple pills, the particles are immediate-release particles, the multiple pills are sustained-release multiple pills, and the particles contain 42.3 wt% levorotatory Dopa, 45.7% by weight carbidopa monohydrate, 1.9% by weight sodium lauryl sulfate, 4.8% by weight hydroxypropyl methyl cellulose (HPMC) E5, 4.8% by weight croscarmellose sodium And 0.5wt% magnesium stearate; and/or, the multi-pill contains 70.41wt% levodopa, 19.03wt% microcrystalline cellulose, 3.81wt% sodium lauryl sulfate, 1.90wt% Povidone K29/32 , 4.12wt% cellulose acetate 39.8 and 0.73wt% Copovidon (Kollidone VA64).
  • the coating level of the sustained-release multiple pills is 5.1-10.9 wt%, preferably 7.7%. More preferably, the sustained-release multiple pills are coated
  • the oral drug delivery device contains particles, the particles containing 0.83 wt% montelukast sodium, 93.67 wt% mannitol, 5.00 wt% hydroxypropyl cellulose and 0.50 wt% magnesium stearate.
  • the particles are preferably 500 mg (4 mg montelukast), 625 mg (5 mg montelukast), 1250 mg (10 mg montelukast) and 500 mg (10 mg montelukast).
  • the oral drug delivery device contains particles and multiple pills, the particles are amoxicillin particles and clarithromycin particles, and the multiple pills are lansoprazole delayed release Pills, the filling weight of the lansoprazole delayed-release multiple pills, amoxicillin granules and clarithromycin granules are 480 mg, 1334 mg and 840 mg, respectively.
  • the lansoprazole delayed-release multiple pills include a core and an enteric coating
  • the core contains 6.3 wt% lansoprazole, 31.3 wt% sugar pills, 11.3 wt% corn starch, 12.1 wt% sucrose, 1.3 wt% Low-substituted hydroxypropyl cellulose, 0.8wt% hydroxypropyl cellulose and 6.3wt% magnesium carbonate
  • the enteric coating contains 13.1wt% Eudragit L-30D solid component, 4.0wt% talc, 1.3wt% PEG6000 , 0.7wt% Tween 80 and 1.8wt% titanium dioxide.
  • the amoxicillin particles 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.
  • the oral administration delivery device contains particles and multiple pills, the particles are amoxicillin particles and clarithromycin particles, and the multiple pills are omeprazole delayed release Pills, the filling weights of the omeprazole delayed-release multiple pills, amoxicillin granules and clarithromycin granules are 320 mg, 1334 mg and 840 mg, respectively.
  • the omeprazole delayed-release multiple pills include a core and an enteric coating
  • the core contains 6.3wt% omeprazole, 31.3wt% sugar pills, 11.3wt% corn starch, 12.1wt% sucrose, 11.3wt% Low-substituted hydroxypropyl cellulose, 0.8wt% hydroxypropyl cellulose and 6.3wt% magnesium carbonate
  • the enteric coating contains 13.1wt% Eudragit L-30D solid component, 4.0wt% talc, 1.3wt% PEG6000 , 0.7wt% Tween 80 and 1.8wt% titanium dioxide.
  • the amoxicillin particles 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.
  • the oral drug delivery device contains particles, and the active pharmaceutical ingredients of the particles are acetaminophen, dextromethorphan, doxylamine, pseudoephedrine, and diphenhydramine,
  • the dosage ranges 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.
  • Drinkable liquids can be used to carry drug-containing granules or multiple pills through the tubular portion of the device by normal sipping.
  • the liquid is preferably any drinkable liquid, including but not limited to water, lemonade, fruitless juice, milk, soda, coffee and tea.
  • One of the technical solutions of the present invention is to provide a method for preparing an oral drug delivery device, which includes the following steps:
  • a step of filling the medicine is further included.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive progress effect of the present invention is that: the oral administration delivery device of the present invention provides adequate mixing of drug-containing granules or multiple pills with drinkable liquid for normal sipping effect; and the device of the present invention is scalable and reduces Small size, easy to carry.
  • the granules or multi-pills containing the drug whose active ingredient is dabigatran etexilate show significantly faster dissolution at acidic pH, and show less precipitation at neutral pH.
  • the preparation method of the oral drug delivery device of the present invention is simple and the use effect is good.
  • FIG. 1 is a schematic diagram of an oral drug delivery device having a stepped structure turbulence generating member, type I: a. contracted state, b. stretched state + before sipping, c. stretched state + when sipping;
  • FIG. 2 is a schematic diagram of an oral drug delivery device having a stepped turbulence generating component, type II: a. contracted state, b. stretched state + before sipping, c. stretched state + sipping;
  • Figure 3 is a schematic diagram of an oral drug delivery device having a turbulence generating structure with a wrinkled portion structure: a. contracted state, b. stretched state + before sipping, c. stretched state + when sipping;
  • FIG. 4 is a schematic diagram of plug flow-turbulent flow: a. turbulent flow formed by the oral drug delivery device having a stepped structure turbulence generating member of the present invention; b. oral drug delivery by the turbulent flow generating member of the present invention having a wrinkle structure Turbulence formed by the device;
  • FIG. 5 is a dissolution curve of particles described in Example 1.
  • FIG. 6 is the dissolution curve of the multi-pill described in Example 2.
  • the present invention prepares an oral drug delivery device having a turbulence generating member with a stepped structure.
  • 1 and 2 respectively show cross-sectional views of a telescope type type I (type I) and type II (type II) of an oral drug delivery device according to the present invention.
  • the oral drug delivery device is in a contracted state before use ( Figure 1a or 2a), in a stretched state before sipping ( Figure 1b or 2b), and in the form of particle suspension during sipping ( Figure 1c or 2c).
  • the oral drug delivery device shown in FIGS. 1 and 2 includes a stretchable or contractible tubular member 1 having a first opening 2, a second opening 3 and a device cap 4.
  • Figures 1 and 2 illustrate a tubular member consisting of three pipe sections 11, 12, 13 respectively. In FIG.
  • the inner diameter of the first pipe section 11 from the first opening 2 to the second opening 3 is the same as the inner diameter of the third pipe section 13, and the outer diameter of the second pipe section 12 is smaller than the first pipe section 11 So that the first pipe section 11 and the third pipe section 13 can be axially stretched (Figures 1b and 1c) or contracted (Figure 1a) along the second pipe section 12.
  • Figures 1b and 1c axially stretched
  • Figure 1a contracted
  • the inner diameter of the first pipe section 11, the outer diameter of the second pipe section 12, the inner diameter of the third pipe section 13 and the outer diameter of the third pipe section 13 gradually decrease from the first opening 2 to the second opening 3, but
  • the edges of the three pipe sections on the same side of the cross section are parallel to each other, so that the third pipe section 13 and the second pipe section 12 can be axially stretched (Figure 2b and 2c) or contracted (Figure 2a) along the first pipe section 11 .
  • the medicine accommodating part 6 is provided in the inner cavity 9 of the tubular member 1 near the first opening 2.
  • the figure shows the configuration when it contains particles or multiple pills 5.
  • the end of the first opening 2 is shrunk 21, so that the diameter of the opening after the inner shin is smaller than the minimum diameter of the structure of the medicine accommodating member 6; the end of the second opening 3
  • the inner portion 31 makes the opening diameter after the inner portion smaller than the maximum diameter of the structure of the medicine accommodating member 6, thereby maintaining the medicine accommodating member 6 in the inner cavity.
  • a device cap 4 is provided outside the second opening 3.
  • the medicine accommodating part 6 cooperates with the tubular member 1 to form a space that can accommodate medicines (in the example of the present invention, in a granular and multi-pill structure, in which a pharmaceutical active ingredient is contained in a granular or multi-pill structure) 5.
