WO2015127857A1 - 脑靶向的经鼻腔给药装置及其体位固定器 - Google Patents

脑靶向的经鼻腔给药装置及其体位固定器 Download PDF

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Publication number
WO2015127857A1
WO2015127857A1 PCT/CN2015/072648 CN2015072648W WO2015127857A1 WO 2015127857 A1 WO2015127857 A1 WO 2015127857A1 CN 2015072648 W CN2015072648 W CN 2015072648W WO 2015127857 A1 WO2015127857 A1 WO 2015127857A1
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WIPO (PCT)
Prior art keywords
user
head
headrest
brain
drug
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PCT/CN2015/072648
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English (en)
French (fr)
Inventor
钱明心
何仁扬
施俊巍
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苏州同力生物医药有限公司
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Publication of WO2015127857A1 publication Critical patent/WO2015127857A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61G—TRANSPORT, PERSONAL CONVEYANCES, OR ACCOMMODATION SPECIALLY ADAPTED FOR PATIENTS OR DISABLED PERSONS; OPERATING TABLES OR CHAIRS; CHAIRS FOR DENTISTRY; FUNERAL DEVICES
    • A61G13/00—Operating tables; Auxiliary appliances therefor
    • A61G13/10—Parts, details or accessories
    • A61G13/12—Rests specially adapted therefor; Arrangements of patient-supporting surfaces
    • A61G13/1205—Rests specially adapted therefor; Arrangements of patient-supporting surfaces for specific parts of the body
    • A61G13/121—Head or neck
    • A61G13/1215—Head or neck with patient airway positioning devices

Definitions

  • the present invention relates to a drug delivery device and, more particularly, to a brain-targeted technique for nasal administration. It is generally suitable for drugs and preparations that target to the brain after nasal administration, especially for targeted delivery of various therapeutic drugs to the brain including but not limited to insulin and its derivatives to improve Al Clinical signs of Alzheimer's disease and other central nervous system diseases.
  • the central nervous system plays a pharmacodynamic role.
  • CNS central nervous system
  • more clinically applied methods are to reversibly open the blood-brain barrier, intrathecal injection and carotid injection, so that the drug can pass through and enter the CNS.
  • these methods have high operational requirements, high security risks, and are subject to certain constraints in application.
  • the treatment of brain diseases by nasal administration is non-invasive, has high brain bioavailability, can bypass the first pass metabolism and systemic circulation and blood-brain barrier, and is convenient to operate.
  • drug molecules small molecules, peptide hormones, protein biologics, etc.
  • the drug mode also enables these drug molecules to accumulate in the olfactory region of the upper nasal cavity that extends from the olfactory nerve of the brain. It has been reported that drugs (small molecules, peptides, proteins) accumulated in the olfactory region can directly penetrate into the brain (see Arun et al., 2012), although this infiltration is based on intercellular or intracellular transport.
  • adrenocorticotropic hormone ACTH
  • vasopressin vasopressin
  • insulin in the cerebrospinal fluid were found to be higher than the endogenous concentrations of blood hormones, indicating that these hormones are in addition to the periphery.
  • the central nervous system may also play a different important role.
  • insulin Specific intranasal administration of insulin in the olfactory zone, in 36 healthy subjects, the average concentration of insulin in the cerebrospinal fluid was twice that of endogenous insulin, while the plasma insulin concentration did not change significantly (see table). 1). This result suggests that when appropriate methods are used to accumulate insulin in the olfactory region, insulin can enter the central nervous system directly through this region (see Born et al., 2002).
  • the fold increase is obtained by calculating the ratio of the exposure of the experimental group in the different compartments (CSF or serum) to the exposure of endogenous hormones in the placebo group.
  • the study found that the 312, 616 or 636 serine residues (IRS-1pSer312, 616 or 636) of the insulin receptor 1 in the brain are Phosphorylation in the basal state is a major feature of the insulin resistance of the brain of AD users. This finding suggests that even in normal individuals, the actual demand for insulin in the brain is far beyond the normal physiological state.
  • Table 2 lists some evidence of brain-targeted transnasal insulin administration for neurological and neurobehavioral treatment. These data fully demonstrate that a proper and simple method of nasal insulin administration that effectively increases cerebrospinal fluid concentration can have profound effects on neurobehavioral behavior without altering systemic plasma insulin concentrations. To date, nasal administration of 160 IU of insulin does not cause any toxic side effects to the nasal cavity and the olfactory area, nor does it trigger side effects of the peripheral system or other adverse effects of the nervous system. Therefore, brain-targeted transnasal insulin administration can be considered as a safe and effective method for treating and improving neurologically impaired diseases.
  • Table 2 Effect of intranasal administration of insulin brain targeting on neurobehavioral diseases and their symptoms
  • Alzheimer's disease Although the exact mechanism of neurobehavioral function of Alzheimer's disease is not fully understood, it can be determined that increasing insulin levels in the central nervous system can affect cognitive, imaging, and biochemical parameters of adult users of Alzheimer's disease. And the prodromal symptoms of the disease, mild cognitive impairment (MCI). Experiments have shown that direct introduction of insulin into the central nervous system of animal models of Alzheimer's disease can improve its nerve damage. In some clinical trials, it has been demonstrated that intranasal administration of insulin into the brain in a complex manner can improve the user's mild cognitive dysfunction. In summary, increasing insulin levels in the brain and central nervous system will help improve the neurobehavioral function of the user.
  • MCI mild cognitive impairment
  • the brain-targeted drug delivery system is a very active research field in the fields of pharmacy, neurology, tumor and other related medical fields.
  • the nasal drug delivery system for brain targeting is a research hotspot in recent years.
  • the brain-targeted nasal administration requires a certain method to accumulate the drug in the upper nasal cavity, that is, the olfactory area, so as to avoid the absorption into the systemic circulation through the respiratory tract and the digestive tract, thereby directly entering the central nervous system.
  • the present invention provides a brain-targeted transnasal drug delivery device and a body position fixator, which, in combination with a specific drug delivery position, enables a drug administered through the nasal cavity to enter the olfactory region of the upper nasal cavity, and has a targeted effect.
  • the brain-targeted transnasal drug delivery device and the position fixer provided by the invention are also suitable for field first aid, for example, in the battlefield environment, the device provided by the invention can be used in the case of insufficient time, medical equipment and medical personnel. Simple, rapid brain-targeted administration, such as for relieving symptoms of the central nervous system.
  • the invention provides a post-nasal body position holder for brain targeting, the position holder comprising:
  • the head carrier is configured to carry the head of the user and maintain the head such that the drug administered nasally can enter the olfactory region of the upper nasal cavity.
  • the head carrying portion includes: a headrest for carrying a head of the user, a support frame for supporting the headrest, and rotatably supporting the headrest on the support frame The middle shaft.
  • the headrest includes: an inner bracket supported on the center shaft; and a pillow covering or covering the inner bracket.
  • the headrest is divided into a first portion and a second portion; wherein the first portion is disposed to be supported by a portion of the inner bracket at an angle of 50 to 70, preferably 60; and/or the second The portion is arranged to be supported by an angle of 20° to 40° by another portion of the inner bracket, preferably 30°.
  • the headrest includes: having a supine position for administration The first side and the double side pillow for the second side of the lateral position administration.
  • the first surface comprises a neck bearing surface and a head bearing surface
  • the shape of the head bearing surface and the neck bearing surface is designed to fit the curve of the head and neck of the human body when lying on the back.
  • the second surface also includes a neck bearing surface and a head bearing surface, and the head bearing surface and the neck bearing surface are shaped to fit the curve of the human head and neck when lying on the side.
  • the pillow may be a portable, inflatable pillow or other padded pillow.
  • the support frame is generally H-shaped, A-shaped, L-shaped, inverted Y-shaped, M-shaped or other operable shape.
  • the central shaft penetrates transversely to the center of the first portion and the second portion of the headrest of the headrest, or transversely penetrates the neck bearing surface end of the double-sided pillow of the headrest.
  • the head carrying portion further includes:
  • a height adjustment mechanism for adjusting a height of the center shaft and the headrest to which the headrest is attached to the support frame to adjust the height of the headrest.
  • the position fixer further includes:
  • a first robot arm operatively engaged with the head carrier for adjusting an angle of the center shaft and the headrest to which it is attached.
  • the position fixer further includes:
  • a motor operatively coupled to the head carrier for adjusting an angle of the headrest under control of a computer, smartphone or remote control.
  • the position fixer further includes: a scale indicator that accurately detects the elevation angle between the nose and the neck of the user by the laser beam to instruct the user to adjust the head to an appropriate position. Or the optimal dosing angle for individualized administration.
  • the position fixer further includes:
  • An audio player for playing an audio file that guides the user in adjusting the position
  • a video player that plays a video file that guides the user in adjusting the position.
  • the position fixer further includes: a platform supporting the head carrying portion and the user's body, for example, including but not limited to: a mat, a bed, a chair, a table, a counter, a floor, And other similar support planes.
  • a platform supporting the head carrying portion and the user's body for example, including but not limited to: a mat, a bed, a chair, a table, a counter, a floor, And other similar support planes.
  • the bearing surface of the platform for carrying the user's body can be adjusted in angle to match the angle of the headrest, so that the user can maintain a more comfortable passage.
  • the nasal brain is targeted for administration to the body.
  • the present invention also provides a brain-targeted transnasal drug delivery device, wherein the device comprises:
  • the applicator has a shape at which the drug delivery end has a shape matching with the nasal cavity of the user, and is used to deliver the drug to the user through the nasal cavity in the case where the body position holder holds the user in the above position, so that the drug is directed into the brain. .
  • the brain-targeted transnasal drug delivery device further comprises:
  • a second robotic arm has one end coupled to the applicator and the second robotic arm configured to be adjustable to support the applicator in position. Wherein the other end of the second robot arm is connected to the body position fixer.
  • the brain-targeted transnasal drug delivery device further comprises:
  • An intelligent control element for adjusting the time, speed and dosage of administration by controlling the action of the applicator and the second robot arm including receiving, processing, integrating externally input information, automatically controlling according to the input information, The administration time, speed and dosage of the applicator are adjusted, wherein the input information includes a physiological index, a biochemical indicator, a cognitive function score, and the like of the user.
  • the applicator comprises a drug container.
  • the drug container can be a biocompatible, sterile, and/or disposable container.
  • the drug container may be a fixed volume container or a syringe with a quantifiable push or squeeze device.
  • a brain-targeted transnasal drug delivery device and a body position fixer thereof are mainly used for drug delivery treatment of central nervous system diseases, including but not limited to Alzheimer's disease, brain tumor, Multiple sclerosis, Parkinson's disease, epilepsy, AIDS, tuberculosis, viral, bacterial, parasitic or other microbial infections, pituitary-hypothalamic hormone deficiency or disorders, and for relieving central nervous system Related symptoms.
  • central nervous system diseases including but not limited to Alzheimer's disease, brain tumor, Multiple sclerosis, Parkinson's disease, epilepsy, AIDS, tuberculosis, viral, bacterial, parasitic or other microbial infections, pituitary-hypothalamic hormone deficiency or disorders, and for relieving central nervous system Related symptoms.
  • the position fixator according to various embodiments of the present invention and the drug delivery device with the body position fixer can be easily operated by the patient himself or a home care person, for example, placing the patient's head in a supine or lateral position.
  • the body position fixer can achieve nasal targeted nasal administration.
