WO2017017543A1 - Système d'administration de médicament et procédé d'administration contrôlée et continue de médicaments dans le cerveau en contournant la barrière hémato-encéphalique - Google Patents

Système d'administration de médicament et procédé d'administration contrôlée et continue de médicaments dans le cerveau en contournant la barrière hémato-encéphalique Download PDF

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Publication number
WO2017017543A1
WO2017017543A1 PCT/IB2016/053899 IB2016053899W WO2017017543A1 WO 2017017543 A1 WO2017017543 A1 WO 2017017543A1 IB 2016053899 W IB2016053899 W IB 2016053899W WO 2017017543 A1 WO2017017543 A1 WO 2017017543A1
Authority
WO
WIPO (PCT)
Prior art keywords
implant
drug
external
inlet
drug delivery
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2016/053899
Other languages
English (en)
Inventor
Anoop U.R
Kavita VERMA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/177,347 external-priority patent/US11207461B2/en
Application filed by Individual filed Critical Individual
Priority to EP16741684.1A priority Critical patent/EP3359221B1/fr
Priority to EP25182157.5A priority patent/EP4606401A3/fr
Priority to AU2016300184A priority patent/AU2016300184C1/en
Priority to CA2994251A priority patent/CA2994251A1/fr
Priority claimed from IN3904CH2015 external-priority patent/IN2015CH03904A/en
Publication of WO2017017543A1 publication Critical patent/WO2017017543A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14276—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body specially adapted for implantation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0687—Skull, cranium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0693—Brain, cerebrum