  • the medicine containing member 6 is a hole-shaped structure, and the hole-shaped structure contains a plurality of holes 61 whose diameter is smaller than the diameter of the granules or multi-pills 5, which can allow the drinkable liquid to pass through;
  • the Heduo pill 5 remains in the inner cavity 9 of the tubular member 1.
  • the oral drug delivery device forms a stepped structure 7 by stretching.
  • the stepped structure 7 is shown in FIGS.
  • the step structure 7 illustrated in FIGS. 1 and 2 has a first step 71 and a second step 72.
  • the drinkable liquid generates turbulent flow through the steps 71 and 72, thereby enhancing the drug-containing particles or multi-pills 5 and the Drink a mixture of liquids.
  • the Reynolds number that forms turbulent flow increases; in addition, when the thickness of the step structure increases conventionally in the art, turbulent flow forms The Reynolds number also increases.
  • the present invention also prepares an oral drug delivery device with a turbulence generating member having a wrinkle structure.
  • Fig. 3 shows a cross-sectional view of the structure of an accordion-like fold group of an oral drug delivery device according to the present invention.
  • the device is in a contracted state before use ( Figure 3a), in a stretched state before sipping (Figure 3b), and in the form of particle suspension during sipping (Figure 3c).
  • the oral drug delivery device shown in FIG. 3 includes a stretchable tubular member 1 having a lumen 9 and a plurality of fold group structures, and two fold group structures 81 and 82 are shown in FIG. 3.
  • Each wrinkle group structure has a plurality of wrinkle structure 811.
  • the oral drug delivery device has a first opening 2, a second opening 3, and a device cap 4. Contained in the inner cavity 9 of the tubular member are granules or multiple pills 5 containing the active pharmaceutical ingredient and the medicine containing member 6. After placing the medicine accommodating member 6 in the inner cavity, the end of the first opening 2 is buckled in, so that the diameter of the opening after the inner chucking is smaller than the minimum diameter of the medicine accommodating member 6; the end of the second opening 3 is buckled in 31, The diameter of the opening after the internal retraction is made smaller than the maximum diameter of the structure of the medicine accommodating member 6, thereby maintaining the medicine accommodating member 6 in the inner cavity. And a device cap 4 is provided outside the second opening 3. The medicine containing part 6 shown in FIG.
  • the medicine accommodating part 6 cooperates with the tubular member 1 to form a space in which particles or multi-pills 5 containing active medicine ingredients can be accommodated.
  • the pore diameter 61 of the hole-like structure is smaller than the diameter of the granules or multi-pills 5 and may allow the drinkable liquid to pass, but when no liquid passes, the granules or multi-pills 5 are stored in the inner cavity 9 of the tubular member 1.
  • the drinkable liquid flows through the fold structure 811 to generate turbulence, thereby enhancing the mixing of the active pharmaceutical ingredient-containing particles or pills 5 with the drinkable liquid.
  • the turbulent Reynolds number increases; in addition, when the height of the fold structure to the lumen direction is in the field As the internal increase increases, the Reynolds number that forms turbulence also increases.
  • the device cap 4 may be directly provided outside the second opening 3. At this time, since the device cap is sealingly connected to the second opening, even if the end of the second opening 3 is not tucked in, the medicine accommodating member 6 will not reach the cavity 9 due to the presence of the step structure or the wrinkle structure Outside the second opening 3, the medicine containing member 6 can be maintained in the inner cavity 9.
  • the diameter of the opening after turning down is smaller than the maximum diameter of the medicine receiving member, so as to further ensure that the medicine receiving member 6 is used during the use of the oral drug delivery device Will not be sucked into the patient's mouth and cause a medical accident.
  • Fig. 4 schematically shows plug flow and turbulence generated by an oral drug delivery device having a turbulence generating part of a step structure or a fold structure according to the present invention.
  • the tubular member 1 of the oral drug delivery device generally has an outer diameter between 4.0 mm and 15.0 mm.
  • the inner cavity 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 prepared form, and between 10 cm and 30 cm in its elongated form.
  • the preferred materials for manufacturing the tubular member 1, the drug receiving member 6, and the device cap 4 are polymers of the polypropylene and polyolefin family conventional in the art.
  • the active pharmaceutical ingredients (API) covered by the present invention include but are not limited to dabigatran etexilate or a pharmaceutically acceptable salt thereof, levodopa/carbidopa, montelukast, lansoprazole, omeira Azole, amoxicillin, clarithromycin, acetaminophen, dextromethorphan, doxylamine, pseudoephedrine and diphenhydramine.
  • the oral drug delivery device comprises a solubility-enhanced dabigatran etexilate methylate (DEM) in the form of granules, which is prepared by using a hot melt granulation method.
  • DEM dabigatran etexilate methylate
  • the oral drug delivery device comprises multi-pill form of enhanced solubility dabigatran etexilate methylate (DEM), which is prepared by using a spray process.
  • EDM enhanced solubility dabigatran etexilate methylate
  • the oral drug delivery device comprises a sustained release levodopa/carbidopa formulation in the form of multiple pills, which is prepared by utilizing extrusion, spheronization, and coating processes.
  • the oral drug delivery device contains montelukast granules, which are prepared by conventional granulation methods, including wet granulation, fluidized bed granulation, dry granulation, and the like.
  • the oral administration delivery device contains lansoprazole in the form of multiple pills and amoxicillin and clarithromycin in the form of granules.
  • the multiple pills are prepared by spraying and coating processes, while the granules are prepared by conventional methods.
  • the granulation method of preparation including wet granulation, fluidized bed granulation, dry granulation and so on.
  • the oral administration delivery device contains omeprazole in the form of multiple pills and amoxicillin and clarithromycin in the form of granules.
  • the multiple pills are prepared by spraying and coating processes, while the granules are prepared by conventional methods.
  • the granulation method of preparation including wet granulation, fluidized bed granulation, dry granulation and so on.
  • an oral drug delivery device contains cold medicine granules prepared by conventional granulation methods, 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 having a stepped structure turbulence generating member.
  • One configuration of the device can be manufactured by the following manufacturing steps. First, a tubular member (type I or type II, see Fig. 1a and 2a) composed of three parts is manufactured by a conventional method of manufacturing a straw. Next, the medicine containing part 6 is inserted into the first opening 2 end of the tubular member 1. Next, the end is squeezed so that the medicine containing part 6 can be held in the inner cavity 9 of the tubular member 1. Then, granules or multiple pills 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 in an aluminum bag (not shown).
  • Another oral drug delivery device in the present invention is an oral drug delivery device having a turbulence generating member with a wrinkle structure.
  • the device can be manufactured by the following manufacturing steps. First, the tubular member 1 having three groups of accordion-like fold groups 8 is manufactured by a conventional process for manufacturing straws. Next, the medicine containing part 6 is inserted into the first opening 2 end of the tubular member 1. Next, the end of the first opening 2 is squeezed so that the medicine containing part 6 can be held in the inner cavity 9 of the tubular member 1. Then, granules or multiple pills 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 in an aluminum bag (not shown).
  • the composition comprises 40% by weight dabigatran etexilate (DEM), 10% polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Soluplus and 50% polyoxygen Ethylene polyoxypropylene block copolymer Kolliphor P407.
  • these solid components were dissolved in 92% ethanol to prepare a coating solution having a solid content of 24.2%.
  • a multi-pill containing DEM 552.4 mg in 50 mg dose and 648.6 mg in 75 mg dose
  • Soluplus powder 120 mg in 50 mg dose and 180 mg in 75 mg dose
  • Table 1 lists the composition of the multi-pill filled formulation in the device.
  • a granule formulation containing DEM was prepared by the hot melt granulation method.
  • Table 2 lists the composition of the hot melt DEM formulation.
