WO2024050072A2

WO2024050072A2 - Retainers for intraoral drug delivery devices and methods of use thereof

Info

Publication number: WO2024050072A2
Application number: PCT/US2023/031825
Authority: WO
Inventors: Ephraim Heller; John Spiridigliozzi
Original assignee: Synagile Corporation
Priority date: 2022-09-01
Filing date: 2023-09-01
Publication date: 2024-03-07
Also published as: WO2024050072A3

Abstract

Retainers for attaching an intraoral drug delivery device to a surface of the mouth for continuous extrusion of a drug-containing fluid into the mouth are disclosed. Also disclosed are methods of extruding a drug into the mouth from a retainer-mounted drug delivery device and methods of treating a disease by such extrusion.

Description

RETAINERS FOR INTRAORAL DRUG DELIVERY DEVICES AND METHODS OF USE THEREOF

Field of the Invention

The invention features retainers for anchoring a drug delivery device in the mouth for continuously administering a pharmaceutical composition to a patient.

Background of the Invention

Continuous or semi-continuous drug administration via the oral (e.g., swallowed, buccal, or sublingual) route could provide several advantages for drugs that would otherwise have to be taken several times throughout the day (e.g., as a tablet), such as drugs with short physiological half-lives (e.g., shorter than 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 min, 20 min or 10 min), poor absorption, and/or narrow therapeutic windows. These advantages include convenience, improved pharmacokinetics (e.g., reduced fluctuation in drug concentration in an organ or body fluid) and efficacy, reduced side effects, and increased patient compliance. Continuous or semi-continuous administration can be particularly beneficial for drugs with a short half-life (e.g., in the plasma), and/or short persistence of the drug’s physiological effect, and/or a narrow therapeutic window, such as levodopa (LD), muscle relaxants (e.g., baclofen for managing spasticity), anti-epileptics (e.g., oxcarbazepine, topiramate, lamotrigine, gabapentin, carbamazepine, valproic acid, levetiracetam, pregabalin), parasympathomimetics (e.g., pyridostigmine), and sleep medications (e.g., zaleplon). Medical conditions that can be managed by continuously orally administered drugs include Parkinson’s disease, spasticity, muscular weakness, bacterial infections, viral infections, fungal infections, parasite caused diseases, cancer, pain, organ transplantation, disordered sleep, epilepsy and seizures, anxiety, mood disorders, post-traumatic stress disorder, arrhythmia, hypertension, heart failure, dementia, allergies, and diabetic nephropathy.

Despite the potential benefits of continuous or semi-continuous intraoral administration, it remains challenging to configure an intraoral drug delivery system that works for all possible patients. Dental anatomy varies from person to person, yet it is not feasible to re-design the drug delivery device for each patient. For example, it is particularly difficult to configure intraoral drug delivery systems for patients with upper and lower third molars, as the presence of third molars puts additional constraints on space in the mouth and presents obstacles when trying to adapt a drug delivery system tested in patients without third molars for use in patients with third molars. Accordingly, there is a need for an oral apparatus that can make a drug delivery device suitable for most patients, and particularly for patients with upper and lower third molars.

Summary of the Invention

The present invention features a retainer for securing on the buccal side of the upper or lower teeth a drug delivery device for continuously administering a pharmaceutical composition to the oral cavity in the mouth of a patient, such as a patient having upper and lower third molars. Also featured are methods of using a retainer-mounted drug delivery device to administer a drug to a patient, such as for treatment of a disease.

In a first aspect, the invention provides a retainer configured to removably secure a drug delivery device including a delivery tube to a buccal side of one or more teeth of a patient, in which the retainer: (i) is configured to cover an occlusal surface of at least a first tooth (e.g., a molar) and to leave at least a portion of an occlusal surface of a second tooth (e.g., a second tooth in the same area of the mouth as the first tooth, for example, the first tooth and second tooth can be two different molars in the same quadrant of the mouth) uncovered; and (ii) contains a pocket for securing the drug delivery device to the buccal side of the one or more teeth of the patient, in which said pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into a mouth of the patient the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than an external diameter of the delivery tube or (b) wherein the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than 50% (e.g., equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In some embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than 75% (e.g., equal to or greater than 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In particular embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than an external diameter of the delivery tube. In some embodiments, the retainer is configured such that the occlusal surface covered by the retainer is positioned in front of (i.e., anterior to or on the mesial side of) the delivery tube and the occlusal surface that is left uncovered extends from said delivery tube (e.g., from just anterior to the delivery tube or from the anterior side of said delivery tube) to a rear (i.e., a distal side) of said patient’s rearmost tooth (i.e., the most distal tooth or back tooth) in a quadrant of the mouth containing the delivery tube when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient (e.g., all of the occlusal surfaces starting from the location of the delivery tube and extending distally to the distal side of the rearmost tooth are uncovered, see, e.g., FIG. 4A for an example of a retainer having this configuration). In some embodiments, the retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer (e.g., the drug delivery device is pushed into the pocket from behind, such that the drug delivery device moves toward an anterior portion of the retainer as it is inserted into the pocket). In some embodiments, the retainer contains a recess that is configured to leave the portion of the occlusal surface of the second tooth uncovered that has a depth and width equal to or greater than the external diameter of the delivery tube (i.e., the portion of the second tooth that is uncovered is uncovered due to the recess). In some embodiments, the pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to or toward the lingual side of the tooth.

In another aspect, the invention provides a retainer configured to removably secure a drug delivery device including a delivery tube to a buccal side of one or more teeth of a patient, in which the retainer: (i) is configured to cover an occlusal surface of at least a first tooth and contains a recess configured to leave at least a portion of an occlusal surface of a second tooth uncovered (e.g., a second tooth in the same area of the mouth as the first tooth, for example, the first tooth and second tooth can be two different molars in the same quadrant of the mouth); and (ii) includes a pocket for securing the drug delivery device to the buccal side of one or more teeth of the patient, in which said pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into a mouth of a patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the recess has a depth and width equal to or greater than an external diameter of the delivery tube or (b) wherein the recess has a depth and width equal to or greater than 50% (e.g., equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In some embodiments, the recess has a depth and width equal to or greater than 75% (e.g., equal to or greater than 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In particular embodiments, the recess has a depth and width equal to or greater than an external diameter of the delivery tube. In some embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than the external diameter of the delivery tube.

In another aspect, the invention provides a system including a retainer and a drug delivery device configured to be removably secured to one or more teeth of a patient, in which: (i) said retainer is configured to cover an occlusal surface of at least a first tooth of the patient and to leave at least a portion of an occlusal surface of a second tooth of the patient uncovered (e.g., a second tooth in the same area of the mouth as the first tooth, for example, the first tooth and second tooth can be two different molars in the same quadrant of the mouth), in which said retainer includes a pocket on a buccal side of the retainer that is configured to secure the drug delivery device to a buccal side of the one or more teeth of said patient when the retainer is worn; and (ii) said drug delivery device is suitable for insertion into the retainer pocket and includes a delivery tube, in which the delivery tube is configured such that when the drug delivery device is inserted into the retainer pocket and the retainer is inserted into a mouth of the patient, the delivery tube extends across the portion of the occlusal surface of the second tooth that is left uncovered by the retainer from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than an external diameter of the delivery tube or (b) wherein the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than 50% (e.g., equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In some embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than 75% (e.g., equal to or greater than 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In particular embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than an external diameter of the delivery tube. In some embodiments, the retainer is configured such that the occlusal surface covered by the retainer is positioned in front of (i.e., anterior to or on the mesial side of) the delivery tube and the occlusal surface that is left uncovered extends from said delivery tube (e.g., from just anterior to the delivery tube or from the anterior side of said delivery tube) to a rear (i.e., a distal side) of said patient’s rearmost tooth (i.e., the most distal tooth or back tooth) in a quadrant of the mouth containing the delivery tube when the drug delivery device is inserted into the retainer pocket and the retainer is inserted into the mouth of the patient (e.g., all of the occlusal surfaces starting from the location of the delivery tube and extending distally to the distal side of the rearmost tooth are uncovered). In some embodiments, the retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer (e.g., the drug delivery device is pushed into the pocket from behind, such that the drug delivery device moves toward an anterior portion of the retainer as it is inserted into the pocket). In some embodiments, the retainer contains a recess that is configured to leave the portion of the occlusal surface of the second tooth uncovered that has a depth and width equal to or greater than the external diameter of the delivery tube (i.e. , the portion of the second tooth that is uncovered is uncovered due to the recess). In some embodiments, the pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to or toward the lingual side of the tooth.