  • FIG. 1 shows an embodiment 1 of a head carrier for a nasally administered body position anchor for brain targeting, a pillow pad not shown;
  • Embodiment 2 shows a headrest according to Embodiment 1, wherein, in order to show the inside of the headrest, the pillow is taken in a perspective manner;
  • Figure 3 shows the internal structure of the headrest after removing the pillow according to Embodiment 1;
  • FIG. 4 illustrates an embodiment 2 of a head carrier for a nasally targeted body position anchor for brain targeting, not showing a pillow, in accordance with an embodiment of the present invention
  • Figure 5 shows a headrest according to Embodiment 2, wherein in order to show the inside of the headrest, the pillow is taken in a perspective manner;
  • Figure 6 shows the internal structure of a headrest with a pillow removed according to Embodiment 2;
  • Figure 7 is a view showing the internal structure of a headrest with a pillow removed according to Embodiment 2, wherein the center shaft passes through the inner bracket of the headrest;
  • Figure 8 illustrates an embodiment 3 of a head carrier for a nasally targeted body position anchor for brain targeting, in accordance with an embodiment of the present invention
  • Figure 9 illustrates an embodiment 4 of a head carrier for a nasally targeted body position anchor for brain targeting, in accordance with an embodiment of the present invention
  • Figure 10 illustrates an embodiment 5 of a head carrier for a nasally targeted body position anchor for brain targeting in accordance with an embodiment of the present invention
  • Figure 11 is a view schematically showing a state in which the user's head is in a supine position
  • Figure 12 is a view schematically showing a state in which the user's head is in a lateral position
  • Figure 13 illustrates an embodiment 6 of a head carrier for a nasally targeted body position anchor for brain targeting, in accordance with an embodiment of the present invention
  • Figure 14 shows the user taking the supine (Mygind) position for administration
  • Figure 15 shows the administration of the user in a side position (Regan);
  • Figure 16 illustrates a body position holder placed on a platform in accordance with an embodiment of the present invention
  • Figure 17 is an illustration of a nasal anatomy of a supine position administration using an embodiment of the present invention.
  • a nasally targeted transnasal drug delivery device having a body position fixator is described herein in accordance with various embodiments of the present invention, wherein the body position anchor is used to hold a user in a manner suitable for facilitating drug entry into the upper nasal cavity and further The position of the brain from the olfactory area.
  • the brain-targeted transnasal drug delivery device further comprises an applicator having a drug delivery end having a shape that cooperates with a user's nasal cavity for retaining the user in the body position holder In the case of the above position, the nasal cavity is administered to the user to facilitate the orientation of the drug into the brain.
  • the body position holder includes a head carrier for carrying a user's head and holding the head such that the drug administered nasally can enter the upper nasal cavity
  • the olfactory zone for example, maintains the user's head and neck at a specific angle to ensure that the drug administered intranasally can enter the olfactory region of a particular upper nasal cavity periodically and quantitatively for precise individualized brain targeted administration. This will be described in detail below.
  • FIG. 1 shows a head carrier 100 for a nasally-targeted body position anchor for brain targeting according to an embodiment of the present invention, wherein the pillow is not shown for ease of showing the internal structure of the head carrier;
  • FIG. A headrest 110 is shown on the inner bracket 111 covered with a pillow 112.
  • the pillow 112 is taken in a perspective manner, that is, it can be seen through the pillow 112.
  • FIG. 3 shows the internal structure of the headrest 110 after removing or removing the pillow 112 according to an embodiment of the present invention.
  • the body position holder is used to hold the user in a position suitable for facilitating entry of the drug into the upper nasal cavity and further into the brain from the olfactory region.
  • the body position holder includes a head carrier 100 for carrying a user's head and holding the head such that the nasally administered drug can enter the olfactory region of the upper nasal cavity, as shown in FIG.
  • the portion 100 includes, but is not limited to, a headrest 110 for carrying a user's head, a support frame 120 for supporting the headrest 110, and a center shaft 130 for rotatably supporting the headrest 110 on the support frame 120.
  • the support frame 120 is two H-shaped brackets, and each H-shaped bracket is composed of two vertically disposed columns 121 and transverse connecting arms 122 that laterally connect the columns, and the central shaft 130 The two ends are rotatably supported on the transverse link arms 122 ("-" in the middle of the "H") of each of the H-shaped brackets, respectively.
  • the present invention is not limited thereto, and various embodiments may be modified or evolved without departing from the principles of the present invention.
  • multiple H-shaped brackets may be used,
  • Other support structures may also be employed, such as support frames in the shape of an A, L, inverted Y, M or other operable shape, as will be described in more detail below.
  • the headrest 110 includes an inner bracket 111 supported on the center shaft 130, and a pillow 112 covering the inner bracket 111, for example, A pillow 112 can be wrapped around the inner bracket 111.
  • the inner bracket 111 includes a plurality of support rods 113 extending along the surface of the center shaft 130 radially outward at different positions in the axial direction of the center shaft 130, along the central axis.
  • a plurality of long connecting rods 114 that laterally connect the ends of the plurality of support rods 113 in a substantially parallel direction, and a short connecting rod 115 that connects the ends of the plurality of long connecting rods 114.
  • the plurality of short connecting rods 115 at the end of the inner bracket 111 form an approximately quadrangular shape, so that the end surface of the headrest 110 has a substantially quadrangular shape.
  • the inner bracket 111 may be any structure configured to support the pillow 112 on the center shaft 130.
  • the inner bracket may be inserted through the middle shaft.
  • the plurality of support plates and the ends connecting the support plates form a web that carries the surface of the pillow, as will be described in detail below.
  • the pillow 112 can be constructed of any material known in the art that conforms to the ergonomics of the human head and neck, for example, the pillow can be a portable, inflatable pillow or other padded pillow. Pad to provide comfort.
  • the headrest 110 is divided into a first portion and a second portion.
  • the first portion ie, the substantially quadrilateral end surface of the headrest of FIG. 2 is at an angle of 60° to the diagonal.
  • the portion where the edge is located is disposed to be supported by a portion of the inner bracket 111 at an angle of 50 to 70, for example, at an angle of 50° from a portion of the inner bracket 111, or at an angle of 70° from a portion of the inner bracket 111.
  • Support preferably at an angle of about 60° for the user or user Nasal brain targeted administration is carried out in a supine position (ie, supine position); the second part (ie, the portion of the substantially quadrilateral end face of the headrest in FIG.
  • the support is at an angle of about 30[deg.] for the user or the user to take a naso-brain targeted administration in a laterally lying position (ie, a lateral position).
  • the central shaft 130 extends transversely to the center of the first portion and the second portion of the headrest, and the first portion and the second portion are selectively used by rotating the headrest 110 about the central shaft 130.
  • the angle of the center shaft 130 and the headrest 110 to which it is attached can be adjusted by a robotic arm (not shown) that operatively engages the head carrier 100.
  • a motor (not shown) operatively coupled to the head carrier, such as a small or micro motor, for adjusting the angle of the headrest under the control of a computer, smartphone or remote control, may be employed, Thereby, the position of the user is precisely controlled so that the drug administered nasally is optimally absorbed into the brain.
  • FIG. 4 illustrates a head carrier 200 for a nasally-targeted body position anchor for brain targeting in accordance with an embodiment of the present invention, wherein a pillow is not shown for ease of showing the internal structure of the head carrier 200;
  • FIG. 5 shows the headrest 210 covered with a pillow 212 on the inner bracket 211.
  • the pillow 212 takes a perspective drawing, that is, it can pass through the pillow 212.
  • FIG. 6 shows the internal structure of the headrest 210 from which the pillow 212 is removed, according to an embodiment of the present invention, which shows that the shaft 230 passes through the inner bracket 211 in order to facilitate the embodiment of the present invention.
  • the inner bracket 211 is supported.
  • the body position holder is used to hold the user in a position suitable for facilitating entry of the drug into the upper nasal cavity and further into the brain from the olfactory region.
  • the body position holder includes a head carrier 200 for carrying a user's head and holding the head such that the drug administered through the nasal cavity can enter the olfactory region of the upper nasal cavity, as shown in FIG.
  • the head carrying portion 200 includes, but is not limited to, a headrest 210 for carrying a user's head, and a support for supporting the headrest 210.
  • a frame 220 and a center shaft 230 that rotatably supports the headrest 210 on the support frame 220.
  • the support frame 220 is two approximately A-shaped brackets, and each of the A-shaped brackets is composed of two oblique columns 221 and a transverse connecting arm 222, wherein the upper ends of the two inclined columns 221 are connected Together, the lower ends are separated and connected together by the transverse connecting arms 222 between the upper and lower ends; the two ends of the central shaft 230 rotatably support the transverse connecting arms 222 of the respective A-shaped brackets (the middle of the "A" "-” on).
  • the headrest 210 includes an inner bracket 211 supported on the center shaft 230, and a pillow 212 covering the inner bracket 211.
  • the inner bracket 211 includes at least two support plates 213 and a plurality of connecting rods 214 that connect the support plates, wherein the support plates 213 are respectively disposed at least at two ends of the inner bracket 211, and the support plate 213 Roughly quadrangular, and as shown in FIG.
  • the two opposite sides of the pair of diagonals of the quadrilateral are formed such that one side is 60° to the diagonal of the diagonal pair of the connection, and One side is at 30° to the diagonal, thereby dividing the headrest 210 into a first portion (ie, a portion where the side at an angle of 60° to the diagonal) and a second portion (ie, the diagonal) The part where the edge of the angle of 30° is located).
  • the support plate 213 has a hole 215 in a central portion of the above diagonal line. As shown in FIG. 7, the center shaft 230 passes through the hole 215 and is coupled to the support plate 213, thereby rotatably supporting the headrest 210 on the support. On the rack 220.
  • the plurality of connecting rods 214 respectively connect different supporting plates 213 at four corners or partial corners of the quadrilateral supporting plate 213 to form an inner bracket 211, and the plurality of connecting rods 214 are used for supporting and covering thereon. Pillow pad 212.
  • the present invention is not limited thereto, and the support plate 213 is not limited to a quadrilateral, and may be any other shape.
  • a connecting plate may be used instead of the plurality of connecting rods 214, for example, four connecting plates are used.
  • the four sides of the support plate 213 connect the different support plates, and the connection plates are configured to support the pillow 212.
  • the pillow 212 can be constructed of any material known in the art that conforms to the ergonomics of the human head and neck, for example, the pillow is a portable, inflatable pillow or other padded pillow. To provide comfort.
  • the first portion of the head restraint 210 is configured to be supported by a portion of the inner bracket 211 at an angle of 50° to 70°, for example, by a portion of the inner bracket 211 at an angle of 50°. Or by a part of the inner bracket 211 at an angle of 70°, preferably The ground is supported at an angle of about 60° for the user or the user to perform nasal-targeted dosing in the supine position; the second portion of the headrest 210 is set to be 20° to 40° from the other portion of the inner bracket 211.
  • the angular support for example, is supported at an angle of 20° by another portion of the inner bracket 211, or at an angle of 40° from another portion of the inner bracket 211, preferably at an angle of about 30° for the user or
  • the user performs targeted intranasal brain administration in the lateral position.
  • the nasal head brain targeted administration is performed by rotating the headrest 210 about the central shaft 230 to selectively use the first portion and the second portion, thereby selecting to take different postures.
  • the angle of the center axle 230 and the headrest 210 to which it is attached may be adjusted, for example, by a robotic arm (not shown) that operatively engages the head carrier 200.
  • a micro-motor (not shown) having an angled display operatively coupled to the head carrying portion may be employed for adjusting the angle of the headrest under the control of a computer, thereby accurately controlling the user's The position is such that the drug administered nasally is optimally absorbed into the brain.
  • the pillow pad 312 adopting a perspective drawing, that is, it can be permeable according to an embodiment of the present invention.
  • the pillow 312 sees its interior.
  • the body position holder maintains the user in a position suitable for facilitating entry of the drug into the upper nasal cavity and further into the brain from the olfactory region.