  • the hot melt granulation process is briefly described as follows. First, the Soluplus Grind and pass through an 80-mesh sieve, grind and pass a Kolliphor P188 through a 40-mesh sieve, then pass the sieved Soluplus The powder is mixed with other excipients other than magnesium stearate in a high-shear granulator with a thermal jacket at 65-75°C until consistent and uniform granules are formed. Next, the hot melt particles are passed through a 20 mesh sieve and then mixed with magnesium stearate.
  • the hot-melt DEM granule formulation (336.1 mg in 50 mg dose and 504.1 mg in 75 mg dose) is filled into the tubular member 1 inside the first opening 2 end through the second opening 3 end. Finally, the filled tubular member is closed by the device cap and wrapped in an aluminum bag (not shown).
  • the filled formulation consists of immediate-release levodopa/carbidopa granules and levodopa sustained-release multiple pills.
  • Table 3 lists the composition of the filling formulation.
  • the conventional wet granulation process is used to prepare quick-release granules, and the extrusion/spheronization/spraying process is used to prepare sustained-release multiple pills.
  • the coating level of sustained-release multiple pills was 5.1% by weight, and 90% of levodopa was released after about 3.9 hours.
  • a A A Sustained-release multiple pills A A Levodopa 70.41 200.0 Microcrystalline cellulose 19.03 54.1 Sodium dodecyl sulfate 3.81 10.8 Povidone K29/32 1.90 5.4 Cellulose acetate 39.8 4.12 11.7 Copovidon(KollidoneVA64) 0.73 2.1 Total content 100.00 284.1
  • Example 3 At the coating levels of 7.7% and 10.9% instead of 5.1%, in this example, the preparation process and filled formulation of the sustained-release multiple pills in Example 3 were repeated, and 90% of L-duo was released in about 6.6 hours and 9.3 hours, respectively. bar.
  • sustained-release multiple pills described in Examples 3 and 4 are coated with an enteric composition conventional in the art at a coating level of 3-10%.
  • the filled formulation is in the form of granules and contains montelukast sodium, mannitol, hydroxypropyl cellulose, and magnesium stearate.
  • the immediate release granules are prepared by a wet granulation process using a high shear granulator.
  • Table 4 lists the composition of the filling formulation.
  • montelukast sodium is equivalent to 4 mg of montelukast.
  • the montelukast granule preparation (500 mg) is filled into the tubular member 1 inside the first opening 2 end through the second opening 3 end. Finally, the filled tubular member is closed by the device cap and wrapped in an aluminum bag (not shown).
  • the montelukast sodium in the filled formulation can be quickly dissolved in an aqueous medium, and the dissolution time of 85% of the drug does not exceed 30 minutes.
  • Example 6 The procedure of Example 6 was repeated in this example to provide the same filled formulation.
  • the fill weight was changed to 625mg.
  • Each filling device includes 5 mg montelukast.
  • Example 6 The procedure of Example 6 was repeated in this example to provide the same filled formulation.
  • the fill weight was changed to 1250mg.
  • Each filling device includes 10 mg montelukast.
  • Example 6 The procedure of Example 6 was repeated in this example to provide a filled formulation, the composition of which is listed in Table 5.
  • the fill weight is 500 mg.
  • Each filling device includes 10 mg montelukast.
  • montelukast sodium *10.4 mg of montelukast sodium is equivalent to 10 mg of montelukast.