In another aspect, the invention provides a system including a retainer and a drug delivery device configured to be removably secured to one or more teeth of a patient, in which: (i) said retainer is configured to cover an occlusal surface of at least a first tooth of the patient and contains a recess configured to leave at least a portion of an occlusal surface of a second tooth of the patient uncovered (e.g., a second tooth in the same area of the mouth as the first tooth, for example, the first tooth and second tooth can be two different molars in the same quadrant of the mouth), in which said retainer contains a pocket on a buccal side of the retainer that is configured to secure the drug delivery device to a buccal side of the one or more teeth of said patient when the retainer is worn; and (ii) said drug delivery device is suitable for insertion into the retainer pocket and includes a delivery tube, in which the delivery tube is configured such that when the drug delivery device is inserted into the retainer pocket and the retainer is inserted into a mouth of the patient, the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is left uncovered from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the recess has a depth and width equal to or greater than an external diameter of the delivery tube or (b) the recess has a depth and width equal to or greater than 50% (e.g., equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In some embodiments, the recess has a depth and width equal to or greater than 75% (e.g., equal to or greater than 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In particular embodiments, the recess has a depth and width equal to or greater than an external diameter of the delivery tube. In some embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than the external diameter of the delivery tube.

In another aspect, the invention provides a method of administering a pharmaceutical composition to a patient on or near a lingual side of said patient’s teeth, the method including the steps of: (i) inserting into a mouth of the patient a retainer-mounted drug delivery device including a drug reservoir containing said pharmaceutical composition in fluid communication with a delivery tube, in which the drug delivery device is inserted into a pocket in the retainer that is configured to secure the drug delivery device to a buccal side of one or more teeth of the patient, in which the retainer is configured to cover an occlusal surface of at least a first tooth of the patient and to leave at least a portion of an occlusal surface of a second tooth of the patient uncovered (e.g., a second tooth in the same area of the mouth as the first tooth, for example, the first tooth and second tooth can be two different molars in the same quadrant of the mouth), wherein (a) the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than an external diameter of the delivery tube or (b) wherein the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than 50% (e.g., equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube, and in which the delivery tube extends across the portion of the occlusal surface of the second tooth that is left uncovered by the retainer from a buccal side of the tooth to or toward a lingual side of the tooth; (ii) administering said pharmaceutical composition on the lingual side of said patient’s teeth via said delivery tube; and (iii) removing the retainer-mounted drug delivery device from the mouth of said patient after said administering. In some embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than 75% (e.g., equal to or greater than 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In particular embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than an external diameter of the delivery tube. In some embodiments, the retainer is configured such that the occlusal surface covered by the retainer is positioned in front of (i.e., anterior to or on the mesial side of) the delivery tube and the occlusal surface that is left uncovered extends from said delivery tube (e.g., from just anterior to the delivery tube or from the anterior side of said delivery tube) to a rear (i.e., a distal side) of said patient’s rearmost tooth (i.e., the most distal tooth or back tooth) in a quadrant of the mouth containing the delivery tube when the retainer-mounted drug delivery device is inserted into the mouth of the patient (e.g., all of the occlusal surfaces starting from the location of the delivery tube and extending distally to the distal side of the rearmost tooth are uncovered). In some embodiments, the retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer (e.g., the drug delivery device is pushed into the pocket from behind, such that the drug delivery device moves toward an anterior portion of the retainer as it is inserted into the pocket). In some embodiments, the retainer includes a recess that is configured to leave the portion of the occlusal surface of the second tooth uncovered having a depth and width equal to or greater than the external diameter of the delivery tube (i.e., the portion of the second tooth that is uncovered is uncovered due to the recess). In some embodiments, the pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to or toward the lingual side of the tooth.

In another aspect, the invention provides a method of administering a pharmaceutical composition to a patient on or near a lingual side of said patient’s teeth, the method including the steps of: (i) inserting into a mouth of the patient a retainer-mounted drug delivery device including a drug reservoir containing said pharmaceutical composition in fluid communication with a delivery tube, in which the drug delivery device is inserted into a pocket in the retainer that is configured to secure the drug delivery device to a buccal side of one or more teeth of the patient, in which the retainer is configured to cover an occlusal surface of at least a first tooth of the patient and includes a recess configured to leave at least a portion of an occlusal surface of a second tooth of the patient uncovered (e.g., a second tooth in the same area of the mouth as the first tooth, for example, the first tooth and second tooth can be two different molars in the same quadrant of the mouth), wherein (a) the recess has a depth and width equal to or greater than an external diameter of the delivery tube or (b) the recess has a depth and width equal to or greater than 50% (e.g., equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube, and in which the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is left uncovered by the retainer from a buccal side of the tooth to or toward a lingual side of the tooth; (ii) administering said pharmaceutical composition on the lingual side of said patient’s teeth via said delivery tube; and (iii) removing the retainer-mounted drug delivery device from the mouth of said patient after said administering. In some embodiments, the recess has a depth and width equal to or greater than 75% (e.g., equal to or greater than 75%, 80%, 85%, 90%, 95%, or more) of an external diameter of the delivery tube. In particular embodiments, the recess has a depth and width equal to or greater than an external diameter of the delivery tube. In some embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than the external diameter of the delivery tube.

In some embodiments of any of the foregoing aspects, the retainer is configured such that the drug delivery device is inserted into the pocket from below an occlusal plane of the retainer (e.g., the drug delivery device is pushed into the pocket from below, such that if the drug delivery device were to be inserted into the retainer when it was already placed on the teeth, the drug delivery device would move in a direction that is toward the roots of the teeth as it was inserted into the pocket). In some embodiments, the retainer is configured such that the drug delivery device is inserted into the pocket from a side of the retainer (e.g., from the buccal side of the retainer, such that if the drug delivery device were to be inserted into the retainer when it was already placed on the teeth, the drug delivery device would move in a direction that is away from the cheek and toward the buccal surface of a tooth that is adjacent to the pocket when the retainer is worn). Insertion of the drug delivery device from below an occlusal plane of the retainer or from the side of the retainer is suitable for a retainer containing a recess through which a delivery tube can extend.

In some embodiments of any of the foregoing aspects, the recess spans an interproximal space between two teeth.

In some embodiments of any of the foregoing aspects, the second tooth is a second molar (e.g., a portion of the second molar is left uncovered by the retainer and the delivery tube is configured to extend across the portion of the occlusal surface of the second molar that is uncovered).

In some embodiments of any of the foregoing aspects, the patient has upper and lower third molars.

In some embodiments of any of the foregoing aspects, the first tooth is a molar (e.g., a first molar). In some embodiments of any of the foregoing aspects, the first tooth is a premolar (also called a bicuspid).

In some embodiments of any of the foregoing aspects, the second tooth is a molar (e.g., a second molar).

In some embodiments of any of the foregoing aspects, the first tooth is a first molar and the second tooth is a second molar.