  • the head carrying portion 300 includes, but is not limited to, a headrest 310 for carrying a user's head, a support frame 320 for supporting the headrest 310, and the headrest 310 A center shaft 330 rotatably supported on the support frame 320.
  • the head carrying portion 300 has a height adjustment function, and specifically, the support frame 320 has a height adjustment feature.
  • the two support frames 320 are respectively substantially H-shaped, wherein each of the support frames 320 includes two uprights 321 and one horizontal connecting arm 322, wherein different on the single upright 321
  • the height position has a slit 323, and the slits on the two uprights 321 have a one-to-one correspondence on the heights of the respective pillars 321 .
  • the two ends of the cross-linking arms 322 respectively have protrusions 324, and the protrusions 324 are respectively placed in the height.
  • the two columns 323 are in the same height of the slit 323, so that the two columns 324 are connected to form the support frame 320.
  • the center shaft 330 is coupled to a central portion of the cross link arm 322.
  • a central portion of the cross link arm 322 is provided with a hole or opening to receive the end of the center shaft 330, or is known in the art.
  • Other ways rotatably connect the cross link arm 322 with the center shaft 330 to rotatably support the headrest 310 on the support frame 320.
  • the slits 323 are placed on the column 321 at different heights to adjust the height of the cross-link 322, thereby adjusting the height of the center shaft 330, and thereby adjusting the height of the headrest 310, thereby meeting the needs of different individuals and different postures. Provides better comfort for the user of the drug, and the support frame can be placed on any level.
  • the present invention is not limited to the H-shaped support frame being provided with a height adjustment function, and the support frame of other shapes can be set to have a height adjustment function in the same manner, for example, the inclination of the A-shaped support frame. Cuts are provided at different heights on the column to adjust the height of the cross-linking arms.
  • the support frames of various embodiments of the present invention may be configured to achieve height adjustment by other height adjustment methods known in the art, for example, a pulley type lifting mechanism may be employed. Hydraulic lifting mechanism and so on.
  • the side surface of the headrest 310 may be substantially quadrangular, and the entire headrest is composed of an inner bracket and an outer soft pillow pad filler, and may be divided into upper and lower parts (which may be reversed) (ie, the above-mentioned The first part, the second part) has a rotatable central shaft 330 passing through.
  • a soft pillow padding material is selected to cover the inner bracket (similar to the inner bracket 111 in embodiment 1) to provide comfort.
  • the upper part of the headrest 310 is designed to be supported by the inner bracket and allows a rotation angle of about 60° (for example, 50°-70°) around the central axis, so that the user can take the nasal head target by taking the body supine and the head reclining posture.
  • the lower part of the headrest 310 is designed to be supported by the inner bracket and allows a rotation angle of about 30° (20°-40°) around the central axis, so that the user can adopt the lateral lying posture for targeted intranasal administration.
  • the angle of the center axle 330 and the headrest 310 to which it is attached may be adjusted, for example, by a robotic arm that operatively engages the head carrier 300.
  • a micro-motor (not shown) having an angled display operatively coupled to the head carrying portion may be employed for adjusting the angle of the headrest under the control of a computer, thereby accurately controlling the user's The position is such that the drug administered nasally is optimally absorbed into the brain.
  • Figure 9 illustrates an embodiment 4 of a head carrier for a nasal-targeted body position anchor for brain targeting, indicated at 400, in accordance with an embodiment of the present invention.
  • the pillow 412 takes a perspective The method, that is, the inside can be seen through the pillow 412.
  • the head carrier 400 can be applied to a body position holder that holds the user in a position suitable for facilitating entry of the drug into the upper nasal cavity and further into the brain from the olfactory region.
  • the head carrying portion 400 includes, but is not limited to, a headrest 410 for carrying a user's head, a support frame 420 for supporting the headrest 410, and the headrest 410.
  • a center shaft 430 rotatably supported on the support frame 420.
  • the support frame 420 is similar to the support frame 320 of the embodiment 3 and has similar height adjustment features.
  • the headrest 410 is similar to the headrest 210 of the second embodiment, and adopts an inner bracket 411 formed by a support plate 413. Other components or features are similar to embodiments 1, 2 or 3.
  • the side surface of the headrest 410 may also be substantially quadrangular, and the entire headrest is composed of an inner bracket and an outer soft pillow pad filler, and may be divided into upper and lower parts (which may be reversed) (ie, the above-mentioned The first part, the second part) has a rotatable central shaft 430 passing through.
  • a soft pillow padding material is selected to cover the inner support frame 420 to provide comfort.
  • the upper portion of the headrest 410 is designed to be supported by the inner bracket 411, and allows a rotation angle of about 60° (for example, 50°-70°) around the central axis, so that the user can take the posture of the body and the back of the head to perform the nasal brain.
  • Targeted administration The lower portion of the headrest 410 is designed to be supported by the inner bracket 411 and allows a rotation angle of about 30° (20°-40°) around the central axis for the user to adopt a lateral lying posture for targeted intranasal administration.
  • a micro-motor (not shown) having an angled display operatively coupled to the head carrier can be employed for adjusting the angle of the headrest under the control of a computer.
  • the user of the drug is provided with better comfort.
  • the head carrier 500 illustrates a head carrier 500 having a height adjustment function and a scale indication for a nasally targeted body position anchor for brain targeting, the pillow pad 512 taking a perspective view, ie, : The inside can be seen through the pillow 512.
  • the head carrier 500 can be applied to a body position holder that holds the user in a position suitable for facilitating entry of the drug into the upper nasal cavity and further into the brain from the olfactory region.
  • the head carrying portion 500 includes, but is not limited to, a headrest 510 for carrying a user's head, a support frame 520 for supporting the headrest 510, and the headrest 510.
  • a center shaft 530 rotatably supported on the support frame 520.
  • the support frame 520 is similar to the support frames 320 and 420 of the embodiments 3 and 4, and has similar height adjustment features.
  • the headrest 510 is similar to the headrest 110 of the first embodiment, and adopts a support rod 513 and a plurality of lengths.
  • the connecting rod 514 and the short connecting rod 515 constitute an inner bracket 511.
  • Other department A piece or feature is similar to embodiment 1, 2, 3 or 4.
  • Embodiment 5 differs from the above embodiment in that the body position fixing further includes a scale indicator (not shown) that emits a laser beam by the laser 540 to accurately detect the elevation angle between the nose and the neck of the user to indicate the user. The angle at which the nose needs to be adjusted.
  • a digitally controlled (or similarly acting) scale indicator known in the art is provided with a laser for paralleling the angle of the nose, and the laser indication allows the user to precisely adjust the angle of the nose to the Mygind position (The required position for transnasal brain targeted administration as shown in Figure 11 or Regan position (as shown in Figure 12).
  • Figure 13 illustrates a height-adjusting head carrier 600 for a nasally-targeted body position anchor for brain targeting in accordance with an embodiment of the present invention.
  • the head carrier 600 can be applied to a body position holder that holds the user in a position suitable for facilitating entry of the drug into the upper nasal cavity and further into the brain from the olfactory region.
  • the head carrying portion 600 includes, but is not limited to, a headrest 610 for carrying a user's head, a support frame 620 for supporting the headrest 610, and the headrest 610 A center shaft 630 rotatably supported on the support frame 620.
  • the headrest 610 includes a double-sided pillow having a first side 611 for administration in a supine position (a face up in the figure) and a second side for side-lying administration 612 (the face of the page facing down).
  • the first surface 611 includes a neck bearing surface and a head bearing surface, and the two bearing surfaces are shaped to fit the human head and neck curve 613 when lying on the back.
  • the second surface 612 includes a neck bearing surface and a head bearing surface. The two bearing surfaces are shaped to fit the human head and neck curve 614 when lying on the side, wherein the curvature of the curve 614 is greater than the curvature of the curve 613. .
  • the center shaft 630 extends transversely to the end of the neck bearing surface of the double-sided pillow of the headrest, and is rotated to selectively use the first surface and the second surface thereof.
  • the angle of the central shaft 630 and the headrest 610 to which it is attached can be adjusted by a robotic arm (not shown) to effect nasal administration to the olfactory region, ultimately achieving brain targeted administration.
  • a micro-motor (not shown) having an angled display operatively coupled to the head carrier can be employed for adjusting the angle of the headrest under the control of a computer.
  • the support frame 620 includes two H-shaped brackets, and each H-shaped bracket is composed of two vertical columns 621 and a transverse connecting arm 622 connecting the columns.
  • the two ends of the central shaft 630 are respectively It is rotatably supported on the cross arm 622 of the corresponding H-bracket (on the "-" in the middle of "H”).
  • each of the H-shaped brackets has a limiting member 623, 624 at a position near the upright 621 at both ends of the lateral connecting arm 622.
  • the stopper members 623 on the two H-shaped brackets are used to respectively support both ends of the second face 612 of the headrest 610, thereby supporting the headrest 610 as It is suitable for supine administration, so that the drug passes through the nasal cavity to reach the olfactory area, and then penetrates into the brain.
  • the two limiting members 624 are used to respectively support the two ends of the first face 611 of the headrest 610, thereby supporting the headrest 610 to be suitable for carrying out
  • the supine position is administered so that the drug passes through the nasal cavity to the olfactory area and then penetrates into the brain.
  • the present invention is not limited thereto, and the function of the limiting component may be implemented by using a horizontal bar connecting two horizontal connecting arms, and of course, it is also known in the art. The other way to achieve it.
  • the support frame 620 has a height adjustment feature similar to that of the embodiment 3, and provides a better comfort for the user by adjusting the height to meet the needs of different individuals and different postures. It will be understood by those skilled in the art that the present invention is not limited thereto, and the support frame may have an A shape, an L shape, an inverted Y shape, an M shape, or other operable shape.
  • the double-sided pillow in the present embodiment can replace the pillow in each of the above embodiments, and the embodiment thus formed also falls within the scope of the claims of the present invention.
  • the double sided pillow may be a portable, inflatable pillow or other padded pillow.
  • the body position fixer may further include: an audio player for playing an audio file guiding the user to adjust the body position; and/or a video player, Play a video file that guides the user to adjust the position. For example, by adding some audio or video prompts for smartphones, remote controls, or other wearable smart devices, the user can adjust the head position to the preset program.
  • the user can realize a specific head position administration by a flexible rotatable headrest, so that the user himself or the medical assistant can fully utilize the specific shape formed by the device.
  • the above-mentioned head and shoulder position and the anatomical space of the upper nasal cavity are used to achieve a satisfactory, time-quantized, individualized brain-targeted drug concentration after nasal administration, thereby ensuring the therapeutic effect of the drug on central nervous system diseases.
  • the position fixer may further include: a platform supporting the head bearing portion and the user's body, and specifically, the platform includes: a mat, Beds, chairs, tables, counters, floors, and other similar support planes.
  • the bearing surface of the platform for carrying the user's body can be angle-adjusted (as shown in FIG. 16) to match the angle of the headrest, so that the user can maintain more comfortable.
  • the device for adjusting the position of the head and nose can be mounted or placed on a variety of different platforms, including but not limited to mats (like yoga mats), regular or hinged beds, ordinary or mechanized chairs, tables.
  • the head carrying portion is mounted on a supporting plane of the supporting mechanism with the tilting adjustment function so that the head and neck of the user can perform brain-targeted nasal administration without excessive reclining. This enhances comfort and thus provides individualized nasal-targeted drug delivery.
  • a post-nasal body position anchor for brain targeting has been described, in particular, a head carrier involved in the body position holder.
  • a brain-targeted transnasal drug delivery device provided by the present invention is described below.