  • the filling consists of three formulations, the first is lansoprazole delayed-release multiple pills, the second is amoxicillin granules, and the third is clarithromycin granules.
  • Table 6 lists the filler composition.
  • the filling weights of lansoprazole delayed-release multiple pills, amoxicillin granules and clarithromycin granules were 480 mg, 1334 mg and 840 mg, respectively.
  • Each filling device includes 30 mg lansoprazole, 1000 mg amoxicillin and 500 mg clarithromycin.
  • the filling consists of three formulations, the first is omeprazole delayed-release multiple pills, the second is amoxicillin granules, and the third is clarithromycin granules.
  • Table 7 lists the filler composition.
  • the filling weights of omeprazole delayed-release multiple pills, amoxicillin granules and clarithromycin granules are 320 mg, 1334 mg and 840 mg, respectively.
  • Each filling device includes 20 mg omeprazole, 1000 mg amoxicillin and 500 mg clarithromycin.
  • the filled formulation in the form of particles contains each individual drug or a combination thereof, 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 dosage ranges of these APIs.

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Abstract

本发明公开了一种口服给药递送装置，其包括：一管状构件、一药物容置部件、一装置帽和一湍流产生部件，其中，所述管状构件具有两端开口及内腔，其一端开口为第一开口，另一端开口为第二开口，所述内腔连通所述第一开口和第二开口；所述湍流产生部件包含台阶结构或褶皱部结构，并设置于所述内腔中、介于所述第二开口和所述药物容置部件之间的位置；所述药物容置部件和装置帽的结构及其与管状构件的连接关系如本发明中所述。通过本发明的口服给药递送装置，可在正常的啜吸过程中产生湍流，提供含药物颗粒或多丸与可饮用的液体的充分混合；且该装置可伸缩，减小了尺寸，方便携带。

Description

一种口服给药递送装置
本申请要求申请日为2019/1/7的中国专利申请2019100129354的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及医疗器械领域，尤其涉及一种口服给药递送装置。
背景技术
片剂和胶囊是方便和最可接受的口服剂型。但是一些病人，特别是儿童和老人，通常难以吞咽大尺寸的药片和胶囊。有些病人因为感觉到不可接受的坏味道而不愿意服用这种口服药物。因此，已经提供了各种给药装置，其能促进大片剂和胶囊的吞咽，并尽可能减少患者对给药剂量的感知。以下与啜吸设备相关的专利和申请通过引用结合于此。
EP0383503 A1描述了一种改进的装置，其用于将单位剂量的治疗剂保持和定位在管中，该装置适应于通过患者的正常啜吸动作将液体流通过管输送该治疗剂。该装置具有筛网，该筛网的表面积大于管的内腔横截面积，从而在啜吸动作期间使得对流体流动的阻力最小化。
美国专利6096003描述了一种啜吸装置，其包括细长管状构件，该细长管状构件具有可变形的闭合装置(相当于单向阀门，不产生湍流)，该闭合装置适于在正常啜吸动作产生变形时允许递送活性剂。
美国专利6109538揭示了一种啜吸装置，该装置包括细长管，该细长管具有设置在管腔中的一对筛网，以限制调味对象，从而通过管腔将香味传递给可饮用的液体。
EP1517628 B1描述了一种由吸管、可移动或固定塞子和盖子组成的啜吸装置，用于口服施用至少部分可溶于可饮用的液体中的维生素和/或营养制剂。
美国专利6210713 B1描述了一种啜吸装置，其包括细长管状构件，该细长管状构件具有用作关闭装置的单向阀，并且还允许流体在通过正常的啜吸动作时通过单向阀。
美国专利8334003描述了一种啜吸装置，其包括细长管状构件，在管状构件的每一端具有一对过滤装置，以将调味颗粒保持在过滤装置内，从而通过正常啜吸使调味剂进入普通饮料中。
美国专利6024721描述了一种啜吸装置，其包括细长管状构件，该细长管状构件具有混合室，该混合室的直径大于管状构件的直径，以在装置中提供可饮用的液体与活性剂的改进混合。然而，这种装置很难实践，也很难制造。此外，将内径大于管状构件内径的混合室结合到啜吸装置中，将通过正常的啜吸作用降低可饮用的液体进入口中的流速，从而增加感知活性剂不良味道的可能性。
发明内容
为了解决现有技术中缺乏一种有效地促进药物吞咽的装置的技术问题，本发明提供一种口服给药递送装置及其制备方法。
本发明的技术方案之一为提供一种口服给药递送装置，其包括：一管状构件、一药物容置部件、一装置帽和一湍流产生部件，其中，所述管状构件具有两端开口及内腔，其一端开口为第一开口，另一端开口为第二开口，所述内腔连通所述第一开口和第二开口；所述药物容置部件具有孔状结构，并维持于所述内腔中、近第一开口处，且用于容置含有活性药物成分的颗粒或多丸；所述孔状结构具有一个或多个允许液体通过的孔，所述孔的直径小于所述含有活性药物成分的颗粒或多丸的直径；所述装置帽为可拆卸的连接，并设置于所述第二开口的外部；所述湍流产生部件具有台阶结构或褶皱部结构，并设置于所述内腔中、介于所述第二开口和所述药物容置部件之间的位置。
使用时，将所述装置帽从所述第二开口上拆卸下来；所述第一开口端与可饮用液体接触；所述第二开口端放置在患者口中；所述管状构件允许所述可饮用液体通过；所述药物容置部件位于所述管状构件内部靠近第一开口端(即液体端)，以保持药物的颗粒或多丸形式。将第二开口端(即嘴端)置于口中，第一开口端接触可饮用液体，由于所述湍流产生部件的作用，所述口服给药递送装置中可形成湍流，从而改善含药物的颗粒或多丸与可饮用液体的混合。
在一较佳的实施例中，提供了一种如上所述的口服药物递送装置，其中，所述第一开口的直径小于所述药物容置部件的最小直径，由此将药物容置部件维持于所述内腔中。本发明中，由于药物容置部件为圆柱体或圆台类似形状，其截面的直径不尽相同。由此，药物容置部件不需使用其他固定装置就能维持在管状构件的内腔中。所述药物容置部件与管状构件相配合时，形成一可容纳含有药物的颗粒和多丸的内腔。由此，在啜吸时，可饮用液体通过所述第一开口流经所述药物容置部件的孔状结构，从而到达所述第二开口。所述第二开口的直径可设置为小于所述药物容置部件的最大直径，这样，当不使用装置帽封闭连接第二开口时，即使所述药物容置部件意外地通过了台阶结构或褶皱部结构，也可以维持于所述内腔中而不会脱落出来。