In some embodiments of any of the foregoing aspects, the portion of the occlusal surface that is left uncovered (e.g., exposed) is a portion of an occlusal surface of an upper third molar, a lower third molar, an upper second molar, a lower second molar, an upper first molar, a lower first molar, an upper pre-molar, or a lower pre-molar. In some embodiments of any of the foregoing aspects, the portion of the occlusal surface that is left uncovered (e.g., exposed) is a portion of an occlusal surface of an upper second molar. In some embodiments of any of the foregoing aspects, the portion of the occlusal surface that is left uncovered (e.g., exposed) is a portion of an occlusal surface of a lower second molar. In some embodiments of any of the foregoing aspects, the portion of the occlusal surface that is left uncovered is a portion of an occlusal surface of two or more teeth (e.g., two or more adjacent teeth, such as two upper molars, e.g., the upper second and third molars or the upper first and second molars).

In some embodiments of any of the foregoing aspects, the retainer is attached to (e.g., covers when worn) one or more molars and/or pre-molars. The retainer may cover the occlusal, buccal, and/or lingual side of one or more molars and/or pre-molars. In some embodiments, the retainer is attached to (e.g., covers when worn) a first and second pre-molar (also called bicuspids) and a first and second molar. In some embodiments, the retainer is attached to (e.g., covers when worn) a first and second premolar and a first, second, and third molar (e.g., in a subject having third molars). The retainer may cover one or more molars and/or premolars on only one side of the mouth (e.g., in a unilateral retainer) or on both sides of the mouth (e.g., in a bilateral retainer).

In some embodiments of any of the foregoing aspects, the retainer is unilateral (e.g., attached to or worn on teeth on either the left side or right side of the mouth, such as teeth in the right upper quadrant or teeth in the left upper quadrant).

In some embodiments of any of the foregoing aspects, the retainer is bilateral (e.g., attached to or worn on teeth on both the right and left sides of the mouth, such as the left and right upper teeth or the left and right lower teeth). In some embodiments, the retainer includes a palatal strap or bar (i.e. , a palatal strap or bar connecting the right and left sides of the retainer). In some embodiments, the retainer (e.g., the palatal strap or bar) is in a position spanning approximately halfway the hard and soft palates (e.g., approximately half of the hard palate and half of the soft palate is covered by the retainer). In some embodiments, the retainer has an aligner-style design (e.g., the retainer contains a strap covering the incisors to connect the right and left sides of the retainer). In some embodiments, the retainer has a partial aligner-style design (e.g., the retainer includes a strap positioned behind the lingual surface of the incisors to connect the right and left sides of the retainer).

In some embodiments of any of the foregoing aspects, the retainer is designed to cover (e.g., cover at least a portion of an occlusal surface of, or cover a buccal, lingual, and occlusal surface of) 10 or fewer teeth (e.g., 10, 9, 8, 7, 6, 5, 4, 3, or 2 teeth) when worn in the mouth of a patient. In some embodiments, the retainer is bilateral and is designed to cover 10 or fewer teeth (e.g., 10, 9, 8, 7, 6, 5, or 4 teeth) when worn in the mouth of a patient. In some embodiments, the retainer is unilateral and is designed to cover 5 or fewer teeth (e.g., 5, 4, 3, or 2 teeth) when worn in the mouth of a patient.

In some embodiments of any of the foregoing aspects, the retainer is bilateral and is designed to cover (e.g., cover at least a portion of an occlusal surface of, or cover a buccal, lingual, and occlusal surface of) all of the upper or lower teeth (not accounting for the presence of a recess). This configuration may be found in an aligner-style retainer.

In some embodiments of any of the foregoing aspects, the retainer is designed to cover (e.g., cover at least a portion of an occlusal surface of, or cover a buccal, lingual, and occlusal surface of) 8 or more teeth (e.g., 8, 9, 10, 11 , 12, 13, 14, or more teeth) when worn in the mouth of a patient. In some embodiments, the retainer is bilateral and is designed to cover 8 or more teeth (e.g., 8, 9, 10, 11 , 12, 13, 14, or more teeth) when worn in the mouth of a patient.

In some embodiments of any of the foregoing aspects, the retainer is configured to be worn on the upper teeth of the patient. In some embodiments of any of the foregoing aspects, the recess spans an interproximal space between the upper second and third molars. In some embodiments of any of the foregoing aspects, the recess spans an interproximal space between the upper first and second molars. In some embodiments of any of the foregoing aspects, the recess spans at least a portion of an occlusal surface of an upper second molar. In some embodiments, the retainer (e.g., the pocket in the retainer) secures the drug delivery device at a buccal side of an upper molar of the patient (e.g., an upper first molar). In some embodiments, the retainer (e.g., the pocket in the retainer) secures the drug delivery device at a buccal side of an upper pre-molar (bicuspid) of the patient (e.g., an upper second pre-molar).

In some embodiments of any of the foregoing aspects, the retainer is configured to be worn on the lower teeth of the patient. In some embodiments of any of the foregoing aspects, the recess spans an interproximal space between the lower second and third molars. In some embodiments of any of the foregoing aspects, the recess spans an interproximal space between the lower first and second molars. In some embodiments of any of the foregoing aspects, the recess spans at least a portion of an occlusal surface of a lower second molar. In some embodiments, the retainer (e.g., the pocket in the retainer) secures the drug delivery device at a buccal side of a lower molar of the patient (e.g., a lower first molar). In some embodiments, the retainer (e.g., the pocket in the retainer) secures the drug delivery device at a buccal side of a lower pre-molar (bicuspid) of the patient (e.g., a lower second pre-molar).

In some embodiments of any of the foregoing aspects, the recess extends from the buccal side of the second tooth to the lingual side of the second tooth (e.g., as shown in FIGS. 1 A, 3A, and 3C).

In some embodiments of any of the foregoing aspects, the pocket is fabricated as an integral part of the retainer.

In some embodiments of any of the foregoing aspects, the retainer is configured to maintain a neutrocentric occlusion.

In some embodiments of any of the foregoing aspects, the retainer (e.g., the pocket in the retainer) is configured to position the drug delivery device coplanar with an occlusal plane of a molar. In some embodiments, the retainer (e.g., the pocket in the retainer) is configured to position the drug delivery device coplanar with the occlusal plane of the first or second molar.

In some embodiments of any of the foregoing aspects, the retainer (e.g., the pocket in the retainer) is configured to position the drug delivery device such that it only spans the first and second molars. In some embodiments of any of the foregoing aspects, the retainer (e.g., the pocket in the retainer) is configured to position the drug delivery device such that a posterior end of the drug delivery device is between a midline and a posterior of the patient’s rear-most molar.

In some embodiments of any of the foregoing aspects, the retainer (e.g., the pocket in the retainer) is configured to position the drug delivery device such that it is set on the Wilson plane.

In some embodiments of any of the foregoing aspects, the retainer is configured such that the patient’s oral anatomy would mechanically interfere with and prevent the removal of the drug delivery device from the retainer when the drug delivery device is inserted into the pocket and the retainer is being worn by the patient. In some embodiments of any of the foregoing aspects, the pocket is configured such that it has a friction fit with the drug delivery device and thereby prevents the drug delivery device from being dislodged from the pocket during insertion of the retainer into the mouth or administration of drug. Alternatively, the drug delivery device is reversibly secured in the pocket with a detent, groove, snap, or lock.

In some embodiments of any of the foregoing aspects, the retainer is made of a plastic (e.g., transparent plastic). In some embodiments, the retainer is 3D-printed or milled (e.g., 3D-printed using a resin suitable for dental applications, such as KeySplint Soft®). In some embodiments, the plastic is an acrylate-containing polymer, a thermoplastic polyolefin, or nylon. For example, the retainer may be made of a thermoplastic polyolefin, such as polypropylene. The plastic may be an Essix® PLUS™ plastic, an Essix A+® plastic, an Essix C+® plastic, an Essix ACE® plastic, an Essix® dual laminate plastic, an Essix® nightguard laminate plastic, an Essix® sports mouthguard material, an Essix® laminated sports mouthguard material, an Essix® bleach tray and model duplication material, an Essix Tray Rite® plastic, a Dreve Drufosoft® Pro plastic, a Dreve Kombiplast plastic, a Dreve BioIon plastic, or a Dreve Drufosoft® sports mouthguard material.