  • a brain-targeted transnasal delivery device comprises: a body position holder as described above in connection with various embodiments for maintaining a user's body position for nasal administration of a drug The olfactory region capable of entering a specific upper nasal cavity; the applicator having a shape that cooperates with the nasal cavity of the user for the nasal cavity to be used while the body position holder holds the user in the above position
  • the drug is administered to direct the drug into the brain.
  • the shape and material of the applicator according to the embodiment of the present invention conform to the requirement of nasal administration, and can well conform to the anatomical and physiological structure of the human nasal cavity, and have no stimulation to the nasal mucosa.
  • the brain-targeted transnasal drug delivery device further comprises:
  • a robotic arm one end of which is coupled to the applicator, and the robotic arm is configured to be adjustable to support the applicator in place.
  • the other end of the robot arm is coupled to the body position holder.
  • the brain-targeted transnasal drug delivery device further comprises: an intelligent control element for regulating by controlling an action of the applicator and the second robot arm The time, speed and dosage of the drug, and can automatically control and adjust the applicator according to the input information by receiving, processing, and integrating information input by the outside world, such as physiological indicators, biochemical indicators, and cognitive function scores of the user. Drug time, speed and dose.
  • the applicator can include a drug container.
  • the medicament container is a biocompatible, sterile, and/or disposable container.
  • the drug container may be a fixed volume container or a syringe with a quantifiable push or squeeze device.
  • the fixed volume ranges from 10 ⁇ L to 10 mL, preferably from 25 ⁇ L to 2 mL.
  • the present invention provides a nasal-targeted brain-targeting technique that facilitates administration by maintaining the user in a specific position (ie, Mygind position, see Figure 14; or Regan position, see Figure 15).
  • a specific position ie, Mygind position, see Figure 14; or Regan position, see Figure 15.
  • the shape of the applicator can cater to the human nasal anatomy and facilitate insertion into the nasal cavity for administration.
  • the device can give a predetermined volume of the drug in the form of a drop or a spray, the specific dose will vary according to the characteristics of different diseases and different drugs, but the device is accommodated in consideration of the volume limitation of intranasal administration.
  • the total volume of the drug ranges from 10 ⁇ L to 10 mL, preferably from 25 ⁇ L to 2 mL.
  • the loaded drug may be any one of a small molecule, a polypeptide, a protein, and a biological preparation, or may be a combination of any one or more of the above.
  • the drop is a liquid
  • the spray may be a liquid or a solid powder.
  • the above drugs may be natural drugs, traditional Chinese medicines, or any processed preparations.
  • the ratio of the absorption enhancer contained in the dosage form is 0% to 30% (mass ratio)
  • the absorption enhancer is an ionic or nonionic surfactant, sodium cholate, and a ring.
  • These drug indications include any disease associated with the central nervous system.
  • the devices of the various embodiments of the present invention can be used to load insulin and its derivatives in various dosage forms, including various human insulin instant release dosage forms derived from animal sources or obtained by genetic recombination techniques, A rapid release dosage form, a sustained release dosage form, a long-acting release dosage form, protamine zinc insulin, or a combination of two or more of the above two dosage forms to treat and ameliorate the clinical symptoms of Alzheimer's disease (AD).
  • various human insulin instant release dosage forms derived from animal sources or obtained by genetic recombination techniques A rapid release dosage form, a sustained release dosage form, a long-acting release dosage form, protamine zinc insulin, or a combination of two or more of the above two dosage forms to treat and ameliorate the clinical symptoms of Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • the device may be a disposable aseptic drug delivery device or a device that can be repeatedly used by dosing.
  • Administration of a brain-targeted transnasal delivery device and a body position fixator thereof includes, but is not limited to, the following steps:
  • the subject should be placed in a flat position or other suitable position so as to raise the head so that the lower jaw faces upward (as shown in Fig. 14 and Fig. 15), and the angle between the vertical axis of the human head and the horizontal plane is between 0° and 90 degrees. Between ° and preferably between 40 and 80 degrees, the purpose is to allow the nostrils to face upwards or obliquely upwards, thereby facilitating administration and allowing the drug to enter the upper nasal cavity, as shown in FIG.
  • the upper nasal cavity is located at the lowermost end of the entire nasal cavity, and the drug drainage is accumulated in the olfactory region by gravity. Breathing through the nose several times is to ensure that the drug enters the upper nasal cavity as much as possible, rather than entering the respiratory or digestive tract, causing side effects caused by peripheral absorption. During the period, it is required to maintain the body position for at least 1 minute in order to allow the drug to have sufficient time to contact the olfactory nerve of the olfactory area, thereby directly entering the central nervous system and exerting its efficacy.