在一较佳的具体实施例中，提供一种如上所述的口服给药递送装置，其中，所述管状构件具有至少2个管段，所述管段之间密封连接并可沿所述管状构件轴向拉伸或收缩；所述管状构件呈拉伸状态时形成具有至少1个台阶结构的湍流产生部件。所述湍流产生部件可以由于例如相邻的所述管段在截面方向内径不同，从而形成台阶结构。更具体地，所述台阶的厚度是由伸缩嵌套连接的相邻2个管段中内径较小的那个管段的厚度决定的。在可实施的数量范围内，台阶结构的数目越多，则产生湍流的雷诺数越大；在合理范围内，台阶结构的厚度越大，则产生湍流的雷诺数也越大。在本发明中，该口服给药递送装置的伸缩嵌套连接的管段类似于望远镜的套筒构造，因此也称为望远镜式结构或望远镜式伸缩套筒结构。所述沿管状构件轴向拉伸或收缩可以是套筒式拉伸或收缩，也可以是通过例如旋转实现的其他任何拉伸或收缩方式。
在一更佳的具体实施例中，提供一种如上所述的口服给药递送装置，其中，所述管段的数量为2-5个；优选2-4个；最优选3个。
在一更佳的具体实施例中，提供一种如上所述的口服给药递送装置，其中，当所述管段的数量为3个时：其由所述第一开口至所述第二开口方向上的第一管段的内径与第三管段的内径相同，第二管段的外径小于所述第一管段的内径，且每一管段可沿其他管段轴向拉伸或收缩；或，其由所述第一开口至所述第二开口方向上的第一管段的内径、第二管段的外径、内径和第三管段的外径逐渐减小，且每一管段可沿其他管段轴向拉伸 或收缩。由于三个管段在剖面上的边线是相互平行的，因此相邻的管段可以在轴向上实现拉伸或收缩。
当所述管段的数量为4个时：其由所述第一开口至所述第二开口方向上的第一管段的内径与第三管段的内径相同，第二管段的内径与第四管段的内径相同，其中，所述第二管段的内径小于所述第一管段，且每一管段可沿其他管段轴向拉伸或收缩；或，其由所述第一开口至所述第二开口方向上的第一管段至第四管段的内径逐渐减小，且每一管段可沿其他管段轴向拉伸或收缩。由于每一管段在剖面上的边线是相互平行的，因此相邻的管段可以在轴向上实现拉伸或收缩。管段数量大于4个的情况可以由上类推。
在一较佳的具体实施例中，提供一种如上所述的口服给药递送装置，其中，所述管状构件具有至少1个褶皱部结构，所述褶皱部结构具有1对翼部和1个转折端；所述褶皱部结构可沿所述管状构件轴向拉伸或收缩，并在所述拉伸时形成湍流产生部件。所述转折端为褶皱部从一翼部到另一翼部的弯曲部位。在横剖面上，所述转折端通常为一个点，因此1对翼部和1个转折端通常组成一个角的结构。所述一个角可以为锐角、直角或钝角。
当管状构件含多个连续的褶皱部结构即形成褶皱群结构时，该褶皱群结构类似于手风琴式结构，因此在本发明中，所述褶皱群也被称为手风琴式结构或手风琴状褶皱群。在一更佳的具体实施例中，提供一种如上所述的口服给药递送装置，其中，多个连续的褶皱部结构形成一个褶皱群结构，所述褶皱群结构的数量为1-5个；优选2-3个。
在一更佳的具体实施例中，提供一种如上所述的口服给药递送装置，其中，所述褶皱部结构处的内腔截面直径小于与所述管状构件与所述褶皱部结构连接处的内腔截面直径，且，所述褶皱部结构处的内腔截面的最小内径不小于所述管状构件的内腔截面直径的五分之一。此时褶皱部结构的转折端朝向管状构件轴心方向形成突起，可以使得所述口服给药递送装置在收缩状态下就已形成了湍流产生部件。
在一较佳的具体实施例中，提供一种如上所述的口服给药递送装置，其中，所述管状构件的最大外径为4.0-15.0mm，最小内径为2.0-14.8mm；和/或，所述管状构件的长度在收缩状态时为5-30cm，在拉伸状态时为10-50cm。
所述活性药物成分可与其它赋形剂通过一定工艺制备成颗粒或多丸，如果掺入颗粒或多丸中的药物味道不好，可能需要用掩味组合物涂覆它们。多丸也可以分别用肠溶包衣或缓释包衣或肠溶包衣和缓释包衣涂覆，用于缓释或延迟释放或肠溶/缓释。因此，在一更佳的具体实施例中，提供一种如上所述的口服给药递送装置，当所述药物容置部件具有含活性药物成分的颗粒或多丸时，所述颗粒和多丸的直径为50-5000μm，优选为75-2000μm，更优选为100-1000μm；所述活性药物成分包括但不限于以下的一种或多种：达比加群酯或其药学上可接受的盐、左旋多巴/卡比多巴、孟鲁司特、兰索拉唑、奥美拉唑、阿莫西林、克拉霉素、对乙酰氨基酚、右美沙芬、多西拉敏、伪麻黄碱和苯海拉明。
在一较佳的实施例中，所述口服给药递送装置中含颗粒或多丸，所述颗粒或多丸含9-48wt％的甲磺酸达比加群酯、9-44wt％的Soluplus
Figure PCTCN2020073865-appb-000001
、0-30wt％的Kolliphor P407、0-23wt％的Kolliphor P188、0-58wt％的乳糖一水合物、0-32wt％的甘露醇、0-20wt％的交联羧甲基纤维素钠、0-5wt％的二氧化硅和0-3wt％的硬脂酸镁。优选地，所述颗粒或多丸含10.4-17.2wt％的达比加群酯甲磺酸盐、24.3-35.7wt％的Soluplus
Figure PCTCN2020073865-appb-000002
、13.1wt％的Kolliphor P407或19.0wt％的Kolliphor P188、0-52.2wt％的乳糖一水合物、0-17.9wt％的甘露醇、0-9.7wt％的交联羧甲基纤维素钠和0-0.5wt％的硬脂酸镁。
在一具体的实施例中，所述口服给药递送装置中含多丸，所述多丸含10.4wt％甲磺酸达比加群酯、2.6wt％Soluplus
Figure PCTCN2020073865-appb-000003
、13.1wt％Kolliphor P407、52.2wt％蔗糖丸芯和21.7wt％Soluplus粉。所述多丸优选为50mg和75mg活性药物成分的剂量。
在一具体的实施例中，所述口服给药递送装置中含颗粒，所述颗粒含17.2wt％甲磺酸达比加群酯、35.7wt％Soluplus
Figure PCTCN2020073865-appb-000004
、17.9wt％甘露糖醇、19.0wt％Kolliphor P188、9.7wt％交联羧甲基纤维素钠和0.5wt％硬脂酸镁。所述颗粒优选为50mg和75mg活性药物成分的剂量。
在一较佳的具体实施例中，所述口服给药递送装置中含颗粒与多丸，所述颗粒或多丸含42.3-70.41wt％左旋多巴、0-45.7wt％卡比多巴一水合物、1.9-3.81wt％十二烷基硫酸钠、4.8-19.03wt％填充剂(例如微晶纤维素、羟丙基纤维素和甘露醇中的一种或多种)、1.9-4.8wt％粘合剂(例如甲基纤维素、羟丙甲纤维素、羟丙纤维素、羧甲基纤维素钠、聚 维酮和明胶中的一种或多种)。优选地，所述多丸还包含包衣膜，所述的包衣膜含醋酸纤维素和共聚维酮，所述醋酸纤维素为所述包衣膜50～90wt％；所述共聚维酮为所述包衣膜10～50wt％。
在一较佳的具体实施例中，所述口服给药递送装置中含颗粒与多丸，所述颗粒为速释颗粒，所述多丸为缓释多丸，所述颗粒含42.3wt％左旋多巴、45.7wt％卡比多巴一水合物、1.9wt％十二烷基硫酸钠、4.8wt％羟丙基甲基纤维素(HPMC)E5、4.8wt％交联羧甲基纤维素钠和0.5wt％硬脂酸镁；和/或，所述多丸含70.41wt％左旋多巴、19.03wt％微晶纤维素、3.81wt％十二烷基硫酸钠、1.90wt％Povidone K29/32、4.12wt％醋酸纤维素39.8和0.73wt％Copovidon(Kollidone VA64)。优选地，所述缓释多丸的包衣水平为5.1-10.9wt％，优选7.7％。更优选地，所述缓释多丸用肠溶组合物以3-10wt％的包衣水平包覆。
在一较佳的具体实施例中，所述口服给药递送装置中含颗粒，所述颗粒含0.83wt％孟鲁司特钠、93.67wt％甘露醇、5.00wt％羟丙基纤维素和0.50wt％硬脂酸镁。所述颗粒优选为500mg(4mg孟鲁司特)、625mg(5mg孟鲁司特)、1250mg(10mg孟鲁司特)和500mg(10mg孟鲁司特)。
在一较佳的具体实施例中，所述口服给药递送装置中含颗粒和多丸，所述颗粒为阿莫西林颗粒和克拉霉素颗粒，所述多丸为兰索拉唑迟释多丸，所述兰索拉唑迟释多丸、阿莫西林颗粒和克拉霉素颗粒的填充重量分别为480mg、1334mg和840mg。所述兰索拉唑迟释多丸包括核心和肠溶包衣，所述核心含6.3wt％兰索拉唑、31.3wt％糖丸、11.3wt％玉米淀粉、12.1wt％蔗糖、1.3wt％低取代羟丙基纤维素、0.8wt％羟丙基纤维素和6.3wt％碳酸镁，所述肠溶包衣含13.1wt％Eudragit L-30D固体成分、4.0wt％滑石粉、1.3wt％PEG6000、0.7wt％吐温80和1.8wt％二氧化钛。所述阿莫西林颗粒含75.0wt％阿莫西林三水合物、24.5wt％微晶纤维素和0.5wt％硬脂酸镁。所述克拉霉素颗粒含59.5wt％克拉霉素、30.0wt％微晶纤维素、5.0wt％交联羧甲基纤维素钠、5.0wt％Povidone和0.5wt％硬脂酸镁。