In some embodiments of any of the foregoing aspects, the delivery tube is part of a polymeric fluidic channel containing a bend of 45 to 135 degrees. In some embodiments, the polymeric fluidic channel contains a bend of 80 to 100 degrees. In some embodiments, the polymeric fluidic channel contains a bend of 90 degrees. In some embodiments, the bend in the polymeric fluidic channel is upstream of (e.g., closer to the drug reservoir than) the delivery tube. In some embodiments, the component of the polymeric fluidic channel that contains the bend is a nozzle adaptor. In some embodiments, the nozzle adaptor is connected to the drug reservoir (e.g., forms a hermetic seal with the drug reservoir). In some embodiments, the nozzle adaptor is fluidically connected to the delivery tube.

In some embodiments of any of the foregoing aspects, the delivery tube is part of an L-shaped polymeric fluidic channel (e.g., polymeric fluidic channel that contains a 90-degree bend).

In some embodiments of any of the foregoing aspects, the distal end of the delivery tube (i.e., the end of the delivery tube from which the pharmaceutical composition is released) is on the lingual side of the patient’s teeth (e.g., on the lingual side of the second tooth of the patient, such as on the lingual side of the second molar of the patient; i.e., the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to the lingual side of the tooth and terminates at or beyond the lingual side of the tooth). In other embodiments, the distal end of the delivery tube is on an occlusal surface of the teeth (e.g., on the occlusal surface of the second tooth) while still allowing drug to be delivered on the lingual side of the patient’s teeth (e.g., the delivery tube terminates before reaching the lingual side of the second tooth but still releases drug on the lingual side of the tooth). In some embodiments, the delivery tube terminates about halfway across the occlusal surface of the second tooth (i.e., the distal end of the delivery tube is at the midpoint of the occlusal surface of the second tooth, for example, the delivery tube may terminate about halfway across the occlusal surface of the second molar). In some embodiments, the delivery tube terminates about two thirds of the way or three quarters of the way across the occlusal surface of the second tooth (e.g., a second molar). In some embodiments of any of the foregoing aspects, the delivery tube that extends across the portion of the occlusal surface of the second tooth that is uncovered is not compressed when the patient wearing the retainer bites down.

In some embodiments of any of the foregoing aspects, the delivery tube that extends across the portion of the occlusal surface of the second tooth that is uncovered is partially and reversibly compressed when the patient wearing the retainer bites down.

In some embodiments of any of the foregoing aspects, said drug delivery device includes a pump and a drug reservoir, in which said drug reservoir comprises a pharmaceutical composition and is in fluid communication with said delivery tube.

In some embodiments of any of the foregoing aspects, the drug delivery device includes a nozzle adaptor connected to the drug reservoir that makes a 90-degree bend (e.g., a bend toward the teeth when the drug delivery device is worn on the buccal side of the teeth, e.g., toward an occlusal surface of a tooth, e.g., to direct the fluid path of the pharmaceutical composition toward the lingual side of the teeth).

In some embodiments of any of the foregoing aspects, the delivery tube is straight. In some embodiments of any of the foregoing aspects, the delivery tube is fluidically connected to said nozzle adaptor (e.g., to the end of the nozzle adaptor beyond the bend, e.g., the end of the nozzle adaptor that is configured to face the teeth when the drug delivery device is worn on a buccal side of the teeth, e.g., an occlusal surface of the teeth, to direct the straight delivery tube across an occlusal surface of a tooth in the direction of the lingual side of the teeth).

In some embodiments of any of the foregoing aspects, the pocket is configured such that the drug delivery device can be pushed into the pocket before the retainer is inserted into the mouth of the patient. In some embodiments of any of the foregoing aspects, the drug delivery device can be removed from the pocket by pushing on the device (e.g., when the device is outside of the mouth of a patient).

In some embodiments of any of the foregoing aspects, the retainer is matched to the dentition of the patient.

In another aspect, the invention provides a method of administering a pharmaceutical composition on or near a lingual side of a patient’s teeth, the method including the steps of: (i) inserting a drug delivery device into the pocket of the retainer of any of the foregoing aspects and embodiments, in which the drug delivery device includes a drug reservoir containing a pharmaceutical composition in fluid communication with a delivery tube configured to deliver said pharmaceutical composition from a buccal side to the lingual side of the patient’s teeth; (ii) inserting the retainer containing the drug delivery device into a mouth of the patient; (iii) administering said pharmaceutical composition to the patient; and (iv) after said administering, removing the retainer from the mouth of the patient. In some embodiments, the drug delivery device is inserted into the pocket from a rear of the retainer (e.g., insertion of the device from the posterior of the pocket toward the anterior of the pocket). In some embodiments, the drug delivery device is inserted into the pocket from below the occlusal plane of the retainer (e.g., insertion of the device from the bottom of the pocket to the top of the pocket). In some embodiments, the drug delivery device is inserted into the pocket from the side of the retainer (e.g., from the buccal side).

In another aspect, the invention provides a method of administering a pharmaceutical composition on or near a lingual side of a patient’s teeth, the method including the steps of: (i) inserting the system of any of the foregoing aspects and embodiments into a mouth of the patient, in which the drug delivery device is inserted into the retainer pocket and includes a drug reservoir containing a pharmaceutical composition in fluid communication with the delivery tube; (ii) administering said pharmaceutical composition to the patient; and (iii) after said administering, removing the retainer from the mouth of the patient.

In some embodiments of any of the foregoing aspects, the method further includes treating a disease in said patient.

Definitions

The term “about,” as used herein, refers to a number that is ±10% of a value that this term precedes except when the value is that of a temperature. For temperatures “about” means ± 3°C.

The term “administration” or “administering” refers to a method of giving a dosage of a therapeutic drug, such as LD and/or carbidopa (CD), to a patient. The drug may be formulated as a fluid, such as a viscous suspension. The drug is preferably administered into the mouth using a drug delivery device attached to a retainer of the invention and the drug can be swallowed and/or absorbed anywhere within the mouth or via the stomach. Typical durations of administration from a single device or drug reservoir are greater than 4, 8, 12, or 16 hours per day, up to and including 24 hours per day. Administration can also take place over multiple days from a single device or drug reservoir, e.g., administration of a drug for 2 or more days, 4 or more days, or 7 or more days.

As used herein, the terms “aligner style-design” and “aligner-style retainer” refer to a bilateral retainer that covers all or most of the upper or lower teeth including the front teeth (i.e., the incisors and canines). A retainer having an aligner-style design may be a retainer (e.g., a clear retainer) that is molded to fit over the teeth (e.g., over the buccal, lingual, and occlusal surfaces of the teeth) and may resemble an aligner, such as Invisal ign®. For example, a retainer that has an aligner style-design may be a clear retainer that covers all of the upper teeth or all of the lower teeth (not accounting for the presence of a recess).

As used herein, the term “bilateral” when used to describe a retainer refers to a retainer that is attached to or covers teeth on both sides of the mouth when worn. For example, a bilateral retainer covers teeth in the upper left and right quadrant or the lower left and right quadrant, such as at least one molar and/or pre-molar in each of the upper left quadrant and upper right quadrant or at least one molar and/or pre-molar in each of the lower left quadrant and lower right quadrant. A bilateral retainer includes a means for connecting the right and left sides, such as a palatal strap or bar, a lingual connector (e.g., in a partial aligner-style retainer), or an incisor connector (e.g., in an aligner-style retainer).

The term “compatible” means that a material contacting a pharmaceutical composition does not substantially change the chemical, physical, or pharmacological properties of the pharmaceutical composition.

As used herein “continuous administration” or “continuous infusion” refers to uninterrupted administration or infusion of a drug in solid or fluid form.

As used herein, the term “drug particle” refers to solid particles including a drug. The drug particles can be included in the pharmaceutical compositions that can be delivered using a drug delivery device mounted in a retainer described herein. For example, the pharmaceutical composition can contain particulates containing or formed from LD, LD salts, CD, or CD salts.