  • This mode of administration is simple and easy to perform, and can be done independently by the user at home, and for a user who is inconvenient to move, with the assistance of a family member or a nursing staff, the administration can be easily and accurately performed.
  • the technical solution of the present invention can be used to improve early cognitive impairment of Alzheimer's disease.
  • various pharmaceutical preparations in which insulin or a derivative thereof is the main active ingredient are directly passed through the nasal cavity into the brain by the posture and administration step, thereby exerting a therapeutic effect.
  • the cognitive function of the user is better improved by recording and evaluating through the periodic preliminary mental cognitive ability test.
  • the technical solution of the present invention can also be used for treating brain tumor, multiple sclerosis, Parkinson's disease, epilepsy, AIDS, tuberculosis, viral or bacterial infection of the brain, pituitary-hypothalamic hormone deficiency or disorder. Disease, as well as for relieving symptoms related to the central nervous system.
  • the brain-targeted transnasal drug delivery device provided by the embodiments of the present invention overcomes the following drawbacks of the prior art: many current diseases of the central nervous system need to rely on brain-targeted therapy, but due to the operation The professional difficulty, as well as potential peripheral absorption effects such as the respiratory tract or / and digestive tract, have made the application of nasal targeting brain targeting technology not fully promoted.
  • the application of the brain-targeted transnasal drug delivery device provided by the method will help to popularize and individualize the very complicated and high-end brain-targeted nasal drug delivery technology, so that more users can be technically and economically. It has the ability to undertake brain-targeted treatments for nasal administration.
  • the present invention is intended to provide the above-mentioned drug delivery device for improving the early cognitive dysfunction of the disease. If supplemented by periodic recording and evaluation of the initial mental cognitive ability test, combined with the necessary insulin blood/cerebrospinal drug concentration test involved in the present invention, it will help to evaluate and determine the therapeutic effect for the benefit of numerous Alzheimer's patients. .

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Abstract

一种脑靶向的经鼻腔给药装置及其体位固定器。脑靶向的经鼻腔给药装置包括：体位固定器，用于将使用者的体位保持成使经鼻腔给药的药物能够进入特定的上鼻腔的嗅区；给药器，其给药端具有与使用者的鼻腔配合的形状，用于在体位固定器将使用者保持成上述体位的情形下经鼻腔向使用者给药，定向进入脑部。具体地，体位固定器包括：头承载部（600），用于承载使用者的头部并使头部保持成使经鼻腔给药的药物能够进入上鼻腔的嗅区。其中，头承载部（600）包括：用于承载使用者的头部的头枕（610）、支撑架（620）、以及用于将头枕（610）可旋转地支撑在所述支撑架（620）上的中轴杆（630）。通过将使用者保持在特定的给药体位，并由智能元件控制，使经鼻腔给药的药物能够定时、定速、定量进入上鼻腔的嗅区，并靶向性作用于脑部。

Description

脑靶向的经鼻腔给药装置及其体位固定器
本申请要求于2014年2月28日提交中国国家知识产权局、申请号为201410072934.6、发明名称为“脑靶向的经鼻腔给药装置及其体位固定器”的中国专利申请的优先权，该中国专利申请的全部内容通过引用并入本文中。
技术领域
本发明涉及一种给药装置，更为具体而言，涉及一种脑靶向的经鼻腔给药的技术。通常适用于在经鼻给药之后，靶向性作用于脑部的药物及制剂，尤其适用于对脑部靶向性递送各种治疗药物包括但不限于胰岛素及其衍生物，用以改善阿尔茨海默病和其它中枢神经系统疾病的临床症状。
背景技术
在治疗脑部疾病如多发性硬化症、帕金森病、癫痫症、老年痴呆症、脑部肿瘤以及艾滋病时，医学上一直存在着一个难题，即：如何克服血脑屏障，使药物能够进入中枢神经系统(central nervous system,CNS)内以发挥药效作用。目前临床上应用较多的方法是通过可逆性开启血脑屏障，鞘内注射以及颈动脉注射给药，使药物透过并进入CNS。但是，这些方法在操作技术上要求高、安全风险大，在应用上受到一定制约。基于鼻腔的特殊结构，通过鼻腔给药治疗脑部疾病具有非侵入性、脑生物利用度高、可以绕过首次通过代谢和体循环和血脑屏障等优点，且方便操作。
通常，经过鼻腔给药后，药物分子(小分子、多肽激素、蛋白质生物制剂等)会被吸入肺部后入血，或直接进入消化系统后吸收入血，然而通过恰当的装置加上鼻腔给药方式，也能使这些药物分子蓄积在上鼻腔的起始于脑部的嗅神经延伸段的嗅区。已有报道显示蓄积于嗅区的药物(小分子、多肽、蛋白质)能够直接渗透入脑(参见Arun et al.,2012)，尽管这种渗透是基于细胞间还是细胞内转运尚无明确定论。另外，在临床研究中，发现许多激素，如促肾上腺皮质激素(ACTH)、加压素(Vasopressin)、胰岛素在脑脊液中的浓度均高于血中激素内源性浓度，说明这些激素除了在外周发挥作用外，在中枢神经系统也可能发挥着不同的重要作用。例如，就胰岛素而言，通过 特定的将胰岛素蓄积于嗅区的鼻腔给药方式，在36个健康受试者中，平均脑脊液中胰岛素浓度是内源性胰岛素浓度的2倍，而血浆中胰岛素浓度则没有明显变化(见表1)。这一结果提示当使用恰当的方法使胰岛素蓄积于嗅区，胰岛素可以通过该区域直接进入中枢神经系统(参见Born et al.,2002)。
表1：人类鼻腔给药后脑脊液及血清的药物暴露量(n＝36)*
Figure PCTCN2015072648-appb-000001
*9位女性和27为男性受试者分别接受了胰岛素或促肾上腺皮质激素(黑皮质素)的鼻腔给药，并测量血清及脑脊液(CSF)药物浓度。通过计算药-时曲线下的面积来评价药物在中枢神经系统及血液循环系统中的暴露量。数据来自于Born et al.,2002。
a增加倍数是通过计算不同房室(CSF或血清)中实验组药物暴露量与安慰剂组内源性激素暴露量之比所得。
胰岛素及其衍生物的各种注射剂已经被广泛用于控制糖尿病病人的血糖指数。十多年前，曾有报道发现血浆内胰岛素浓度的暂时升高，伴随着脑脊液中胰岛素浓度的升高能够增强健康人的非文字记忆(参见Kern W et al.,2001)。在健康学生的试验中，连续7周每天经鼻腔给药160IU胰岛素，能够提高延迟回忆功能。Talbot等最近研究表明由于胰岛素抵抗导致脑内胰岛素样生长因子-1(IGF-1)通路信号传递障碍，是阿尔茨海默病(Alzheimer’s Disease,AD)脑部病变的一个特征表现(参见Talbot,K.J.Clin.Invest.2012：1316-1338)。在一些神经功能受损的疾病，如阿尔茨海默病中，研究发现脑部胰岛素受体1的312、616或636位丝氨酸残基(IRS-1pSer312,616或636)在 基础状态下的磷酸化是AD使用者的脑部胰岛素抵抗的一大特征。这一发现提示甚至在正常个体中，脑内胰岛素的实际需求也是远远超过正常生理状态的。
表2罗列了一些脑靶向经鼻腔胰岛素给药对于神经学和神经行为学治疗效果的证据。这些数据充分证明通过一种恰当、简单易行的能够有效提高脑脊液浓度的鼻腔胰岛素给药方法，能够对神经行为产生深远的影响，且不会改变体循环血浆胰岛素浓度。迄今为止，经鼻给予160IU胰岛素不会对鼻腔以及嗅区产生任何毒副作用，也不会触发胰岛素在外周系统的副作用或其他神经系统的不良反应。因此，脑靶向经鼻胰岛素给药可以被认为是治疗、改善神经功能受损疾病的安全、有效的方法。
表2：胰岛素脑靶向经鼻给药对于神经行为疾病及其症状的影响
Figure PCTCN2015072648-appb-000002
a数据来源于Benedict et al.,2004,Psychoneuroendocrinology
b数据来源于Reger et al.,2008,J Alzheimer’s Disease 13,323
虽然有关阿尔茨海默病的神经行为功能的确切机制并不完全清楚，可以确定的是增加中枢神经系统的胰岛素水平能够影响到阿尔茨海默病成人使用者的认知、成像、和生化参数及该病的前驱症状，即轻度认知功能障碍(MCI)。有实验证明直接将胰岛素引入阿尔茨海默病动物模型的中枢神经系统，能够改善其神经损伤。在一些临床试验中，已经证明通过复杂的方式将胰岛素经鼻腔给药引入大脑，能够改善使用者的轻度认知功能障碍。综上所述，提升大脑和中枢神经系统中的胰岛素水平，将有助于改善使用者的神经行为功能。因此，亟需一种能够由病人自身或家庭护理人员单独在家完成脑靶向鼻腔给药的装置及方法，这一装置或方法需要操作简单、容易上手，能够克服以往 这类给药方式需要复杂昂贵的仪器以及经过严格专业训练的医护人员才能操作的缺点，使使用者无需去医院就能轻松完成日常的给药工作。
发明内容
脑靶向给药系统是药学及神经病、肿瘤等相关医学领域中一个非常活跃的研究领域，以脑靶向为目的经鼻腔给药系统则是近年来的一个研究热点。而脑靶向的经鼻腔给药，需要通过一定方法使药物蓄积于上鼻腔，即嗅区，以避开经呼吸道及消化道吸收入体循环，从而直接进入中枢神经系统。为此，本发明提供了一种脑靶向的经鼻腔给药装置及其体位固定器，结合特定的给药体位使经鼻腔给药的药物能够进入上鼻腔的嗅区，并靶向性作用于脑部，其将复杂的脑靶向经鼻给药系统简单化，使使用者能够亲自或者由家属、家庭护理人员等协助，在家庭环境中便能完成操作，并达到定时、定速、定量脑靶向给药的目的。本发明提供的脑靶向的经鼻腔给药装置及其体位固定器也适用于野外急救，如在战场环境下，在时间、医疗器械、医务人员不足的情况下，可以用本发明提供的装置进行简单、快速地脑靶向给药，如用于缓解中枢神经系统的症状等。
一方面，本发明提供了一种用于脑靶向的经鼻腔给药的体位固定器，该体位固定器包括：