Definitions

  • the drugs also have to withstand mucociliary clearance, local enzymatic degradation and cross the epithelial layer before they reach the underlying connective tissue for further absorption. Hence only a smaller quantity of the total drug that is delivered, is finally absorbed.
  • Drugs modified for endogenous transport mediated delivery across the blood brain barrier, using the naturally occurring molecular transport mechanisms at the endothelial cell have been developed for a few medical conditions. Yet the concentration of the drug delivered across the blood brain barrier using this technique is not predictable. Protein mediated drug delivery and viral mediated gene therapy may also induce immune mediated complications. Systemic routes like intra venous or intra-arterial need high concentration of the drug. Moreover intra-arterial route results in severe complications. Therefore an effective alternative route which can deliver drugs into the brain in a controlled and continuous manner, for a long period of time, without any complications or discomfort to the patient holds immense potential.
  • [0012]It therefore would be desirable to deliver drugs into the brain using a device without any need for surgical manipulation of the brain. It would further be desirable to provide a device which can be surgically implanted with its delivery tip located beneath or above the respiratory mucosa, by surgically creating a window on the bone overlying the respiratory mucosa and accessing the connective tissue side of the respiratory mucosal lining from the oral or maxillofacial region. It would also be desirable to deliver the drug in a controlled and continuous manner by connecting the device to an external drug infusion pump. The drug from the respiratory mucosa can be transported through the neural, vascular, lymphatic, inhalation or a combination of all these routes and delivered into the brain by bypassing the blood brain barrier and without causing any systemic toxicity.
  • the drug can also be transported through the ostial opening into the middle meatus and onto the nasal respiratory mucosa by muco-ciliary action. This results in increased retention time of the drug on the mucosal surface and so higher quantity of the drug can be absorbed into the connective tissue vasculature at the respiratory mucosa and the olfactory mucosa.
  • Another aspect of the invention provides drug molecules that are engineered for uptake into the goblet cells of the maxillary sinus lining epithelium, from the underlying connective tissue for further secretion by the goblet cells along with mucus. This can result in mucus loaded with high concentration of drug molecule for inhalation, which can be deposited on the nasal respiratory mucosa and the olfactory mucosa for further absorption.
  • Fig.2 shows the isometric side view, longitudinal sectional view and three dimensional view of a multi-unit device comprising an implant with a central tubular inlet with external threads, a drug delivery assembly and a retention cap
  • Fig 12 shows the implant with the porous apical tip located above the level of the respiratory mucosa.
  • Fig 15 shows the brain values of dopamine in a rabbit obtained using High performance Liquid Chromatography, after in vivo drug delivery of dopamine from beneath the respiratory mucosa.
  • Fig 16 shows the blood values of dopamine in a rabbit obtained using High performance Liquid Chromatography, after in vivo drug delivery of dopamine from beneath the respiratory mucosa.
  • distal part refers to the part which is away from the point of reference or the part that is farther away from the median plane of the device.
  • cervical third refers to the upper third part of the lower part of the body of the device that extends from below the level of the ring, or to the upper third part of the body of the device in the form of a dental implant, wherein the body is divided horizontally by imaginary lines into three equal parts
  • middle third refers to the middle third part of the lower part of the body of the device that extends from below the level of the ring, or to the middle third part of the body of the device in the form of a dental implant, wherein the body is divided horizontally by imaginary lines into three equal parts
  • apical wall may be used to refer to the wall comprising the rounded apical end and part of the apical third of the lower part of the device.
  • external drug delivery tubing or “external tubing” may be used interchangeably to refer to the lateral tube extending from the side of the vertical part intended for placement in the slot of an inlet.
  • intra-pulpal part refers to the part that is within the pulp cavity of the tooth.
  • osteointegration refers to the process of bone formation around the implant and on the surface of the implant facing the bone.
  • internal involute spline refers to an involute spline whose tip surface is located on the internal surface of the body of the embodiment.
  • the central lumen further opens to the external surface at the coronal part through an inlet and at the apical end through a plurality of holes at the apical wall of the implant body.
  • This porous apical end is placed in close proximity to the respiratory mucosa.
  • the coronal end of the implant has an external hex for holding and placement of the implant.