As used herein the term “engineering plastic” is synonymous with the terms “engineered plastic”, “engineered polymer” and “engineering polymer.” The term means a polymer differing from the most widely used polymers in its superior mechanical properties, or in its superior resistance to chemicals or its lesser wetting by water or by oils, or its lesser swelling in water or in oils. Exemplary engineering plastics include polyamides such as Nylon 6, Nylon 6-6 and other Nylons; polyesters like polybutylene terephthalate or polyethylene terephthalate; polycarbonates; polyetheretherketones; polyetherketones; polyimides; polyoxymethylenes such as polyacetals or polyformaldehydes; polyphenylene sulfide; polyphenylene oxide; polysulfone; polytetrafluoroethylene; polyvinylidene difluoride; ultra-high-molecular- weight polyethylene; and strong elastomers such as highly crosslinked acrylonitrile butadiene styrene, and their co-polymers.

As used herein, the term “fluid” encompasses any drug-including liquid, gel, or non-pourable suspension that can be pumped or extruded. The fluid can be a Newtonian or a non-Newtonian fluid; it can be an easy to deform solid or a soft paste, which may move as a plug via slip flow. It can be, for example, a viscous Newtonian or non-Newtonian suspension. The term encompasses, for example, true solutions, colloidal solutions, emulsions, pastes, suspensions, and dense semi-solid toothpaste-like suspensions deforming under pressure sufficiently to be extruded into the mouth. The fluid infused can be aqueous, non-aqueous, single phase, two-phase, three- phase or multiphase. The emulsions can be, for example, oil-in-water or water-in-oil and can include micelles and/or liposomes.

As used herein, the term “incisor connector” refers to a connector that joins the right and left sides of a bilateral retainer worn on either the upper (maxillary) or lower (mandibular) teeth by covering the intervening teeth (e.g., the teeth between the molars and/or pre-molars, such as the canines and incisors). An incisor connector provides continuous coverage of the teeth from one end of the retainer to the other (e.g., in a retainer worn on the upper teeth, the incisor connector allows for covering all of the teeth from the upper left second or third molar to the upper right second or third molar). This type of connector is found in a retainer having an aligner-style design. The incisor connector may be made of the same material as the rest of the retainer (e.g., plastic).

As used herein, “infused” or “infusion” includes infusion into any part of the body, preferably infusion into the mouth or nasal cavity. It is exemplified by extrusion into the mouth.

The term “LD” refers to levodopa, also known as L-DOPA, or a salt thereof.

As used herein, the term “lingual connector” refers to a connector that joins the right and left sides of a bilateral retainer worn on either the upper (maxillary) or lower (mandibular) teeth by passing behind (on the lingual side of) the incisors (e.g., joins a portion of the retainer covering at least one molar and/or pre-molar on the upper right side of the mouth to a portion of the retainer covering at least one molar and/or pre-molar on the upper left side of the mouth). A lingual connector may pass behind any teeth that are not covered by the retainer (e.g., any teeth that are not covered on an occlusal surface by the retainer), which may include the incisors and optionally the canines in a retainer having a partial alignerstyle design (e.g., in a retainer that covers an occlusal surface of at least one molar and/or pre-molar on both the right and left sides of the mouth). The lingual connector may be made of the same material as the portions of the retainer that cover the teeth (e.g., plastic). As used herein, “mechanical pump” means any drug delivery device whose motive force is not electricity, magnetism, or gravity. Examples of mechanical pumps include drug delivery devices wherein the drug is delivered by the force or pressure of a spring, an elastomer, a compressed gas, or a propellant.

As used herein, “mouth” includes the areas of the oral cavity, including those areas of the oral cavity adjacent the lips, cheeks, gums, teeth, tongue, roof of the mouth, hard palate, soft palate, tonsils, uvula, and glands.

The abbreviation “M” means moles per liter. Usage of the term does not imply, as it often does in chemistry, that the drug is dissolved. As used herein 1 M means that a 1 liter volume contains 1 mole of the combination of the undissolved (often solid) and/or the dissolved drug. For example, 1 M LD means that there is 197 mg of solid (undissolved) and dissolved LD in one mL.

As used herein, the terms “palatal bar” and “palatal strap” refer to two types of maxillary connectors that join the right and left sides of a bilateral retainer worn on the upper teeth (e.g., worn on at least one molar and/or pre-molar on the upper right and left sides of the mouth). Both a palatal bar and palatal strap connect the right and left sides of a bilateral retainer worn on the upper teeth by extending across the palate. A palatal strap is typically wide and thin, while a palatal bar is narrow and thick. The palatal bar or palatal strap may be made of the same material as the portions of the retainer that cover the teeth (e.g., plastic).

As used herein, the terms “partial aligner-style design” and “partial aligner-style retainer” refer to a bilateral retainer that covers at least one molar and/or pre-molar (bicuspid) on both the left and right sides of the upper or lower teeth but that does not cover the incisors. A retainer having a partial aligner-style design includes a lingual connector that passes behind (e.g., contacts the lingual side of) any teeth that are not covered by the retainer, which includes at least the incisors and may also include the canines. For example, a retainer having a partial aligner-style design may be a retainer (e.g., a clear retainer) that is molded to fit over the first and second upper molars and pre-molars on the left and right sides of the mouth (e.g., over the buccal, lingual, and occlusal surfaces of the upper left and right first and second molars and pre-molars) and that has a lingual connector positioned behind (on the lingual side of) the upper canines and incisors to connect the right and left sides of the retainer.

As used herein, “pump” refers to any mechanism capable of administering a fluid formulated drug product over a period of 4 or more hours. Examples of pumps include battery-powered pumps (e.g., syringe pumps, piezoelectric, peristaltic pumps, or diaphragm pumps), mechanical devices with or without moving parts that are not battery-powered (e.g., liquefied propellant driven pumps, gas-driven pumps, spring-driven pumps, shape memory alloy driven pumps, and elastomeric pumps), osmotic pumps, and battery-operated electroosmotic pumps (with or without moving parts).

The terms “semi-continuous administration” and “frequent administration,” as used interchangeably herein, refer to an administration (e.g., infusion) of a drug in solid or fluid form at a frequency of at least once every 120 minutes, and preferably at least every 90, 60, 30, 15, or 5 minutes.

As used herein the term “suspension” refers to a mixture including a liquid and particles of at least one solid. The liquid can be aqueous or non-aqueous or an emulsion. The non-aqueous liquid can be an edible oil and the emulsion can include an edible oil. Suspensions may be, for example, flowing suspensions or suspensions that are extruded, i.e. , slipping as a plug (e.g., through a flow-controlling orifice, nozzle, or tubing).

As used herein, the term “treating” refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. To “prevent disease” refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease. To “treat disease” or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease to ameliorate the disease and improve the patient’s condition. The term “treating” also includes treating a patient to delay progression of a disease or its symptoms. Thus, in the claims and embodiments, treating is the administration to a patient either for therapeutic or prophylactic purposes.

As used herein, the term “unilateral” when used to describe a retainer refers to a retainer that is attached to or covers teeth in only one quadrant of the mouth when worn. For example, a unilateral retainer covers teeth in only one of the upper left quadrant, upper right quadrant, lower left quadrant, or lower right quadrant, such as at least one molar and/or pre-molar in a single quadrant of the mouth.

As used herein “viscosity” means dynamic viscosity also known as shear viscosity, measured at a low shear rate.

Other features and advantages of the invention will be apparent from the following Detailed Description, the drawings, and the claims.