在一较佳的具体实施例中，所述口服给药递送装置中含颗粒和多丸，所述颗粒为阿 莫西林颗粒和克拉霉素颗粒，所述多丸为奥美拉唑迟释多丸，所述奥美拉唑迟释多丸、阿莫西林颗粒和克拉霉素颗粒的填充重量分别为320mg、1334mg和840mg。所述奥美拉唑迟释多丸包括核心和肠溶包衣，所述核心含6.3wt％奥美拉唑、31.3wt％糖丸、11.3wt％玉米淀粉、12.1wt％蔗糖、11.3wt％低取代羟丙基纤维素、0.8wt％羟丙基纤维素和6.3wt％碳酸镁，所述肠溶包衣含13.1wt％Eudragit L-30D固体成分、4.0wt％滑石粉、1.3wt％PEG6000、0.7wt％吐温80和1.8wt％二氧化钛。所述阿莫西林颗粒含75.0wt％阿莫西林三水合物、24.5wt％微晶纤维素和0.5wt％硬脂酸镁。所述克拉霉素颗粒含59.5wt％克拉霉素、30.0wt％微晶纤维素、5.0wt％交联羧甲基纤维素钠、5.0wt％Povidone和0.5wt％硬脂酸镁。
在一较佳的具体实施例中，所述口服给药递送装置中含颗粒，所述颗粒的活性药物成分为对乙酰氨基酚、右美沙芬、多西拉敏、伪麻黄碱和苯海拉明，所述活性药物成分的剂量范围分别为250–1000mg、10–30mg、6.25–12.5mg、20–30mg和12.5–25mg。
可饮用的液体可用于通过正常啜吸将含药物的颗粒或多丸携带通过装置的管状部分。该液体优选为任何可饮用的液体，包括但不限于水、柠檬水、无果肉果汁、牛奶、苏打水、咖啡和茶。
本发明的技术方案之一为提供一种制备口服给药递送装置的方法，其包括以下步骤：
1)制备所述湍流产生部件，并将其与所述管状构件组装；
2)制备药物容置部件，并将其维持于所述内腔中、近所述第一开口处；
3)设置装置帽于所述第二开口处。
较佳地，在所述步骤3)前还包括装填所述药物的步骤。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：通过本发明的口服给药递送装置，为正常的啜吸作用提供含药物的颗粒或多丸与可饮用的液体的充分混合；且本发明的装置可伸缩，减小了 尺寸，方便携带。此外，含活性成分为达比加群酯的药物的颗粒或多丸在酸性pH下显示出明显更快的溶解，在中性pH下显示出更少的沉淀。与此同时，本发明的口服给药递送装置的制备方法简便，使用效果良好。
附图说明
图1是具有台阶结构的湍流产生部件的口服给药递送装置的示意图，类型I：a.收缩状态，b.拉伸状态+啜吸前，c.拉伸状态+啜饮时；
图2是具有台阶结构的湍流产生部件的口服给药递送装置的示意图，类型II：a.收缩状态，b.拉伸状态+啜吸前，c.拉伸状态+啜饮时；
图3是具有褶皱部结构的湍流产生部件的口服给药递送装置的示意图：a.收缩状态，b.拉伸状态+啜吸前，c.拉伸状态+啜饮时；
图4是塞流-湍流的示意图：a.由本发明的具有台阶结构的湍流产生部件的口服给药递送装置形成的湍流；b.由本发明的具有褶皱部结构的湍流产生部件的口服给药递送装置形成的湍流；
图5是实施例1中描述的颗粒的溶解曲线。
图6是实施例2中描述的多丸的溶解曲线。
附图标记说明：
1：管状构件
11：第1管段
12：第2管段
13：第3管段
2：第一开口
21：第一开口内拗
3：第二开口
31：第二开口内拗
4：装置帽
5：含活性药物成分的颗粒或多丸
6：药物容置部件
61：孔
7：台阶结构
71：第1台阶
72：第2台阶
8：褶皱群
81：第1褶皱群
811：褶皱部
82：第2褶皱群
9：内腔
具体实施方式
本发明的各种实施例将参照附图进行说明。在说明书附图中，具有类似结构或功能的元件将用相同的元件符号表示。可以理解地，附图只是为了便于说明本发明的各个实施例，并不是要对本发明进行穷尽性的说明，也不是对本发明的范围进行限制。
本发明制备了具有台阶结构的湍流产生部件的口服给药递送装置。图1和2分别示出了根据本发明的口服给药递送装置的望远镜式结构类型I(type I)和类型II(type II)的剖面图。口服给药递送装置在使用前是收缩状态(图1a或2a)，在啜吸前是拉伸状态(图1b或2b)，在啜吸过程中是颗粒悬浮的形式(图1c或2c)。图1和2所示的口服给药递送装置包括可拉伸或收缩的管状构件1，其具有第一开口2、第二开口3和装置帽4。图1和2分别示例了由三个管段11、12、13组成的管状构件。图1中，由所述第一开口2至所述第二开口3方向上的第一管段11的内径与第三管段13的内径相同，第二管段12的外径小于所述第一管段11的内径，从而所述第一管段11和所述第三管段13可沿所述第二管段12轴向拉伸(图1b和1c)或收缩(图1a)。图2中，由所述第一开口2至所述第二开口3方向上的第一管段11的内径、第二管段12的外径、内径和第三管段13的外径逐渐减小，但三个管段在剖面同 一侧的边线相互平行，从而所述第三管段13和所述第二管段12可沿所述第一管段11轴向拉伸(图2b和2c)或收缩(图2a)。
所述药物容置部件6设置于所述管状构件1的内腔9中、靠近第一开口2处，图中示出了其包含颗粒或多丸5时的构造。将药物容置部件6放置于内腔后，所述第一开口2的端部内拗21，使得内拗后的开口直径小于药物容置部件6结构的最小直径；所述第二开口3的端部内拗31，使得内拗后的开口直径小于药物容置部件6结构的最大直径，由此将所述药物容置部件6维持于内腔中。并在所述第二开口3外部设置上装置帽4。药物容置部件6与所述管状构件1相配合，形成一可容纳药物(本发明的示例中呈颗粒和多丸结构，药物活性成分包含在颗粒或多丸结构中)5的空间。药物容置部件6为孔状结构，孔状结构含有多个孔61，所述孔61的直径小于颗粒或多丸5的直径，可以允许可饮用的液体通过；但是在无液体通过时，颗粒和多丸5保留在管状构件1的内腔9中。口服给药递送装置通过拉伸形成台阶结构7，图1和2中示出台阶结构7，所述台阶结构设置于所述内腔9介于所述第二开口3和所述药物容置部件6之间的位置。图1和2示例的所述台阶结构7具有第1台阶71和第2台阶72，通过啜吸作用，可饮用的液体经过台阶71和72产生湍流，从而增强含药物颗粒或多丸5与可饮用液体的混合。本领域技术人员皆知，当管段数量增加时，台阶结构的总数也相应地增加，因此形成湍流的雷诺数也越大；此外，当台阶结构的厚度在本领域常规内增加时，形成湍流的雷诺数也越大。
本发明还制备了具有褶皱部结构的湍流产生部件的口服给药递送装置。图3示出了根据本发明的口服给药递送装置的手风琴状褶皱群结构的剖面图。该装置在使用前是收缩状态(图3a)，在啜吸前是拉伸状态(图3b)，在啜吸过程中是颗粒悬浮的形式(图3c)。图3所示的口服给药递送装置包括可拉伸的管状构件1，该管状构件1具有内腔9和多个褶皱群结构，在图3中显示了两个褶皱群结构81和82。每个褶皱群结构具有多个褶皱部结构811。口服给药递送装置具有第一开口2、第二开口3和装置帽4。包含在管状构件的内腔9中的是包含有活性药物成分的颗粒或多丸5和药物容置部件6。将药物容置部件6放置于内腔后，第一开口2的端部内拗，使得内拗后的开口直径小于药物容置部件6的最小直径；所述第二开口3的端部内拗31，使得内拗后的开口直径小于药物容置部件6结构的最大直 径，由此将所述药物容置部件6维持于内腔中。并在所述第二开口3外部设置上装置帽4。图3中示出的药物容置部件6为孔状结构，其含有多个孔61并位于所述管状构件内腔9中靠近第一开口2处。药物容置部件6与所述管状构件1相配合，形成一可容纳含活性药物成分的颗粒或多丸5的空间。孔状结构的孔直径61小于颗粒或多丸5的直径，可以允许可饮用的液体通过，但是在无液体通过时，颗粒或多丸5被保存在管状构件1的内腔9中。当口服给药递送装置呈拉伸状态时，通过啜吸动作，可饮用的液体流过褶皱部结构811产生湍流，从而增强含活性药物成分的颗粒或多丸5与可饮用的液体的混合。本领域技术人员皆知，当褶皱群数量增加时，褶皱部结构的总数也相应地增加，因此形成湍流的雷诺数也越大；此外，当褶皱部结构向内腔方向的突起高度在本领域常规内增加时，形成湍流的雷诺数也越大。