  • a drug delivery inlet is present below the level of the external hex on the side of the upper part of the body of the implant for the attachment of a drug delivery tubing.
  • the inlet may be in the form of an opening with or without internal threads or in the form of a tubular projection.
  • the tubular inlet may have a smooth external surface or have external or internal threads.
  • FIG. 1 Fig: A refers to the isometric side view of the single unit device.
  • the end two of the tubing is free and has a nozzle at the free end .
  • 106 refers to the nozzle at the free end of the drug delivery tubing which may be placed in the buccal sulcus overlying the mucosa, in the buccal gingival sulcus or in the palatal gingival sulcus.
  • the nozzle at the free end of the tubing can be closed with a temporary cap.
  • 107 refers to the external hex on the head part of the implant which is intended to fit into a placement tool and thereby assist in holding and placement of the implant into the surgical site.
  • Fig: B refers to the longitudinal sectional view of the implant.
  • 101 refers to the smooth and rounded apical end of the implant with a plurality of holes.
  • Fig: C refers to the 3D rendered view of Fig: A.
  • Fig.2 The alternative embodiment is a multiunit device comprising an inlet located centrally at the coronal end of the implant body. The inlet further comprises external threads at its cervical third and a vertical slot extending from its tip to its middle third.
  • the drug delivery assembly comprises an intra implant part and an external drug delivery tubing.
  • 205 Refers to the outer threads on the tubular inlet.
  • 206 Refers to the intra implant part of the drug delivery assembly.
  • 207 Refers to the external tubing of the drug delivery assembly.
  • 208 Refers to the nozzle at the free end of the drug delivery tubing 209.
  • 210 refers to the plurality of holes at the apex of the intra implant part of the drug delivery assembly.
  • Fig: B is a longitudinal sectional view of the lower part of the implant body and the components comprised within. 201. Refers to the porous apical end. 202. Refers to the external threads 203. Refers to the barrier ring. 204.
  • FIG. 3 Another preferred embodiment is illustrated in Fig: 3.
  • the alternative embodiment is a multiunit implant assembly comprising a completely open apex with beveled and outwardly flaring internal walls and smooth and rounded margins and an inlet located centrally at the coronal end of the implant body.
  • the inlet further comprises external threads at its cervical third and a vertical slot extending from its tip to its middle third.
  • the drug delivery assembly comprises an intra implant part and an external drug delivery tubing.
  • the intra implant part is tapering in shape and comprises a central lumen within the body and a plurality of holes through the wall at the apical end.
  • the drug delivery tubing is tubular in shape comprising a central lumen and is attached to the side of the intra-implant part.
  • Fig: B is a longitudinal sectional view of the lower part of the implant body and the components comprised within. 301. Refers to the completely open apex with smooth and rounded margins. 302. Refers to the external threads 303. Refers to the barrier ring. 304. Refers to the external hex. 306. Refers to the intra implant part of the drug delivery assembly with a central lumen and porous tip which is placed short of the apical margin. 307. Refers to the external tubing of the drug delivery assembly.
  • the apical end is rounded with a plurality of holes through the apical wall and the upper end comprises a drug delivery inlet with internal threads.
  • the external surface of the upper part of the body further comprises an external hex below the drug delivery inlet and a barrier ring below the external hex.
  • a central lumen is present within the body comprising tapering walls defined by the internal wall of the body of the device. The central lumen communicates with the exterior through an inlet at the upper end and the plurality of holes in the wall at the apical end. Threads are present on the external surface of the lower part of the body at the cervical third, below the level of the ring.
  • An inlet is located at the upper end of the device, comprising internal threads at its cervical third.
  • An external hex is located below the inlet at the upper part of the device.
  • a circular ring is located below the level of the tubular inlet and comprises a convex and smooth upper surface and a flat and smooth undersurface facing the bone.
  • the drug delivery assembly comprises a tapered intra-implant part with external threads at its upper part and an external drug delivery tubing attached to the upper end of the intra-implant part.
  • the intra- implant part is threaded into the inlet wherein the external walls of the intra implant part fit tightly to the internal walls of the implant except at the apical third.
  • a space is present at the apical third between the internal wall of the implant and the external wall of the intra-implant part, wherein the drug is initially delivered.
  • 5X refers to the external hex on the implant
  • Fig: A Refers to the spanner for placement and removal. 501.
  • Fig: B Refers to an angulated spanner. 503.
  • Fig: C refers to the hand held ratchet. 505.
  • Fig: D refers to an angulated hand held ratchet. 507.