头承载部，用于承载使用者的头部并使头部保持成使经鼻腔给药的药物能够进入上鼻腔的嗅区。
其中，所述头承载部包括：用于承载使用者的头部的头枕、用于支撑所述头枕的支撑架、以及用于将所述头枕可旋转地支撑在所述支撑架上的中轴杆。
在本发明的一种实施方式中，所述头枕包括：内部支架，支撑在所述中轴杆上；枕垫，覆盖于或包覆在所述内部支架上。
并且，所述头枕分为第一部分和第二部分；其中，第一部分设置成由所述内部支架的一部分成50°至70°的角度支撑，优选为60°；和/或所述第二部分设置成由所述内部支架的另一部分成20°至40°的角度支撑，优选为30°。
在本发明的另一种实施方式中，所述头枕包括：具有用于仰卧位给药的 第一面和用于侧卧位给药的第二面的双面枕垫。
其中，所述第一面包括颈部承载面和头部承载面，所述头部承载面和颈部承载面的形状设计成分别贴合仰卧时人体头颈部曲线。所述第二面也包括颈部承载面和头部承载面，所述头部承载面和颈部承载面的形状设计成分别贴合侧卧时人体头颈部曲线。
在本发明的各种实施方式中，所述枕垫可以为便携、可充气枕垫或者其他填充物的枕垫。
在本发明的其他实施方式中，所述支撑架大体为H形、A形、L形、倒Y形、M形或其他可操作的形状。
所述中轴杆横向贯穿于所述头枕的第一部分和第二部分衔接面的中央，或者，横向贯穿于所述头枕的双面枕垫的颈部承载面端。
在本发明另外的实施方式中，所述头承载部还包括：
高度调整机构，用于调整所述中轴杆及其所连接的头枕在所述支撑架上的高度以调整所述头枕的高度。
在本发明另外的实施方式中，所述体位固定器还包括：
第一机械臂，与所述头承载部操作性地接合，用于调整中轴杆及其所连接的头枕的角度。
在本发明另外的实施方式中，所述体位固定器还包括：
电机，与所述头承载部操作性地接合，用于在计算机、智能手机或遥控器的控制下调整所述头枕的角度。
在本发明另外的实施方式中，所述体位固定器还包括：刻度指示器，该刻度指示器通过激光光束精确检测使用者的鼻、颈间的仰角来指示使用者将头部调整到合适的或者最佳的给药角度，以便个体化给药。
在本发明另外的实施方式中，所述体位固定器还包括：
音频播放器，用于播放指导使用者调节体位的音频文件；和/或
视频播放器，用于播放指导使用者调节体位的视频文件。
在本发明各种的实施方式中，所述体位固定器还包括：支撑所述头承载部和使用者身体的平台，例如，包括但不限于：垫子、床、椅子、桌子、柜台、地板、及其它类似支撑平面。其中，所述平台的用以承载使用者身体的承载面可进行角度调节，以配合所述头枕的角度，使使用者保持更舒适的经 鼻脑靶向给药体位。
另一方面，本发明还提供了一种脑靶向的经鼻腔给药装置，其中所述装置包括：
根据上述各种实施方式中任意一种实施方式所述的体位固定器，用于将使用者的体位保持成使经鼻腔给药的药物能够进入特定的上鼻腔的嗅区；和
给药器，其给药端具有与使用者的鼻腔配合的形状，用于在所述体位固定器将使用者保持成上述体位的情形下经鼻腔向使用者给药，使得药物定向进入脑部。
在本发明的其他实施方式中，所述脑靶向的经鼻腔给药装置还包括：
第二机械臂，其一端与所述给药器连接，并且所述第二机械臂配置成能够调节以便将所述给药器支撑在合适的位置。其中，所述第二机械臂的另一端与所述体位固定器连接。
在本发明的进一步实施方式中，所述脑靶向的经鼻腔给药装置还包括：
智能控制元件，用于通过控制所述给药器和第二机械臂的动作来调节给药的时间、速度和剂量，包括接收、处理、整合外界输入的信息，根据所输入的信息自动控制、调节给药器的给药时间、速度和剂量，其中，所述输入的信息包括使用者的生理指标、生化指标、认知功能评分等。
在本发明的另外的实施方式中，所述给药器包括药物容器。例如，所述药物容器可以为生物相容性好的，无菌的、和/或一次性使用的容器。所述药物容器可以为固定体积容器，或者为具有可定量推动或挤压装置的注射器。
本发明各种实施方式所述的一种脑靶向的经鼻腔给药装置及其体位固定器，主要用于中枢神经系统疾病的给药治疗，包括但不限于早老性痴呆、脑部肿瘤、多发性硬化症、帕金森病、癫痫症、艾滋病、结核病、脑部病毒性、细菌性、寄生虫或其它微生物感染、垂体-下丘脑激素缺乏或失调引起的疾病，以及用于缓解中枢神经系统有关的症状。
采用根据本发明各种实施方式所述的体位固定器以及带有该体位固定器的给药装置，可以由病人自身或家庭护理人员简单操作，例如将病人头部以仰卧或侧卧姿势置于所述体位固定器，即可实现脑靶向的经鼻腔给药。采用本发明提供的装置，操作简单、容易上手，克服了以往这类给药方式需要复杂昂贵的仪器以及经过严格专业训练的医护人员才能操作的缺点，使使用者 能轻松完成日常的给药工作。
附图说明
下面结合附图对本发明的各种优点、特征及其各个方面进行详细阐述，在所有描述中采用相似的附图标记表示相似的部件，其中：
图1示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部的实施例1，未示出枕垫；
图2示出了根据实施例1的头枕，其中，为了示出头枕的内部，其枕垫采取了透视画法；
图3示出了根据实施例1的除去枕垫后的头枕的内部结构；
图4示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部的实施例2，未示出枕垫；
图5示出了根据实施例2的头枕，其中，为了示出头枕的内部，其枕垫采取了透视画法；
图6示出了根据实施例2的除去枕垫的头枕的内部结构；
图7示出了根据实施例2的除去枕垫的头枕的内部结构，其中，中轴杆穿过头枕的内部支架；
图8示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部的实施例3；
图9示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部的实施例4；
图10示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部的实施例5；
图11示意性地示出了使用者头部处于仰卧位的状态；
图12示意性地示出了使用者头部处于侧卧位的状态；
图13示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部的实施例6；
图14示出了使用者采取仰卧(Mygind)体位进行给药；
图15示出了采用使用者采取侧卧(Regan)体位进行给药；
图16示出了根据本发明实施方式的放置于平台上的体位固定器；
图17是采用本发明实施方式进行仰卧位给药时鼻腔解剖图示。
具体实施方式
以下结合附图和具体实施方式对本发明的各个方面进行详细阐述。其中，众所周知的装置、处理器、模块及其相互之间的连接、控制或操作没有示出或未作详细说明。并且，所描述的特征、组件、部件、元件或功能可在一个或一个以上实施方式中以任何方式组合。本领域技术人员应当理解，下述的各种实施方式只用于举例说明，而非用于限制本发明的保护范围。还应当理解，本文所述和附图所示的各实施方式中的模块或组件、部件、元件、单元或步骤可以按各种不同配置进行组合和设计。
本文根据本发明的各种实施方式描述了一种具有体位固定器的脑靶向的经鼻腔给药装置，其中，所述体位固定器用于将使用者保持在适于促进药物进入上鼻腔并进一步由嗅区进入脑的体位。其中，所述脑靶向的经鼻腔给药装置还包括给药器，该给药器的给药端具有与使用者的鼻腔配合的形状，用于在所述体位固定器将使用者保持成上述体位的情形下经鼻腔向使用者给药，以便于药物定向进入脑部。由此，实现了脑靶向给药，避免药物进入呼吸道或/和消化道而导致非靶向给药和用药量不够。在本发明的各种实施方式中，所述体位固定器包括头承载部，该头承载部用于承载使用者的头部并将头部保持成使经鼻腔给药的药物能够进入上鼻腔的嗅区，例如，将使用者头颈部保持特定的角度以保证经鼻腔给药的药物能够定时、定量地进入特定的上鼻腔的嗅区，以达到精确的个体化脑靶向给药的目的，这将在下文具体描述。
【实施例1】
图1示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部100，其中为了便于示出头承载部的内部结构，未示出枕垫；图2示出了在内部支架111上覆盖有枕垫112的头枕110，在该图中为了示出头枕110的内部结构，其枕垫112采取了透视画法，即：可以透过枕垫112看到其内部；图3示出了根据本发明实施方式的除去或移除枕垫112后的头枕110的内部结构。在本发明的示例性实施方式中，所述体位固定器用于将使用者保持在适于促进药物进入上鼻腔并进一步由嗅区进入脑部的体位。具体而言， 所述体位固定器包括用于承载使用者的头部并将头部保持成使经鼻腔给药的药物能够进入上鼻腔的嗅区的头承载部100，如图1所示，所述头承载部100包括，但不限于：用于承载使用者的头部的头枕110、用于支撑头枕110的支撑架120和将头枕110可旋转地支撑在支撑架120上的中轴杆130。其中，在本发明实施方式中，支撑架120为两个H形支架，每一个H形支架由两根竖向设置的立柱121和横向连接所述立柱的横连接臂122构成，中轴杆130的两个端部分别可转动地支撑在每个H形支架的横连接臂122(“H”中间的“—”上)上。需要说明的是，本发明并不局限于此，本领域技术人员在不脱离本发明的原理的条件下，可以对各种实施方式进行修改或衍变，例如，可以采用多个H形支架，同时，还可以采用其他支撑结构，例如，呈A形、L形、倒Y形、M形或其他可操作的形状的支撑架，下面将进行具体说明。
在本发明的实施方式中，如图2所示，头枕110包括：内部支架111，其支撑在所述中轴杆130上；枕垫112，其覆盖于所述内部支架111上，例如，枕垫112可以包裹在所述内部支架111上。如图3所示，所述内部支架111包括：在中轴杆130上沿轴向的不同位置，自中轴杆130的表面径向向外延伸设置的多根支撑杆113、沿与中轴杆130大致平行的方向将所述多根支撑杆113的端部横向连接起来的多根长连接杆114、以及将所述多根长连接杆114的端部连接起来的短连接杆115。其中，所述内部支架111端部的所述多根短连接杆115形成近似四边形，从而使得头枕110的端面为大致四边形形状。当然，本领域技术人员应当理解，本发明不限于此，内部支架111可以是配置成将枕垫112支撑在中轴杆130上的任意结构，例如，内部支架可以由让中轴杆贯穿于其中的多块支撑板和连接所述支撑板的端部形成承载枕垫的表面的连接板构成，这将在下文详细描述。此外，所述枕垫112可以采用本领域已知的符合人体头部和颈部的人体工程学的任何材料构成，例如，所述枕垫可以为便携、可充气枕垫或者其他填充物的枕垫，以提供舒适度。
在本发明实施方式中，头枕110分为第一部分和第二部分，如图2所示，第一部分(即，图2中头枕的大致四边形端面的与对角线成60°夹角的边所在的部分)设置成由内部支架111的一部分成50°至70°的角度支撑，例如，由内部支架111的一部分成50°的角度支撑，或者由内部支架111的一部分成70°的角度支撑，优选地，成大约60°的角度支撑，以便使用者或使用者 采取身体仰卧的姿势(即仰卧位)进行经鼻腔脑靶向给药；第二部分(即，图2中头枕的大致四边形端面的与对角线成30°夹角的边所在的部分)设置成由内部支架111的另一部分成20°至40°的角度支撑，例如，由内部支架111的另一部分成20°的角度支撑，或者由内部支架111的另一部分成30°的角度支撑，优选地，成大约30°的角度支撑，以便使用者或使用者采取侧卧的姿势(即侧卧位)进行经鼻腔脑靶向给药。其中，中轴杆130横向贯穿于所述头枕的第一部分和第二部分衔接面的中央，通过使头枕110围绕中轴杆130转动以选择性地使用所述第一部分和第二部分，进而选择采取不同的体位进行经鼻腔脑靶向给药。例如，可以通过与头承载部100操作性地接合的机械臂(未示出)来调整中轴杆130及其所连接的头枕110的角度。作为选择，可以采用与所述头承载部操作性地接合的电机(未示出)，例如小型或微型电机，用于在计算机、智能手机或遥控器的控制下调整所述头枕的角度，从而，精确控制使用者的体位以便使经鼻腔给药的药物最佳地吸收入脑部。
【实施例2】
图4示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部200，其中，为了便于示出头承载部200的内部结构，未示出枕垫；图5示出了在内部支架211上覆盖有枕垫212的头枕210，在该图中为了示出头枕210的内部，其枕垫212采取了透视画法，即：可以透过枕垫212看到其内部；图6示出了根据本发明实施方式的移除枕垫212的头枕210的内部结构，该图示出了根据本发明实施方式中轴杆230穿过内部支架211以便于支撑内部支架211。需要说明的是，本实施例的各个实施方式与实施例1的实施方式类似，本领域技术人员应当理解，实施例1中所述的各种实施方式的全部特征或部分特征可与本实施例2结合或合并到本实施例2中，并且所述结合或合并形成的实施方式也作为本发明的实施方式，并落入本发明的权利要求限定的保护范围之内。
在本发明的示例性实施方式中，所述体位固定器用于将使用者保持在适于促进药物进入上鼻腔并进一步由嗅区进入脑部的体位。具体而言，所述体位固定器包括用于承载使用者的头部并使头部保持成使经鼻腔给药的药物能够进入上鼻腔的嗅区的头承载部200，如图4所示，所述头承载部200包括，但不限于：用于承载使用者的头部的头枕210、用于支撑所述头枕210的支撑 架220和将所述头枕210可旋转地支撑在所述支撑架220上的中轴杆230。其中，在本发明的实施方式中，支撑架220为两个近似A形的支架，每一个A形支架由两根斜立柱221和横连接臂222构成，其中两根斜立柱221的上端连接在一起，下端分开，在上下两端之间通过横连接臂222连接在一起；中轴杆230的两个端部分别可转动地支撑相应的A形支架的横连接臂222(“A”中间的“—”上)上。本领域技术人员应当理解，本发明并不局限于此，可以采用本领域已知的其他支撑结构，例如，呈L形、倒Y形、M形或其他可操作的形状的支撑架，例如，上述的H形支架。