Brief Description of the Drawings

FIGS. 1A-1C are a series of drawings depicting a transparent retainer containing bilateral recesses spanning the interproximal space between the upper second and third molars. The recesses resemble cut-outs in the portion of the retainer configured to cover the occlusal surface of the second and third molars. FIG. 1 A shows the retainer worn on the teeth of the upper arch. The retainer is a transparent, bilateral bite neutral (neutrocentric) retainer having a partial aligner-style design and lingual connector positioned behind the lingual surface of the incisors and canines. The retainer covers the buccal, lingual, and occlusal surfaces of the first and second bicuspids and the first, second, and third molars on both the right and left sides of the mouth. A drug delivery device has been inserted into the pocket of the retainer, which secures the device at a buccal surface of one or more molars (e.g., the first molar). The drug delivery device contains a delivery tube for delivering drug from the buccal side of the teeth to the lingual side of the teeth. Arrows indicate the recesses, which span the interproximal space of the upper second and third molars on both the right and left sides of the mouth and leave a portion of the occlusal surface of the upper third molar uncovered. The portions of the retainer covering the teeth on the right and left side of the mouth are joined by a lingual connector that contacts the lingual side of all of the intervening teeth of the upper arch. FIG. 1 B shows that the thickness of the retainer where it covers the occlusal surface of the upper third molar (indicated by a bracket) is greater than or equal to the outer diameter of the delivery tube. The recess creates a space for the delivery tube to pass across the uncovered portion of the third molar from the buccal side to the lingual side and the thickness of the retainer provides a space for the delivery tube to pass between the occlusal surfaces of the upper and lower third molars without being compressed by the molars when the patient wearing the retainer bites down. FIG. 1 C shows the teeth in the absence of the retainer, demonstrating that there is no space for a delivery tube to pass through the teeth when the retainer is not being worn. FIGS. 2A-2D are a series of drawings depicting a transparent retainer lacking recesses. FIG. 2A shows the retainer worn on the teeth of the upper arch. The retainer is a transparent, bilateral retainer having a partial aligner-style design and lingual connector positioned behind the lingual surface of the incisors and canines. The retainer covers the buccal, lingual, and occlusal surfaces of the first and second bicuspids and the first, second, and third molars on one side of the mouth (the side containing the pocket) and the buccal, lingual, and occlusal surfaces of the first and second bicuspids and the first and second molars on the other side of the mouth (which lacks a third molar). A drug delivery device has been inserted into the pocket of the retainer, which secures the device to a buccal surface of one or more teeth (e.g., a first molar). The drug delivery device contains a delivery tube for delivering drug from the buccal side of the teeth to the lingual side of the teeth. The portions of the retainer covering the teeth on the right and left side of the mouth are joined by a lingual connector that contacts the lingual side of all of the intervening teeth of the top arch. FIG. 2B shows the retainer containing the drug delivery device when it is not in the mouth. FIG. 2C shows a view from the back of the mouth when the retainer containing the drug delivery device is worn (i.e., placed on the teeth) and the patient bites down, which demonstrates that in the absence of a recess, the delivery tube is crushed between the upper and lower third molars. FIG. 2D shows the retainer containing the drug delivery device after the use of FIG. 2C, which demonstrates that the delivery tube has been crushed by the teeth.

FIGS. 3A-3D are a series of three-dimensional drawings depicting a bilateral retainer containing a palatal strap and a recess configured to be worn on the upper teeth of a patient. FIGS. 3A-3B show a view of the underside of the retainer alone (FIG. 3A) or including a drug delivery device (FIG. 3B). The retainer is configured to cover the buccal, lingual, and occlusal surfaces of the first and second bicuspids and the first and second molars on both the right and left sides of the mouth and includes a recess spanning the interproximal space between the first and second molars. A drug delivery device (indicated by a curved line) has been inserted into the pocket (indicated by a dashed arrow) of the retainer in FIG. 3B, which secures the device at a buccal surface of one or more molars and/or bicuspids (e.g., the first molar and second bicuspid). The drug delivery device contains a delivery tube (indicated with an arrowhead in FIG. 3B) for delivering drug from the buccal side of the teeth to the lingual side of the teeth. The delivery tube is fluidically connected to a nozzle adaptor (indicated with a straight line in FIG. 3B) that is L-shaped (contains a single 90-degree bend), and the delivery tube does not extend beyond the lingual side of the first molar. Solid arrows indicate the recess, which spans the interproximal space of the upper first and second molars on one side of the mouth and leaves a portion of the occlusal surface of a molar uncovered. The portions of the retainer covering the teeth on the right and left side of the mouth are joined by a palatal strap (indicated by a dotted arrow). FIGS. 3C-3D show a different view of the same retainer with (FIG. 3D) and without (FIG. 3C) the drug delivery device. As shown in FIGS. 3B and 3D, the recess has a depth and a width that is equal to or greater than the outer diameter of the delivery tube, which allows the delivery tube to fit within the recess and to extend from the buccal side of the teeth to or toward the lingual side of the teeth across the occlusal surface that is uncovered by the recess. As shown in FIG. 3C, the depth of the recess is at least partially due to the thickness of the retainer where it covers the occlusal surface of the teeth (e.g., the occlusal surface of the first molar). Since the delivery tube fits within the recess, it can extend across the occlusal surface of the teeth without being compressed when a patient wearing the retainer-mounted drug delivery device bites down. The retainer shown in FIGS. 3A and 3C contains a pocket that allows for insertion of the drug delivery device from the side of the retainer (e.g., from the buccal side).

FIGS. 4A-4B are a series of drawings depicting a transparent retainer that covers the upper first and second molars and upper first and second bicuspids and that does not cover the upper third molar. FIG. 4A shows the retainer worn on the teeth of the upper arch. The retainer is a transparent, bilateral retainer having a palatal strap connecting the portions of the retainer covering the upper left and right teeth. The retainer covers the buccal, lingual, and occlusal surfaces of the upper first and second bicuspids and the upper first and second molars on both the right and left sides of the mouth. There is only one third molar in the upper arch and it is not covered by the retainer. A drug delivery device has been inserted into the pocket of the retainer, which secures the device at a buccal surface of one or more molars (e.g., the first molar). The drug delivery device contains a delivery tube for delivering drug from the buccal side of the teeth to the lingual side of the teeth that extends across the occlusal surface of the uncovered third molar. The portions of the retainer covering the teeth on the right and left side of the mouth are joined by a palatal strap . FIG. 4B shows that the delivery tube can extend across the occlusal surface of the uncovered upper third molar (e.g., between the upper and lower third molars) from the buccal side to the lingual side without being compressed by the molars when the patient wearing the retainer bites down. This is due to the thickness of the retainer where it covers the occlusal surface of one or more of the covered molars or bicuspids (e.g., that the thickness of the retainer where it covers the occlusal surface of one or more teeth is greater than or equal to the outer diameter of the delivery tube), which provides a space for the delivery tube to pass from the buccal side to the lingual side of the teeth between the occlusal surfaces of the upper and lower third molars without being compressed by the molars when the patient wearing the retainer bites down. The drug delivery device can be inserted into the pocket from the rear of the retainer (e.g., by pushing the retainer into the pocket toward the anterior edge of the pocket, e.g., from back to front).

Detailed Description of the Invention

Described herein are devices, compositions, and methods useful for continuous or semi- continuous oral delivery of medicaments. The invention features a retainer configured to removably secure a drug delivery device including a delivery tube on the buccal side of one or more upper or lower teeth of a patient. The retainer includes a pocket for securing the drug delivery device to the buccal side of the one or more teeth of the patient and is configured to cover the occlusal surface of at least a first tooth and to leave a portion of an occlusal surface of a second tooth uncovered. The portion of the occlusal surface of the second tooth may be uncovered because the retainer is not worn on or attached to the second tooth or because the retainer includes a recess positioned over the portion of the occlusal surface of the second tooth. The retainer is designed for use with a drug delivery device containing a delivery tube that passes across the occlusal surface of the teeth (e.g., from the buccal side to or near the lingual side of the teeth). The delivery tube is able to extend across the occlusal surface (the biting surface) of the teeth without being compressed or crushed by the teeth due to the thickness of the retainer on the occlusal surface of the first tooth (e.g., at least as thick as the external diameter of the delivery tube) and/or due to the recess, which is configured to allow for passage of the delivery tube across the occlusal surface of the portion of the second tooth that is left uncovered (e.g., the recess has a depth and width equal to or greater than the external diameter of the delivery tube).