  • the device is in the form of a hollow dental implant made of titanium alloy or any other biocompatible material with external threads.
  • the implant has micro holes at the apical part of the implant body. The holes connect the central lumen defined by the internal surface of the implant with the nasal respiratory mucosa or the maxillary sinus lining mucosa.
  • the implant has an internal involute spline within the implant body.
  • the implant has internal threads at the cervical end.
  • the disposable abutment made of a bio-compatible material has a body comprising an intra-oral part and an intra-implant part with a barrier ring on the external surface between the two parts.
  • the solvent moves across the semipermeable membrane into the osmotic compartment and causes it to expand, thereby pushing the drug out from the reservoir at a predetermined rate through the apical holes.
  • 701 refers to the inlet on the coronal tip of the abutment intended for delivering the osmotic solvent.
  • 702 refers to the intra-oral part of the abutment that holds the osmotic solvent.
  • 703 refers to the barrier ring.
  • 705 refers to the apical holes.
  • 707 refers to the semipermeable membrane separating the middle part and the upper part of the abutment.708 refers to the osmotic compartment.709 refers to the drug reservoir.
  • 802 refers to the bone compression tool being used for enlarging the soft osteotomy site and for breaking the apical wall to access the respiratory mucosa.803 refers to the osteotomy site in the maxillary region underlying the respiratory mucosa.804 refers the porous apical end of the implant.
  • 805 refers to the body of the implant being placed into the osteotomy site.
  • 806 refers to the placement tool used for placing the implant into the osteotomy.
  • 807 refers to the ratchet for holding the placement tool.
  • 808 shows the abutment placed into the implant.
  • 809 shows the cervical retention cap comprising a central hole being placed across the intra oral part of the abutment.
  • An alternative embodiment comprises a mini plate with a central reservoir dial wherein the reservoir has a porous base with angulated walls and a cap made of a resilient, biocompatible material that self-seals whenever penetrated by a needle.
  • the upper end of the cap has an external hex and the lower part of the cap has internal or external threads. The angulation helps in ease of placing the needle tip into the reservoir for drug delivery from the oral cavity, when the mini plate is located on concave surfaces like the anterior wall of the maxillary sinus.
  • the alternative embodiment is herein illustrated in Figure 10.
  • 1006 refers to the retention screw .
  • Fig B shows the top view of a mini plate with a central drug reservoir dial, comprising a hollow body with an upper angulated part and a lower straight part with straight limbs between the two parts of the dial.
  • 1001 refers to the straight limb with screw holes.
  • 1002 refers to the central drug reservoir dial with angulated walls comprising internal or external threads at the upper part.
  • 1003 refers to the cap that is threaded onto the threads.
  • 1006 refers to the retention screw.
  • Fig C and D show the top view of a mini plate with a central angulated drug reservoir dial comprising a straight limb and an L shaped limb.
  • 1001 refers to the straight limb with screw holes.
  • Fig A shows the device placed at the anterior wall of the maxillary sinus. 1301 refers to the barrier ring. 1302 refers to the external hex. 1303 refers to the drug delivery tubing.
  • Fig B shows the device connected to an external drug reservoir attached to a drug infusion pump. 1304 refers to the external drug infusion pump comprising a drug reservoir that is attached to the free end of the drug delivery tubing of the device.
  • the drug can be directly delivered beneath the respiratory mucosa on the connective tissue side using the drug delivery assembly which is connected to an external drug reservoir attached to a drug infusion pump.
  • a biocompatible cement can be applied to the undersurface of the barrier ring of the implant to fix the barrier ring to the underlying bone. This retains the implant in position and prevents movement during immediate drug delivery.
  • a root canal treated tooth whose apex is in contact with the respiratory mucosa is used as a natural drug delivery device.
  • the coronal part of the tooth is prepared for the crown.
  • An additional vertical slot is prepared on the tooth extending from the occlusal surface to the middle part of buccal or palatal wall.
  • a crown is made using a biocompatible material.
  • Fig: 16 refers to blood values of dopamine in the rabbit after in vivo delivery of dopamine under the maxillary sinus mucosa using the device. This shows that dopamine delivered using the device had reached the brain by bypassing the blood brain barrier and may have effected a low dopamine peripheral response by a feedback mechanism in the brain during drug delivery. The peripheral value would have increased after the central negative feedback control had ceased once the drug delivery was stopped. Moreover there was no increase of the drug in peripheral circulation during drug delivery.
  • Fig: 17 refers to the blood values of Lignocaine in the rabbit after the in vivo delivery of Lignocaine into the maxillary sinus cavity and onto the epithelial surface of the maxillary sinus mucosa using the device