本领域技术人员皆知，当将药物容置部件6从第一开口2端放置于内腔9后，可直接在所述第二开口3外部直接设置装置帽4。此时由于装置帽与第二开口密封连接，所述第二开口3的端部即使不内拗，由于台阶结构或褶皱部结构的存在，药物容置部件6也不会通过腔体9而到达第二开口3外，所述药物容置部件6即可被维持在内腔9中。此时如果将第二开口3的端部内拗后，使内拗后的开口直径小于药物容置部件的最大直径，这样可进一步确保在口服给药递送装置的使用过程中，药物容置部件6不会被吸入患者口中而发生医疗事故。
图4示意性地示出了根据本发明的具有台阶结构或褶皱部结构的湍流产生部件的口服给药递送装置产生的塞流和湍流。
本发明中，口服给药递送装置的管状构件1通常具有4.0mm至15.0mm之间的外径。管状构件1的内腔9具有通常在2.0mm至14.8mm之间的直径。管状构件1的长度在其准备形式中在5cm至15cm之间，并且在其伸长形式中在10cm至30cm之间。
用于制造管状构件1、药物容置部件6和装置帽4的优选材料是本领域常规的聚丙烯和聚烯烃家族的聚合物。
本发明涵盖的活性药物成分(API)包括但不限于达比加群酯或其药学上可接受的盐、左旋多巴/卡比多巴、孟鲁司特、兰索拉唑、奥美拉唑、阿莫西林、克拉霉素、对乙酰氨 基酚、右美沙芬、多西拉敏、伪麻黄碱和苯海拉明。
在一个实施方案中，口服给药递送装置包含颗粒形式的溶解度增强的达比加群酯甲基化物(DEM)，其通过利用热熔造粒方法制备。
在另一个实施方案中，口服给药递送装置包含多丸形式的溶解度增强的达比加群酯甲基化物(DEM)，该DEM通过利用喷涂工艺制备。
在另一个实施方案中，口服给药递送装置包含多丸形式的缓释左旋多巴/卡比多巴制剂，其通过利用挤出、滚圆和包衣工艺制备。
在本发明的另一个实施方案中，口服给药递送装置包含孟鲁司特颗粒，其通过常规的造粒方法制备，包括湿法制粒、流化床制粒、干法制粒等。
在本发明的另一个实施方案中，口服给药递送装置包含多丸形式的兰索拉唑以及颗粒形式的阿莫西林和克拉霉素，多丸通过喷涂和包衣工艺制备，而颗粒通过常规的造粒方法制备，包括湿法制粒、流化床制粒、干法制粒等。
在本发明的另一个实施方案中，口服给药递送装置包含多丸形式的奥美拉唑以及颗粒形式的阿莫西林和克拉霉素，多丸通过喷涂和包衣工艺制备，而颗粒通过常规的造粒方法制备，包括湿法制粒、流化床制粒、干法制粒等。
在本发明的另一个实施方案中，口服给药递送装置包含通过常规的造粒方法制备的感冒药物颗粒，包括湿法制粒、流化床制粒、干法制粒等。
本发明中的口服给药递送装置之一是具有台阶结构的湍流产生部件的口服给药递送装置。该装置的一种构造可以通过以下制造步骤制造。首先，由三个部分组成的管状构件(type I型或type II型，见图1a和图2a)通过传统的制造吸管的方法制造。其次，将药物容置部件6插入管状构件1的第一开口2端。接下来，内拗端部，使得药物容置部件6可以保持在管状构件1的内腔9中。然后，含有活性药物成分的颗粒或多丸5通过管状构件1的第二开口3端填充到管状构件1中。最后，填充的管状构件1被装置帽4封闭，并用铝袋(图未示)包裹。
本发明中的另一口服给药递送装置是具有褶皱部结构的湍流产生部件的口服给药递送装置。该装置可以通过以下制造步骤制造。首先，具有3组手风琴状褶皱群8的管状构 件1通过制造吸管的传统工艺制造。其次，将药物容置部件6插入管状构件1的第一开口2端。接下来，内拗第一开口2的端部，使得药物容置部件6可以保持在管状构件1的内腔9中。然后，含有活性药物成分的颗粒或多丸5通过管状构件1的第二开口3端填充到管状构件1中。最后，填充后的管状构件1被装置帽4封闭，并用铝袋包裹(图未示)。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
通过将固溶体/分散体组合物喷涂到糖丸上制备包含甲磺酸达比加群酯(DEM)的多丸。该组合物包含按重量百分比计40％的甲磺酸达比加群酯(DEM)、10％的聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物Soluplus和50％的聚氧乙烯聚氧丙烯醚嵌段共聚物Kolliphor P407。首先，将这些固体成分溶解在92％乙醇中，制成固体含量为24.2％的涂布溶液。然后，使用带有Wurster插件的流化床造粒机，在合适的进风压力和38-40℃的进风温度下，将714.8g包含173.0g固体组分的涂布溶液喷涂到346.0g预干燥的糖芯上。在涂覆过程中，调节喷涂速度和雾化压力以保持产品温度在28-30℃。在涂覆溶液耗尽后，在流化床中干燥涂覆的小丸，直到含水量低于1.7％。药物层与蔗糖丸芯的目标重量比为0.5:1.0。以粉末形式(<80目)加入额外的Soluplus颗粒(180mg)。本实验中使用的Soluplus粉末是通过研磨Soluplus颗粒并随后用80目筛筛分而获得的。
包含DEM的多丸(50mg剂量为552.4mg，75mg剂量为648.6mg)和Soluplus粉末(50mg剂量为120mg，75mg剂量为180mg)通过第二开口3端填充到第一开口2端内拗的管状构件1中。最后，填充的管状构件被装置帽封闭，并用铝袋包裹(图未示)。表1列出了装置中多丸填充制剂的组成。
表1.实施例1中多丸填充制剂的组成
Figure PCTCN2020073865-appb-000005
Figure PCTCN2020073865-appb-000006
*57.7毫克和86.5毫克DEM分别相当于50毫克和75毫克的游离碱。
使用两阶段方法测量填充制剂的溶解曲线，在胃期(pH2.0)为45分钟，在肠期(pH6.8)为10分钟。如图5所示，与商用产品
Figure PCTCN2020073865-appb-000007
相比，本实施例中的填充制剂在低pH下显示出更快的溶解，在pH6.8下显示更少的沉淀。误差条代表n＝3的标准偏差。
实施例2
在该实施例中，通过热熔造粒方法制备了包含DEM的颗粒制剂。表2列出了热熔DEM配方的组成。
表2.热熔DEM配方的组成
Figure PCTCN2020073865-appb-000008
*57.7毫克和86.5毫克DEM分别相当于50毫克和75毫克的游离碱。
热熔造粒工艺简述如下。首先，将Soluplus
Figure PCTCN2020073865-appb-000009
研磨并通过80目筛，将Kolliphor P188研磨并通过40目筛，然后将过筛后的Soluplus
Figure PCTCN2020073865-appb-000010
粉末与除硬脂酸镁以外的其它赋形剂在65-75℃的带有热夹套的高剪切造粒机中混合，直到形成一致且均匀的颗粒。接下来，热熔颗粒通过20目筛，然后与硬脂酸镁混合。
热熔DEM颗粒制剂(50毫克剂量为336.1毫克，75毫克剂量为504.1毫克)通过第二开口3端填充到第一开口2端内拗的管状构件1中。最后，填充的管状构件被装置帽封闭，并用铝袋包裹(图未示)。使用两阶段方法测量填充制剂的溶解曲线，在胃阶段(pH2.0)后是肠阶段(pH6.8)，共为45分钟。如图6所示，与Pradaxa
Figure PCTCN2020073865-appb-000011
相比，本实施例中的填充制剂在酸性pH下显示出明显更快的溶解，在中性pH下显示出更少的沉淀。误差条代表n＝3的标准偏差。
实施例 3
在该实施例中，填充制剂由速释的左旋多巴/卡比多巴颗粒和左旋多巴缓释多丸组成。表3列出了填充制剂配方的组成。使用常规湿法制粒工艺制备速释颗粒，而使用挤出/滚圆/喷涂工艺制备缓释多丸。缓释多丸的包衣水平为5.1重量％，90％的左旋多巴在大约3.9小时后释放。
表3.实施例3中左旋多巴/卡比多巴制剂的组合物
组分 wt％ mg/片
速释颗粒    
左旋多巴 42.3 50.0
卡比多巴一水合物* 45.7 54.0
十二烷基硫酸钠 1.9 2.4
羟丙基甲基纤维素(HPMC)E5 4.8 5.6
交联羧甲基纤维素钠 4.8 5.6
硬脂酸镁 0.5 0.6
总含量 100.0 118.2
     
缓释多丸    
左旋多巴 70.41 200.0
微晶纤维素 19.03 54.1