The retainers can be used to removably attach at the buccal surface of a molar and/or pre-molar a drug delivery device containing a delivery tube that extends from the buccal side to or near the lingual side of the teeth in patients having a variety of dentition, including patients having upper and lower third molars. The recess, if present, can span an interproximal space between two molars, such as the interproximal space between an upper or lower second and third molar or an upper or lower first and second molar, or can span at least a portion of the occlusal surface of a molar, such as a portion of the occlusal surface of an upper or lower second molar, such that when the patient wearing the retainer bites down the distance between an occlusal surface (e.g., an uncovered occlusal surface) of a tooth and the outer surface of the surrounding retainer (e.g., an occlusal surface of the upper or lower second or third molar and an outer surface of the recess in the retainer) is greater than or equal to the diameter of the delivery tube (e.g., the recess has a depth and width equal to or greater than the external diameter of the delivery tube). This provides a space for the delivery tube to extend across an occlusal surface of a molar (e.g., a molar that the retainer does not fully cover due to the recess) from the buccal side of the teeth to or near the lingual side of the teeth without being crushed when a patient wearing the retainer bites down. The recess in the retainer can be adapted to each patient’s oral anatomy for proper positioning of the drug delivery device. This allows the same drug delivery device to be used for all patients regardless of their oral anatomy (e.g., delivery tube dimensions do not need to be adjusted for different patients). Also described are drug delivery devices that can be used with said retainers and methods of using retainer-mounted drug delivery devices for continuous or semi-continuous intraoral administration of a pharmaceutical composition including a drug.

While syringes, drug reservoirs and pumps outside the mouth can be large because space is typically available, space in the mouth for a drug delivery device is limited and is particularly limited when a drug delivery device is so small that it does not interfere with speaking, swallowing, or drinking. Consequently, the delivered drug, its reservoir and its delivery device must occupy a small volume. In the exemplary management of Parkinson’s disease, the concentration of the orally infused LD and/or carbidopa (CD) including fluid of the invention can be typically greater than 1 M, such as greater than 1 .5 M, 2 M, 2.5 M, 3 M, 3.5 M, 4 M, or 4.5 M. These are substantially higher concentrations than the 0.1 M LD concentration of the Duodopa (also known as Duopa™) gels that are commercially available for jejunal or duodenal infusions. The concentrated drug suspension contained in a drug delivery device of the invention can be viscous, for example its dynamic viscosity at 37 ^eC can be greater than 100 cP, such as greater than 1 ,000 cP, 10,000 cP, 100,000 cP, 500,000 cP, or 1 ,000,000 cP.

The suspension can have, for example, viscosity equal to or greater than that of toothpaste, the viscosity being greater than about 20,000 cP, for example greater than 50,000 cP, such as greater than 500,000 cP. The earlier practice of infusion of viscous fluids through long tubings, typically longer than 50 cm, such as those used for nasogastric, jejunal, or duodenal infusions, required that their internal diameter be large and/or that the pumping pressure be high. Furthermore, when the earlier suspensions were infused through the longer tubings, the likelihood of blockage of the flow because of clustering of the suspended LD particles increased and translucent, very fine particle colloids were used to reduce blockage. In contrast, the herein disclosed orally infused, more much concentrated suspensions are typically opaque because they can contain large solid particles scattering visible-wavelength light. The much more concentrated and much more viscous orally infused suspensions can be rich in particle sizes greater than 1 pm, 5 pm, 10 pm, or even 50 pm. The suspensions can be orally infused, for example, through flow restrictors such as orifices in reservoirs that are narrower than 2 mm, 1 mm, or 0.5 mm and/or flow restrictors such as plastic tubings or nozzles that can be shorter than 5 cm, e.g., shorter than 4 cm, 3 cm, 2 cm, or 1 cm.

The present invention is based in part on the discovery of a solution to the problem of delivering drug on the lingual side of the teeth from a drug reservoir located on the buccal side of the teeth. The solution can be used by almost all patients, including those having third molars. The drug delivery device contains a delivery tube in fluid communication with the drug reservoir that is used to deliver drug from the buccal side to or near the lingual side of a patient’s teeth. The drug delivery device can be secured to a buccal side of one or more of the patient’s teeth using a retainer. In patients without a third molar, the drug delivery device can be positioned in the mouth (e.g., using the retainer) such that the delivery tube passes behind (e.g., wraps around the back of) the second molar. However, the inventors found that the same approach could not be used in patients having third molars since there was a lack of space behind the third molar for the delivery tube. Moving the drug delivery device toward the back of the mouth so the delivery tube could pass behind the third molar also proved problematic, as there was not enough room for the device at the back of the mouth, which caused the device to press against the cheek and led to discomfort in those wearing the device. To ensure that the same drug delivery device could be used by patients with and without third molars (e.g., to avoid the need to re-design the drug delivery device for patients with third molars), the inventors developed retainers that allow the delivery tube to pass across the occlusal surface of the teeth without being compressed or crushed when a patient wearing a retainermounted drug delivery device bites down. The retainers may have a thickness on the occlusal surface of a first tooth that is greater than or equal to the external diameter of the delivery tube to allow the delivery tube to pass across the occlusal surface of a second tooth or a portion of a second tooth that is not covered by the retainer, or the retainer may contain a recess having a width and depth that is equal to or greater than the external diameter of the delivery tube that leaves at least a portion of an occlusal surface of a tooth uncovered, which allows the delivery tube to extend through the recess from the buccal side of the tooth to or near the lingual side of the tooth across the portion of the occlusal surface that is uncovered by the recess without being crushed between the upper and lower teeth when a patient wearing the retainer bites down. Although the retainer is particularly beneficial for patients having upper and lower third molars, it can also be used by patients who lack upper and/or lower third molars if it is determined to be more desirable for the delivery tube to extend across the occlusal surface of the teeth rather than passing behind the second molar.

Using the devices and methods of the invention, drugs can be administered intraorally. The drugs administered intraorally are typically swallowed by the patient, together with the patient’s saliva. The drugs can be diluted by the patient’s saliva and can optionally be partly or fully dissolved in the saliva. The drugs can be absorbed in the patient’s gastrointestinal tract, e.g., in the small intestines or large intestines. Alternatively, the drugs can be absorbed sublingually or buccally. The devices and methods of the invention permit continuous or semi-continuous administration of drugs to subjects to produce reliable and steady pharmacokinetic performance and are needed improve efficacy and/or safety of therapies, particularly for drugs with a short half-life (e.g., in the plasma), and/or short persistence of the drug’s physiological effect, and/or a narrow therapeutic window.

DRUG DELIVERY DEVICES

The drug delivery devices that can be mounted to a retainer described herein are designed to address the requirements for a device that is inserted into the mouth by the patient or caregiver, that resides in the mouth while it is administering drug, and that can be removed from the mouth by the patient or caregiver. Preferred drug delivery devices include drug reservoirs.

The drug delivery devices typically have a total volume of less than about 10 mL, and preferably less than 7.5, 5.0, or 3.0 mL. Preferred volumes for the drug delivery devices are 0.1 -5.0 mL (e.g., 0.5- 3.0 mL), to minimize interference with the patient’s mastication, swallowing and speech.

Although the housing of the typical drug delivery device can be a strong material such as a metal or a ceramic, the housing may include in some embodiments a rigid plastic comprising a strong polymer, such as a polyimide. The plastic may optionally be fiber reinforced, i.e., it may be reinforced, for example, by carbon, metal, or glass fibers. The metallic housing can be a stainless steel such as an austenitic stainless steel, or it can be titanium or an alloy of titanium.

The drug delivery device may be a single unit, or it may have two, three, four, five or more components. The drug delivery device may have one, two, three, four, five or more drug reservoirs in which the solid or fluid drug formulation is contained. These one or more reservoirs may form a single component, or they may form multiple components.