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  • Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

La présente invention concerne des dispositifs et des procédés pour l'administration continue et contrôlée de médicaments dans le cerveau en contournant la barrière hémato-encéphalique, sans qu'aucune manipulation chirurgicale du cerveau ne soit nécessaire. La muqueuse respiratoire dans le sinus maxillaire ou dans la région nasale est atteinte par chirurgie à partir de la région buccale ou maxillo-faciale à travers une fenêtre réalisée sur l'os situé au-dessus de la muqueuse. Le dispositif est utilisé pour administrer des médicaments de manière continue et contrôlée soit au-dessous soit au-dessus de la muqueuse respiratoire en fonction des exigences cliniques, de la formulation de médicament et du volume de médicament utilisé. Le médicament se répand dans le cerveau à partir du site d'administration en contournant la barrière hémato-encéphalique sans provoquer d'augmentation significative du médicament dans la circulation périphérique. Le dispositif peut être utilisé pour l'administration continue et contrôlée de médicament dans le cerveau en contournant la barrière hémato-encéphalique pour un certain nombre d'affections médicales.
PCT/IB2016/053899 2015-07-30 2016-06-29 Système d'administration de médicament et procédé d'administration contrôlée et continue de médicaments dans le cerveau en contournant la barrière hémato-encéphalique Ceased WO2017017543A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP16741684.1A EP3359221B1 (fr) 2015-07-30 2016-06-29 Système d'administration de médicament et procédé d'administration contrôlée et continue de médicaments dans le cerveau en contournant la barrière hémato-encéphalique
EP25182157.5A EP4606401A3 (fr) 2015-07-30 2016-06-29 Système d'administration de médicament et procédé d'administration contrôlée et continue de médicaments dans le cerveau en contournant la barrière hémato-encéphalique
AU2016300184A AU2016300184C1 (en) 2015-07-30 2016-06-29 Drug delivery system and method for controlled and continuous delivery of drugs into the brain by bypassing the blood brain barrier
CA2994251A CA2994251A1 (fr) 2015-07-30 2016-06-29 Systeme d'administration de medicament et procede d'administration controlee et continue de medicaments dans le cerveau en contournant la barriere hemato-encephalique

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN3904/CHE/2015 2015-07-30
IN201641014398 2016-04-26
IN201641014398 2016-04-26
US15/177,347 2016-06-09
US15/177,347 US11207461B2 (en) 2015-07-30 2016-06-09 Drug delivery system and method for controlled and continuous delivery of drugs into the brain by bypassing the blood brain barrier
IN3904CH2015 IN2015CH03904A (fr) 2015-07-30 2016-06-29

Publications (1)

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WO2017017543A1 true WO2017017543A1 (fr) 2017-02-02

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PCT/IB2016/053899 Ceased WO2017017543A1 (fr) 2015-07-30 2016-06-29 Système d'administration de médicament et procédé d'administration contrôlée et continue de médicaments dans le cerveau en contournant la barrière hémato-encéphalique

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022212288A1 (fr) * 2021-03-29 2022-10-06 Massachusetts Eye And Ear Infirmary Appareils, systèmes, et méthodes d'administration sous-muqueuse de médicament implantable

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000033814A2 (fr) * 1998-12-09 2000-06-15 Chiron Corporation Technique d'apport d'agents au systeme nerveux central
US20020183683A1 (en) * 1996-11-19 2002-12-05 Intrabrain International Nv Methods and apparatus for enhanced and controlled delivery of a biologically active agent into the central nervous system of a mammal
US20070255237A1 (en) * 2006-05-01 2007-11-01 Neurosystec Corporation Apparatus and method for delivery of therapeutic and other types of agents
WO2011098768A1 (fr) * 2010-02-12 2011-08-18 Renishaw (Ireland) Limited Répartiteur de fluide implantable

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020183683A1 (en) * 1996-11-19 2002-12-05 Intrabrain International Nv Methods and apparatus for enhanced and controlled delivery of a biologically active agent into the central nervous system of a mammal
WO2000033814A2 (fr) * 1998-12-09 2000-06-15 Chiron Corporation Technique d'apport d'agents au systeme nerveux central
US20070255237A1 (en) * 2006-05-01 2007-11-01 Neurosystec Corporation Apparatus and method for delivery of therapeutic and other types of agents
WO2011098768A1 (fr) * 2010-02-12 2011-08-18 Renishaw (Ireland) Limited Répartiteur de fluide implantable

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022212288A1 (fr) * 2021-03-29 2022-10-06 Massachusetts Eye And Ear Infirmary Appareils, systèmes, et méthodes d'administration sous-muqueuse de médicament implantable

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