十二烷基硫酸钠 3.81 10.8
Povidone K29/32 1.90 5.4
醋酸纤维素39.8 4.12 11.7
Copovidon(Kollidone VA64) 0.73 2.1
总含量 100.00 284.1
*54毫克卡比多巴一水合物相当于50毫克卡比多巴。
实施例4
在7.7％和10.9％而非5.1％的包衣水平下，在本实施例中重复实施例3中缓释多丸的制备过程和填充制剂，在约6.6小时和9.3小时分别释放90％左旋多巴。
实施例5
在该实施例中，实施例3和4中描述的缓释多丸用本领域常规的肠溶组合物以3-10％的包衣水平包覆。
实施例6
在该实施例中，填充制剂为颗粒形式，包含孟鲁司特钠、甘露醇、羟丙基纤维素和硬脂酸镁。速释颗粒通过使用高剪切造粒机的湿法制粒工艺制备。
表4列出了填充制剂配方的组成。
表4. 孟鲁司特填充制剂的配方
组分 mg/片 wt ％
孟鲁司特钠* 4.2 0.83
甘露醇 468.4 93.67
羟丙基纤维素 25.0 5.00
硬脂酸镁 2.5 0.50
总含量 500.0 100.00
*4.2毫克孟鲁司特钠相当于4毫克孟鲁司特。
孟鲁司特颗粒制剂(500mg)通过第二开口3端填充到第一开口2端内拗的管状构件1中。最后，填充的管状构件被装置帽封闭，并用铝袋包裹(图未示)。
填充制剂中的孟鲁司特钠可以快速溶解在水性介质中，85％的药物溶解时间不超过30分钟。
实施例7
在该实施例中重复实施例6的步骤，以提供相同的填充制剂。在本例中，填充重量改为625mg。每个灌装装置包括5毫克孟鲁司特。
实施例8
在该实施例中重复实施例6的步骤，以提供相同的填充制剂。在本例中，填充重量改为1250mg。每个灌装装置包括10毫克孟鲁司特。
实施例9
在本实施例中重复实施例6的步骤，以提供填充制剂，其组成列于表5中。在这个例子中，填充重量是500毫克。每个灌装装置包括10毫克孟鲁司特。
表5. 实施例9中孟鲁司特制剂的组合物
组分 mg/片 wt％
孟鲁司特钠* 10.4 2.08
甘露醇 462.1 92.42
羟丙基纤维素 25.0 5.00
硬脂酸镁 2.5 0.50
总含量 500.0 100.00
*10.4毫克孟鲁司特钠相当于10毫克孟鲁司特。
实施例10
在该实施例中，填充物由三种制剂组成，第一种为兰索拉唑迟释多丸、第二种为阿莫西林颗粒，以及第三种为克拉霉素颗粒。表6中列出了填充物组成。在该实施例中，兰索拉唑迟释多丸、阿莫西林颗粒和克拉霉素颗粒的填充重量分别为480mg、1334mg和840mg。每个灌装装置包括30毫克兰索拉唑、1000毫克阿莫西林和500毫克克拉霉素。
表6. 实施例10中填充制剂组合物
Figure PCTCN2020073865-appb-000012
Figure PCTCN2020073865-appb-000013
实施例11
在该实施例中，填充物由三种制剂组成，第一种为奥美拉唑迟释多丸，第二种为阿莫西林颗粒，以及第三种为克拉霉素颗粒。表7中列出了填充物组成。在该实施例中，奥美拉唑迟释多丸、阿莫西林颗粒和克拉霉素颗粒的填充重量分别为320mg、1334mg和840mg。每个灌装装置包括20毫克奥美拉唑、1000毫克阿莫西林和500毫克克拉霉素。
表7.实施例11中填充制剂组合物
Figure PCTCN2020073865-appb-000014
Figure PCTCN2020073865-appb-000015
Figure PCTCN2020073865-appb-000016
实施例12
在本实施例中，颗粒形式的填充制剂包含每种单独的药物或它们的组合，包括以下感冒药药物：对乙酰氨基酚、右美沙芬、多西拉敏、伪麻黄碱和苯海拉明。速释颗粒可以通过使用高剪切造粒机的湿法制粒工艺制备。表8列出了这些原料药的剂量范围。
表8. 实施例12中感冒药的剂量范围
活性药物制剂(药物) 剂量范围(mg)
对乙酰氨基酚 250-1000
右美沙芬 10-30
多西拉敏 6.25-12.5
伪麻黄碱 20-30
苯海拉明 12.5-25

Claims (11)

  1. 一种口服给药递送装置，其包括：一管状构件、一药物容置部件、一装置帽和一湍流产生部件，其中，所述管状构件具有两端开口及内腔，其一端开口为第一开口，另一端开口为第二开口，所述内腔连通所述第一开口和第二开口；所述药物容置部件具有孔状结构，并维持于所述内腔中、近第一开口处，且用于容置含有活性药物成分的颗粒或多丸；所述孔状结构具有一个或多个允许液体通过的孔，所述孔的直径小于所述含有活性药物成分的颗粒或多丸的直径；所述装置帽为可拆卸的连接，并设置于所述第二开口的外部；所述湍流产生部件具有台阶结构或褶皱部结构，并设置于所述内腔中、介于所述第二开口和所述药物容置部件之间的位置。
  2. 根据权利要求1所述的口服给药递送装置，其中，所述第一开口的直径小于所述药物容置部件的最小直径；优选地，所述第二开口的直径小于所述药物容置部件的最大直径。
  3. 根据权利要求1或2所述的口服给药递送装置，其中，所述管状构件具有至少2个管段，所述管段之间密封连接并可沿所述管状构件轴向拉伸或收缩；所述管状构件呈拉伸状态时形成具有至少1个台阶结构的湍流产生部件。
  4. 根据权利要求3所述的口服给药递送装置，其中，所述管段的数量为2-5个；优选2-4个；最优选3个。
  5. 根据权利要求4所述的口服给药递送装置，其中，当所述管段的数量为3个时：其由所述第一开口至所述第二开口方向上的第一管段的内径与第三管段的内径相同，第二管段的外径小于所述第一管段的内径，且每一管段可沿其他管段轴向拉伸或收缩；或，其由所述第一开口至所述第二开口方向上的第一管段的内径、第二管段的外径、内径和第三管段的外径逐渐减小，且每一管段可沿其他管段轴向拉伸或收缩；
    当所述管段的数量为4个时：其由所述第一开口至所述第二开口方向上的第一管段的内径与第三管段的内径相同，第二管段的内径与第四管段的内径相同，其中，所述第二管段的内径小于所述第一管段，且每一管段可沿其他管段轴向拉伸或收缩；或，其由 所述第一开口至所述第二开口方向上的第一管段至第四管段的内径逐渐减小，且每一管段可沿其他管段轴向拉伸或收缩。
  6. 根据权利要求1或2所述的口服给药递送装置，其中，所述管状构件具有至少1个褶皱部结构，所述褶皱部结构具有1对翼部和1个转折端；所述褶皱部结构可沿所述管状构件轴向拉伸或收缩，并在所述拉伸时形成湍流产生部件。
  7. 根据权利要求6所述的口服给药递送装置，其中，多个连续的褶皱部结构形成一个褶皱群结构，所述褶皱群结构的数量为1-5个；优选2-3个。
  8. 根据权利要求6或7所述的口服给药递送装置，其中，所述褶皱部结构处的内腔截面直径小于与所述管状构件与所述褶皱部结构连接处的内腔截面直径，且，所述褶皱部结构处的内腔截面的最小内径不小于所述管状构件的内腔截面直径的五分之一。
  9. 根据权利要求1-8任一项所述的口服给药递送装置，其中，所述管状构件的最大外径为4.0-15.0mm，最小内径为2.0-14.8mm；所述管状构件的长度在收缩状态时为5-30cm，在拉伸状态时为10-50cm。
  10. 根据权利要求1-9任一项所述的口服给药递送装置，当所述药物容置部件具有含活性药物成分的颗粒或多丸时，所述颗粒和多丸的直径为50-5000μm，优选为75-2000μm，更优选为100-1000μm；所述颗粒和多丸包含的活性药物成分包括但不限于以下的一种或多种：达比加群酯或其药学上可接受的盐、左旋多巴/卡比多巴、孟鲁司特、兰索拉唑、奥美拉唑、阿莫西林、克拉霉素、对乙酰氨基酚、右美沙芬、多西拉敏、伪麻黄碱和苯海拉明。
  11. 一种制备如权利要求1-10任一项所述的口服给药递送装置的方法，其特征在于包括以下步骤：
    1)制备所述湍流产生部件，并将其与所述管状构件组装；
    2)制备药物容置部件，并将其维持于所述内腔中、近所述第一开口处；
    3)设置装置帽于所述第二开口处；
    优选地，在所述步骤3)前还包括装填所述药物的步骤。
PCT/CN2020/073865 2019-01-07 2020-01-22 一种口服给药递送装置 WO2020143843A1 (zh)

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