在本发明的实施方式中，如图5所示，头枕210包括：内部支架211，支撑在所述中轴杆230上；枕垫212，覆盖于所述内部支架211上。如图6和7所示，内部支架211包括至少两个支撑板213和连接支撑板的多根连接杆214，其中，所述支撑板213至少分别设置于内部支架211的两端，支撑板213大致为四边形，并且，如图6所示，该四边形的两对对角中的一对对角各自的两条边构成为：一条边与连接这对对角的对角线成60°，另一条边与所述对角线成30°，从而将头枕210分为第一部分(即与对角线成60°夹角的边所在的部分)和第二部分(即与所述对角线成30°夹角的边所在的部分)。支撑板213在上述的对角线的中央区域具有孔215，如图7所示，中轴杆230穿过孔215并与所述支撑板213连接，从而将头枕210可转动地支撑在支撑架220上。所述多根连接杆214分别在四边形的支撑板213的四个角或部分角处将不同的支撑板213连接起来以构成内部支架211，所述多根连接杆214用于支撑覆盖于其上的枕垫212。
当然，本领域技术人员应当理解，本发明不限于此，支撑板213不限于四边形，可以是其他任何形状，同时，也可以采用连接板替代多根连接杆214，例如，采用四块连接板对应支撑板213的四条边将不同的支撑板连接起来，并且所述连接板配置成支撑枕垫212。此外，所述枕垫212可以采用本领域已知的符合人体头部和颈部的人体工程学的任何材料构成，例如，所述枕垫为便携、可充气枕垫或者其他填充物的枕垫，以提供舒适度。
在本发明的其他实施方式中，头枕210的所述第一部分设置成由内部支架211的一部分成50°至70°的角度支撑，例如，由内部支架211的一部分成50°的角度支撑，或者由内部支架211的一部分成70°的角度支撑，优选 地，成大约60°的角度支撑，以便使用者或使用者进行仰卧位的经鼻腔脑靶向给药；头枕210的第二部分设置成由内部支架211的另一部分成20°至40°的角度支撑，例如，由内部支架211的另一部分成20°的角度支撑，或者由内部支架211的另一部分成40°的角度支撑，优选地，成大约30°的角度支撑，以便使用者或使用者进行侧卧位的经鼻腔脑靶向给药。通过使头枕210围绕中轴杆230转动以选择性地使用所述第一部分和第二部分，进而选择采取不同的体位进行经鼻腔脑靶向给药。优选地，例如，可以通过与头承载部200操作性地接合的机械臂(未示出)来调整中轴杆230及其所连接的头枕210的角度。作为选择，可以采用与所述头承载部操作性地接合的具有角度显示器的微型电机(未示出)，用于在计算机的控制下调整所述头枕的角度，从而，精确控制使用者的体位以便使经鼻腔给药的药物最佳地吸收入脑部。
【实施例3】
图8示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的具有高度调节功能的头承载部300，其枕垫312采取了透视画法，即：可以透过枕垫312看到其内部。在本发明的示例性实施方式中，所述体位固定器将使用者保持在适于促进药物进入上鼻腔并进一步由嗅区进入脑部的体位。如图8所示，所述头承载部300包括，但不限于：用于承载使用者的头部的头枕310、用于支撑所述头枕310的支撑架320和将所述头枕310可旋转地支撑在所述支撑架320上的中轴杆330。
与实施例1和2相比，本实施例3的区别在于所述头承载部300具有高度调节功能，具体而言，支撑架320具有高度调节特征。在本发明的一种实施方式中，两个支撑架320分别大致呈H形，其中，每一个支撑架320包括两根立柱321和一根横连接臂322，其中在单根立柱321上的不同高度位置具有切口323，所述两根立柱321上的切口在各自立柱321上的高度一一对应，所述横连接臂322的两端分别具有凸起324，所述凸起324分别放置于所述两根立柱323上相同高度的切口323中，从而将两根立柱324连接起来构成支撑架320。所述中轴杆330与所述横连接臂322的中央部分连接，例如，横连接臂322的中央部分设置孔或开口以收纳所述中轴杆330的端部，或者通过本领域已知的其他方式将横连接臂322与中轴杆330可转动地连接，从而将头枕310可转动地支撑在支撑架320上。通过将横连接臂322的凸起324放 置于立柱321上不同的高度的切口323中以调节横连接臂322的高度，进而调节中轴杆330的高度，并由此调节头枕310的高度，从而满足不同个体、不同体位的需要，为给药的使用者提供更好的舒适度，并且所述支撑架可以放置于任何水平面上。
需要说明的是，本发明不局限于将H形的支撑架设置成具有高度调节功能，对于其他形状的支撑架可以采用同样的方式设置成具有高度调节功能，例如，对A形支撑架的斜立柱上的不同高度设置切口以便调整其横连接臂的高度。此外，除了采用设置切口的方式进行高度调节外，还可以采用本领域已知的其他高度调节方式对本发明各种实施方式的支撑架进行配置以实现高度调节，例如，可以采用滑轮式升降机构、液压式升降机构等等。
根据本发明的其他实施方式，头枕310的侧面可大致为四边形，整个头枕由内部支架以及外部软性枕垫填充物组成，可分为上、下两部(可颠倒)(即上述的第一部分、第二部分)，中间有可旋转的中轴杆330穿过。在头枕310表面，选择软性枕垫填充材料覆盖于内部支架(类似于实施例1中的内部支架111)上，以提供舒适度。头枕310上部设计为由内部支架支撑、且允许60°左右(例如，50°-70°)绕中轴可旋转角度，以便使用者采取身体仰卧且头部后仰的姿势进行经鼻腔脑靶向给药。头枕310下部设计为由内部支架支撑、且允许30°左右(20°-40°)绕中轴可旋转角度，以便使用者采取侧卧姿势进行经鼻腔脑靶向给药。优选地，例如，可以通过与头承载部300操作性地接合的机械臂来调整中轴杆330及其所连接的头枕310的角度。作为选择，可以采用与所述头承载部操作性地接合的具有角度显示器的微型电机(未示出)，用于在计算机的控制下调整所述头枕的角度，从而，精确控制使用者的体位以便使经鼻腔给药的药物最佳地吸收入脑部。
【实施例4】
本领域技术人员应当理解，实施例1、2中所述的实施方式的全部特征或部分特征可与实施例3结合或合并到实施例3中，或者可以用实施例1、2中的部分特征替代实施例3中的部分特征。所述结合、合并、替代形成的实施方式也属于本发明的实施方式，并落入本发明权利要求限定的保护范围之内。例如，图9示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的头承载部的实施例4，用400表示。在图9中，枕垫412采取了透视画 法，即：可以透过枕垫412看到其内部。在本发明的示例性实施方式中，所述头承载部400可应用至体位固定器中，该体位固定器将使用者保持在适于促进药物进入上鼻腔并进一步由嗅区进入脑部的体位。如图9所示，所述头承载部400包括，但不限于：用于承载使用者的头部的头枕410、用于支撑所述头枕410的支撑架420和将所述头枕410可旋转地支撑在所述支撑架420上的中轴杆430。其中，支撑架420与实施例3中的支撑架320类似，具有类似的高度调节特征；头枕410与实施例2中的头枕210类似，其采用支撑板413构成的内部支架411。其他部件或特征与实施例1、2或3类似。
根据本发明的实施方式，头枕410的侧面也可大致为四边形，整个头枕由内部支架以及外部软性枕垫填充物组成，可分为上、下两部(可颠倒)(即上述的第一部分、第二部分)，中间有可旋转的中轴杆430穿过。在头枕410表面，选择软性枕垫填充材料覆盖于内部支撑架420上，以提供舒适度。头枕410上部设计为由内部支架411支撑、且允许60°左右(例如，50°-70°)绕中轴可旋转角度，以便使用者采取身体仰卧且头部后仰的姿势进行经鼻腔脑靶向给药。头枕410下部设计为由内部支架411支撑、且允许30°左右(20°-40°)绕中轴可旋转角度，以便使用者采取侧卧姿势进行经鼻腔脑靶向给药。例如，可以采用与所述头承载部操作性地接合的具有角度显示器的微电机(未示出)，用于在计算机的控制下调整所述头枕的角度。此外，通过高度调整以满足不同个体、不同体位的需要，为给药的使用者提供更好的舒适度。
【实施例5】
图10示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的具有高度调节功能和刻度指示的头承载部500，其枕垫512采取了透视画法，即：可以透过枕垫512看到其内部。在本发明的示例性实施方式中，所述头承载部500可应用于体位固定器中，该体位固定器将使用者保持在适于促进药物进入上鼻腔并进一步由嗅区进入脑部的体位。如图10所示，所述头承载部500包括，但不限于：用于承载使用者的头部的头枕510、用于支撑所述头枕510的支撑架520和将所述头枕510可旋转地支撑在所述支撑架520上的中轴杆530。其中，支撑架520与实施例3、4中的支撑架320、420类似，具有相似的高度调节特征；头枕510与实施例1中的头枕110类似，其采用支撑杆513、多根长连接杆514和短连接杆515构成的内部支架511。其他部 件或特征与实施例1、2、3或4类似。实施例5与上述实施例的不同在于所述体位固定还包括刻度指示器(未示出)，该刻度指示器通过激光器540发射激光光束精确检测使用者的鼻-颈间的仰角来指示使用者鼻子需要调整的角度。例如，本领域已知的数码控制(或类似作用)的刻度表指示器，该指示器配有激光用以平行鼻子的角度，通过激光指示可以使用户精确的调节鼻子的角度，达到Mygind体位(如图11所示)或Regan体位(如图12所示)的经鼻腔脑靶向给药的要求体位。
【实施例6】
图13示出了根据本发明实施方式的用于脑靶向的经鼻腔给药的体位固定器的具有高度调节功能的头承载部600。在本发明的示例性实施方式中，所述头承载部600可应用于体位固定器中，该体位固定器将使用者保持在适于促进药物进入上鼻腔并进一步由嗅区进入脑部的体位。如图13所示，所述头承载部600包括，但不限于：用于承载使用者的头部的头枕610、用于支撑所述头枕610的支撑架620和将所述头枕610可旋转地支撑在所述支撑架620上的中轴杆630。其中，头枕610包括双面枕垫，所述双面枕垫具有用于仰卧位给药的第一面611(图中页面朝上的面)和用于侧卧位给药的第二面612(图中页面朝下的面)。所述第一面611包括颈部承载面和头部承载面，这两个承载面的形状设计成分别贴合仰卧时人体头颈部曲线613。所述第二面612包括颈部承载面和头部承载面，这两个承载面的形状设计成分别贴合侧卧时人体头颈部曲线614，其中，曲线614的弧度大于曲线613的弧度。其中，中轴杆630横向贯穿于所述头枕的双面枕垫的颈部承载面的端部，通过旋转以选择性地使用其第一面和第二面。作为选择，可以通过机械臂(未示出)调整中轴杆630及其所连接的头枕610的角度，以实现经鼻腔给药至嗅区，最终实现脑靶向给药。作为选择，可以采用与所述头承载部操作性地接合的具有角度显示器的微型电机(未示出)，用于在计算机的控制下调整所述头枕的角度。
本实施例中，支撑架620包括两个H形支架，每一个H形支架由两根竖向的立柱621和连接所述立柱的横连接臂622构成，中轴杆630的两个端部分别可转动地支撑在相应的H形支架的横连接臂622(“H”中间的“—”上)上。在本发明的一种实施方式中，每一个H形支架上，在横连接臂622的两端靠近立柱621的位置分别具有限位部件623、624。其中，当所述头枕610 用作仰卧位给药时，如图13所示的状态，两个H形支架上的限位部件623用于分别支撑头枕610的第二面612的两端，从而将头枕610支撑为适于进行仰卧位给药，使得药物经过鼻腔到达嗅区，进而渗入至脑部。相应地，当所述头枕610用作侧卧位给药时，两个限位部件624用于分别支撑头枕610的第一面611的两端，从而将头枕610支撑为适于进行仰卧位给药，使得药物经过鼻腔到达嗅区，进而渗入至脑部。需要说明的是，本领域技术人员应当理解，本发明不局限于此，所述限位部件的功能可以采用将两个横连接臂连接起来的横杠来实现，当然也可以采用本领域已知的其他方式来实现。此外，支撑架620具有与实施例3类似的高度调整特征，通过高度调整以满足不同个体、不同体位的需要，为使用者提供更好的舒适度。本领域技术人员应当理解，本发明不局限于此，所述支撑架可以呈A形、L形、倒Y形、M形或其他可操作的形状。此外，本实施例中的双面枕垫可以替换上述各实施例中的枕垫，由此形成的实施方式同样落入本发明权利要求请求保护的范围。在本发明的其他实施方式中，所述双面枕垫可以为便携、可充气枕垫或者其他填充物的枕垫。
在上述实施例1-6中，根据本发明的各种实施方式描述的体位固定器进一步可包括：音频播放器，用于播放指导使用者调节体位的音频文件；和/或视频播放器，用于播放指导使用者调节体位的视频文件。例如，通过添加一些音频或视频的适用于智能手机、遥控器、或其他可佩戴智能设备的提示插件来帮助使用者调节头部体位，达到预设程序的规定。
根据上述各种实施方式所述的体位固定器，通过一个灵活的可旋转头枕来帮助使用者实现特定的头部体位给药，使得使用者本人或医疗助手能够充分利用本装置形成的特定的上述头肩部体位与上鼻腔的解剖空间，以实现鼻腔给药后满意的，定时定量的，个体化的脑靶向药物浓度，从而保证药物对中枢神经系统疾病的治疗作用。
根据上述的实施例1-6中各种不同的实施方式所述的体位固定器，进一步可以包括：支撑上述的头承载部和使用者身体的平台，具体而言，所述平台包括：垫子、床、椅子、桌子、柜台、地板、及其它类似支撑平面。在本发明的其他实施方式中，所述平台的用以承载使用者身体的承载面可进行角度调节(如图16所示)，以配合所述头枕的角度，使使用者保持更舒适的个体 化经鼻脑靶向给药体位。例如，用于调整头部及鼻子体位的装置可以安装或放置于各类不同的平台上，这包括但不限于垫子(类似瑜伽垫)、普通或带铰链的床、普通或机械化的椅子、桌子、书桌、柜台，或直接放置于地板上。如图16所示，所述头承载部安装于带有倾仰调节功能的支撑机构的支撑平面上以便使用者的头颈部不需要过度后仰即可进行脑靶向的经鼻腔给药，从而提高舒适度，进而提供个体化的经鼻脑靶向给药。
以上结合各种实施方式，描述了用于脑靶向的经鼻腔给药的体位固定器，尤其是，该体位固定器涉及的头承载部。下面对本发明提供的一种脑靶向的经鼻腔给药装置进行描述。
在本发明的各种实施方式中，脑靶向的经鼻腔给药装置包括：上面结合各种实施方式所述的体位固定器，用于将使用者的体位保持成使经鼻腔给药的药物能够进入特定的上鼻腔的嗅区；给药器，其给药端具有与使用者的鼻腔配合的形状，用于在所述体位固定器将使用者保持成上述体位的情形下经鼻腔向使用者给药，以使药物定向进入脑部。具体而言，本发明实施方式的给药器的形状、用料符合鼻腔给药的需求，能够很好的吻合人类鼻腔内解剖生理结构，且对鼻粘膜没有刺激。
在本发明的其他实施方式中，所述脑靶向的经鼻腔给药装置还包括：
机械臂，其一端与所述给药器连接，并且所述机械臂配置成能够调节以便将所述给药器支撑在合适的位置。作为选择，所述机械臂的另一端与所述体位固定器连接。
在本发明的其他实施方式中，可选地，所述脑靶向的经鼻腔给药装置进一步包括：智能控制元件，用于通过控制所述给药器和第二机械臂的动作来调节给药的时间、速度和剂量，并且能够通过接收、处理、整合外界输入的信息，如使用者的生理指标、生化指标、认知功能评分等，根据输入的信息自动控制、调节给药器的给药时间、速度和剂量。
在本发明的各种实施方式中，所述给药器可包括药物容器。优选地，所述药物容器为生物相容性好的、无菌的、和/或一次性使用的容器。所述药物容器可以为固定体积容器，或者为具有可定量推动或挤压装置的注射器。例如，所述固定体积的范围为10μL-10mL，优选25μL-2mL。
根据上述的脑靶向的经鼻腔给药装置及其体位固定器的各种实施方式的 描述可知，本发明提供的经鼻腔给药脑靶向的技术通过将使用者保持在特定的体位(即Mygind位，见图14；或Regan位，见图15)进行给药操作，从而促进药物通过进入上鼻腔，并进一步由嗅区进入脑，起到脑靶向给药的作用，并避免用药量不够和进入吸道或/和消化道，如图17所示，其示出了仰卧位给药时的鼻腔解剖图。根据本发明各种实施方式所述的脑靶向的经鼻腔给药装置，其给药器的形状能够迎合人体鼻腔解剖结构，便于塞入鼻腔进行给药。并且所述装置能够以滴剂或者喷雾的形式，给予预定体积的药物，具体剂量根据不同疾病、不同药物的特性会有所不同，但考虑到鼻腔内给药的体积限制，该装置内所容纳药物总体积范围在10μL-10mL之间，优选体积为25μL-2mL。所装载的药物，可以是小分子、多肽、蛋白质、生物制剂中的任何一种，也可以是上述任意一种以上药物的复方组合。其中，滴剂为液体，喷雾剂可以为液体也可以为固体粉末。上述药物可以为天然药物、传统中药，也可以为任何经过加工的制剂。当药物为液体剂型时，该剂型中所含有的吸收促进剂的比例为0％-30％(质量比)，该吸收促进剂为离子型或非离子型表面活性剂、胆酸钠类、环糊精类、脂肪酸类、磷脂类、环形肽类中的一种多一种以上的组合。上述药物适应症包括任何与中枢神经系统相关的疾病。
更为具体而言，本发明各种实施方式所述的装置可以用于装载各种剂型的胰岛素及其衍生物，其中包括各种动物来源的或者利用基因重组技术获得的人胰岛素瞬间释放剂型、快速释放剂型、持续缓释剂型、长效释放剂型、精蛋白锌胰岛素或上述2种或2种以上剂型的复方，用以治疗、改善阿尔茨海默病(AD)的临床症状。
如上所述，所述装置可以是一次性的无菌给药装置，也可以是通过加药能够反复使用的装置。
采用本发明各种实施方式所述的脑靶向的经鼻腔给药装置及其体位固定器进行给药包括但不限于下列步骤：
(1)给药对象需采取平躺或其他合适体位，以便于抬头使下颌朝上(如图14，图15所示)，保持在人体头部垂直轴与水平面的夹角在0°至90°之间，优选40°至80°之间，目的在于能够让鼻孔朝向上方或者斜上方，从而有助于给药，并使药物进入上鼻腔，如图17所示。
(2)将所述给药装置插入任意一个鼻孔，将该装置内固定体积的药物注 入，维持上述体位至少1分钟，使药物向上鼻腔方向流动，如图17所示。
(3)移除所述给药装置，暂时堵住对侧非给药鼻孔，仍然维持上述体位，用鼻子深吸气，以利于药物进入上鼻腔。
(4)维持上述体位，对另一侧鼻孔，重复步骤(2)和步骤(3)。
(5)再次轮流按住两侧鼻孔，分别用鼻子深吸气一次。
(6)维持上述体位至少1分钟，深吸气30次以上。
需要说明的是，上述的步骤(1)到(6)的顺序、头与身体角度、维持时间以及吸气次数等可以有所变化，换句话说，本领域技术人员在不脱离本发明的宗旨的条件下，可以基于有利于将所述给药装置注射的药物引入上鼻腔的原则进行各种变化，从而直接通过嗅区进入脑部。
通过采取步骤(1)所述的下颌朝上的姿势，使得上鼻腔位于整个鼻腔的最下端，利用重力作用将药物引流蓄积于嗅区。多次通过鼻子用力吸气，是为了确保药物最大限度的进入上鼻腔，而非进入呼吸道或消化道，导致外周吸收引起的副作用。期间多次要求维持体位至少1分钟是为了使药物有充足的时间与嗅区嗅神经接触，从而直接进入中枢神经系统，发挥药效。这种给药方式操作简便，由使用者在家便能独立完成，而对于行动不便的使用者，只需一个家属或护理人员的协助，亦能轻松准确的完成给药。
根据上文的描述可知，本发明技术方案可以用于改善阿尔茨海默病早期认知障碍。通过上述的经鼻腔给药装置，采用所述体位和给药步骤，使胰岛素或其衍生物为主要活性成分的各种药物制剂直接通过鼻腔进入脑部，起到治疗作用。并且，可以根据病情，每天一次、或两次，连续数天、数月乃至数年。通过他方周期性的初步精神认知能力测试来记录和评价，使用者的认知功能得到较好的改善。此外，本发明技术方案还可以用于治疗脑部肿瘤、多发性硬化症、帕金森病、癫痫症、艾滋病、结核病、脑部病毒性或细菌性感染、垂体-下丘脑激素缺乏或失调引起的疾病，以及用于缓解中枢神经系统有关的症状。
综上所述，通过采用本发明实施方式提供的脑靶向的经鼻腔给药装置克服了现有技术的以下缺陷：目前许多中枢神经系统的疾病需要依赖脑靶向的治疗，但由于操作上的专业难度，以及潜在的经呼吸道或/和消化道等外周吸收副作用，使得经鼻给药脑靶向技术应用一直未得到充分推广。本发明实施 方式提供的脑靶向的经鼻腔给药装置的应用，将有助于使非常复杂、高端的脑靶向鼻腔给药技术大众化和个体化，使得更多的使用者能够有在技术上、经济上有能力承担经鼻给药脑靶向的治疗手段。尽管胰岛素经鼻给药有潜在改善、治疗阿尔茨海默病症已有研究报道，与众不同的是，本发明旨在提供上述给药装置用于改善该病的早期认知功能障碍的作用，如果辅以通过定期记录和评价初步精神认知能力测试，并结合必要的本发明涉及的胰岛素血/脑脊液药物浓度检测，将有助于评价和确定治疗效果，造福众多的阿尔茨海默病患者。
本发明说明书中使用的术语和措辞仅仅为了举例说明，并不意味构成限定。本领域技术人员应当理解，在不脱离所公开的实施方式的基本原理的前提下，对上述实施方式中的各细节可进行各种变化。因此，本发明的范围只由权利要求确定，在权利要求中，除非另有说明，所有的术语应按最宽泛合理的意思进行理解。

Claims (29)

  1. 一种用于脑靶向的经鼻腔给药的体位固定器，其特征在于，该体位固定器包括：
    头承载部，用于承载使用者的头部并将头部保持成使经鼻腔给药的药物能够进入上鼻腔的嗅区。
  2. 如权利要求1所述的体位固定器，其特征在于，所述头承载部包括：
    头枕，用于承载使用者的头部；
    支撑架，用于支撑所述头枕；
    中轴杆，将所述头枕可旋转地支撑在所述支撑架上。
  3. 如权利要求2所述的体位固定器，其特征在于，所述头枕包括：
    内部支架，支撑在所述中轴杆上；
    枕垫，覆盖于所述内部支架上。
  4. 如权利要求3所述的体位固定器，其特征在于，所述头枕分为第一部分和第二部分；
    其中，第一部分设置成由所述内部支架的一部分成50°至70°的角度支撑；和/或
    所述第二部分设置成由所述内部支架的另一部分成20°至40°的角度支撑。
  5. 如权利要求2所述的体位固定器，其特征在于，所述头枕包括：
    双面枕垫，包括用于仰卧位给药的第一面和用于侧卧位给药的第二面。
  6. 如权利要求5所述的体位固定器，其特征在于，所述第一面包括颈部承载面和头部承载面，所述头部承载面和颈部承载面的形状设计成分别贴合仰卧时人体头颈部曲线。
  7. 如权利要求5所述的体位固定器，其特征在于，所述第二面包括颈部承载面和头部承载面，所述头部承载面和颈部承载面的形状设计成分别贴合侧卧时人体头颈部曲线。
  8. 如权利要求3至7任意一项所述的体位固定器，其特征在于，
    所述枕垫为便携、可充气枕垫或者其他填充物的枕垫。
  9. 如权利要求2所述的体位固定器，其特征在于，
    所述支撑架大体为H形、A形、L形、倒Y形、M形或其他可操作的形状。
  10. 如权利要求3所述的体位固定器，其特征在于，
    所述中轴杆横向贯穿于所述头枕的第一部分和第二部分衔接面的中央。
  11. 如权利要求5所述体位固定器，其特征在于，
    所述中轴杆横向贯穿于所述双面枕垫的颈部承载面的端部。
  12. 如权利要求2所述的体位固定器，其特征在于，所述头承载部还包括：
    高度调整机构，用于调整所述中轴杆及其所连接的头枕在所述支撑架上的高度以调整所述头枕的高度。
  13. 如权利要求2所述的体位固定器，其特征在于，所述体位固定器还包括：
    第一机械臂，与所述头承载部操作性地接合，用于调整所述头枕的角度。
  14. 如权利要求2所述的体位固定器，其特征在于，所述体位固定器还包括：
    电机，与所述头承载部操作性地接合，用于在计算机、智能手机、遥控器或可佩戴智能设备的控制下调整所述头枕的角度。
  15. 如权利要求2所述的体位固定器，其特征在于，所述体位固定器还包 括：
    刻度指示器，该刻度指示器通过激光光束精确检测使用者的鼻、颈间的仰角来指示使用者鼻子需要调整能够进行经鼻脑靶向给药的给药角度。
  16. 如权利要求2所述的体位固定器，其特征在于，所述体位固定器还包括：
    音频播放器，用于播放指导使用者调节体位的音频文件；和/或
    视频播放器，用于播放指导使用者调节体位的视频文件。
  17. 如权利要求2所述的体位固定器，其特征在于，所述体位固定器还包括：
    支撑所述头承载部和使用者身体的平台。
  18. 如权利要求17所述的体位固定器，其特征在于，所述平台包括：垫子、床、椅子、桌子、柜台、地板、及其他类似支撑平面。
  19. 如权利要求17所述的体位固定器，其特征在于，所述平台的用以承载使用者身体的承载面可进行角度调节，以配合所述头枕的角度，使使用者保持在能够进行经鼻脑靶向给药的体位。
  20. 如权利要求1至19任意一项所述的体位固定器，其特征在于，所述体位固定器用于中枢神经系统疾病的给药治疗，包括脑退化症、老人失智症、阿尔茨海默病、脑部肿瘤、多发性硬化症、帕金森病、癫痫症、艾滋病、结核病、脑部病毒性、细菌性、寄生虫或其它微生物感染、垂体-下丘脑激素缺乏或失调引起的疾病，以及用于辅助神经性毒气的解毒治疗。
  21. 一种脑靶向的经鼻腔给药装置，其特征在于，包括：
    如权利要求1至20任意一项所述的体位固定器，用于将使用者的体位保持成使经鼻腔给药的药物能够进入上鼻腔的嗅区；和
    给药器，其给药端具有与使用者的鼻腔配合的形状，用于在所述体位固 定器将使用者保持成上述体位的情形下经鼻腔向使用者给药以使药物定向进入脑部。
  22. 如权利要求21所述的装置，其特征在于，所述装置还包括：
    第二机械臂，其一端与所述给药器连接，并且所述第二机械臂配置成能够调节以便将所述给药器支撑在合适的位置。
  23. 如权利要求22所述的装置，其特征在于，所述第二机械臂的另一端与所述体位固定器连接。
  24. 如权利要求22或23所述的装置，其特征在于，所述装置还包括：
    智能控制元件，用于通过控制所述给药器和第二机械臂的动作来调节给药的时间、速度和剂量。
  25. 如权利要求24所述的装置、其特征在于，所述智能控制元件具有如下功能：接收、处理、整合外界输入的信息，根据所输入的信息自动控制、调节给药器的给药时间、速度和剂量，
    其中，所述输入的信息包括使用者的生理指标、生化指标、认知功能评分。
  26. 如权利要求21所述的装置，其特征在于，所述给药器包括药物容器。
  27. 如权利要求26所述的装置，其特征在于，所述药物容器为生物相容性好的、无菌的、和/或一次性使用的容器。
  28. 如权利要求26或27所述的装置，其特征在于，所述药物容器为固定体积容器，或者为具有可定量推动或挤压装置的注射器。
  29. 如权利要求21至28所述的装置，其特征在于，所述装置用于中枢神经系统疾病的给药治疗，包括脑退化症、老人失智症、阿尔茨海默病、脑部 肿瘤、多发性硬化症、帕金森病、癫痫症、艾滋病、结核病、脑部病毒性、细菌性、寄生虫或其它微生物感染、垂体-下丘脑激素缺乏或失调引起的疾病，以及用于辅助神经性毒气的解毒治疗。
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