The drug delivery devices may be reusable, disposable, or they may have one or more reusable components and one or more disposable components. In another preferred embodiment, the one or more drug reservoirs are single use, disposable components. The pump is typically disposable, but it may be reusable. The flow restrictor is typically single use meaning disposable, but it can be reusable in some embodiments.

The drug reservoir is typically single use, but it may be refillable with a solid or fluid drug formulation. In a preferred embodiment, the drug reservoir is a single use disposable. The drug reservoir may be filled by the user, a caregiver, or a pharmacist. In preferred embodiments, the drug reservoir is prefilled.

The drug delivery device may further include one, two, three, four or more orifices for releasing the drug from the device into the mouth.

Durations of administration from a single drug delivery device or drug reservoir typically exceed 4, 8, 12, or 16 hours per day, up to and including 24 hours per day. Administration can also take place over multiple days from a single device or drug reservoir, e.g., administration of a drug for 2 or more days, 4 or more days, or 7 or more days. The devices can be designed such that they can be worn when the patient is awake or asleep.

It is desirable that the patient be able to temporarily remove the drug delivery device from the mouth, for example, to eat meals, brush teeth, or at times when the patient does not want or need the medication (e.g., at night). Consequently, the drug delivery devices can be temporarily removable. The drug delivery devices can be configured and arranged to administer one or more solid or fluid drug formulations from one or more drug reservoirs including a total volume of 0.1 - 10 mL of drugs, e.g., 0.1 -1 .0, 1 .0-2.0, 2.0-3.0, 3.0-4.0, 4.0-5.0, 5.0-6.0, 6.0-7.0, 7.0-8.0, 8.0-9.0, or 9.0-10 mL. The volume of the drug reservoir can be from 0.1 mL to 5 mL. The drug delivery devices are configured and arranged to administer the one or more solid or fluid drug formulations at a rate in the range of 0.03 - 1 .25 mL/hour, e.g., 0.03 - 0.10, 0.10-0.20, 0.20-0.30, 0.30-0.40, 0.40-0.50, 0.50-0.60, 0.60-0.70, 0.70-0.80, 0.80-0.90, 0.90-1 .0, 1 .0-1 .1 , or 1 .1 -1 .25 mL/hour. In some embodiments, they are configured and arranged to administer the drug, (i.e. , the active pharmaceutical ingredient) at an average rate of 0.01 - 1 mg per hour, 1 - 10 mg per hour, 10 - 100 mg per hour, or greater than 100 mg per hour. In other embodiments, the drug product (i.e., the active pharmaceutical ingredient plus excipients) is delivered at an average rate of 0.01 - 1 mg per hour, 1 - 10 mg per hour, 10 - 100 mg per hour or greater than 100 mg per hour.

In preferred embodiments, the drug delivery device administers one or more solid or fluid drug formulations via continuous and/or frequent administration, e.g., infusion. In a preferred embodiment, the solid or fluid drug administration rate is held constant or near constant for a period of 4, 8, 12, 16 or 24 hours during the day. For example, the administered volume may vary by less than ±10% or ± 20% per hour, or by ±10% or ± 20% per 15-minute period, over a period of 4, 8, 12, 16 or 24 hours. In another embodiment, the solid or fluid drug administration rate is held about constant during the awake hours of the day. In another embodiment, the solid or fluid drug formulation administration rate is held about constant during the asleep hours. In another embodiment, the solid or fluid drug formulation administration rate is held about constant during the awake hours of the day, except for the delivery of a bolus at about the time of waking. In one embodiment, the administration rate can be set prior to insertion in the mouth by the patient or by the caregiver. In another embodiment, the administration is semi-continuous and the period between the infusions is less than the biological half-life of the drug ti/2; for example, it can be less than one half of ti/2, less than 1 /3rd of ti/2, or less than 1/4 of ti/2, or less than 1/1 Oth of ti/2.

Retainers

The retainers of the invention are designed for use by most patients and allow for widely varied dentition. For example, the retainers are usable by patients with upper and lower third molars, missing teeth, partial or full dentures, bridges, and caps. The retainers can provide a pathway for a delivery tube to travel across the occlusal surface of the teeth.

To prevent their being accidentally swallowed or aspirated into the trachea, intraoral drug delivery devices are secured in the mouth using a retainer. They may be secured to the surface of one or more teeth and can be secured such that they are positioned on the teeth.

For delivery of some drugs, such as LD or CD, it can be desirable to administer the drugincluding solid or fluid on the lingual side of the teeth, rather than on the buccal side of the teeth, in order to minimize the residence time of the drug in the mouth, thereby avoiding potential accumulation of the drug in the buccal vestibule and minimizing potentially irritating exposure of the buccal tissue to the drug. In a preferred embodiment, pump includes a delivery tube to transport the drug-including fluid into the mouth. The delivery tube carries the drug-including fluid from the drug reservoir located on the buccal side of the teeth to or near the lingual side of the teeth. The retainer or its components may be manufactured using methods known in the art, such as thermoforming, injection molding, pressure molding, and laminating. In addition, the retainer can be personalized to a patient’s dental anatomy for comfortable wear and for absence of interference with speech or drinking. In some embodiments, the retainer (e.g., a transparent retainer) may include 2, 3, 4 or more layers of different hardness, to ease insertion and removal from the teeth. For example, the retainer may include a dual laminate with a softer, inner, tooth-contacting layer, and a harder, outer layer contacting the cheeks and tongue. In some embodiments, the retainer is made of a plastic, such as an acrylate-containing polymer or an olefin-containing polymer. For example, the retainer may be made of a thermoplastic polyolefin, such as polypropylene. The plastic may be an Essix® PLUS™ plastic, an Essix A+® plastic, an Essix C+® plastic, an Essix ACE® plastic, an Essix® dual laminate plastic, an Essix® nightguard laminate plastic, an Essix® sports mouthguard material, an Essix® laminated sports mouthguard material, an Essix® bleach tray and model duplication material, an Essix Tray Rite® plastic, a Dreve Drufosoft® Pro plastic, a Dreve Kombiplast plastic, a Dreve BioIon plastic, or a Dreve Drufosoft® sports mouthguard material. In some embodiments, the retainer is made of nylon. In some embodiments, the retainer is 3D printed, which allows for standardization of certain parts of the retainer (e.g., the pocket) while allowing for variations in dental anatomy. A 3D printed retainer can be made from any suitable resin or other 3D printable material, such as KeySplint Soft®. In some embodiments, the retainer is milled.

In a preferred embodiment, the retainer is reusable, and may be reused for a period of equal to or greater than 7, 30, 60 or 180 days, or one year or two years.

The retainer can include a receptacle, such as a pocket, for holding the drug delivery device, which can be fabricated as an integral part of the retainer, for example, by molding or 3D printing, and it can prevent accidental removal of the device during its handling. The pocket can be positioned to hold the drug delivery device on the buccal side of the teeth, positioning the device in the cheek pocket for comfort. The pocket can be used to attach the device to a buccal surface of one or more teeth, for example, to the buccal surface of the first molar and/or the second bicuspid. The pocket can also prevent dislodging of the device during insertion of the retainer or wear and can position the device such that it is in the proper orientation for administration of a drug-containing fluid into the mouth. In some embodiments, the pocket is designed with a feature that maintains an interference fit (also known as a friction fit) with the drug delivery device by way of friction to prevent the device from becoming dislodged (e.g., dislodged from the pocket during insertion into the mouth or administration of the pharmaceutical composition). For example, the interference fit may be produced by a tight fit between the mating parts (e.g., the pocket of the retainer and the housing of the drug delivery device) that produces a joint that is held together by friction after the drug delivery device is pushed into the pocket of the retainer. Alternatively, the drug delivery device can be reversibly secured in the pocket with a detent, groove, snap, or lock. In some embodiments, the pocket is configured such that the drug delivery device cannot be dislodged from the pocket while being attached to a surface of the patient’s mouth or during use in the mouth. In some embodiments, the pocket is configured such that the patient’s oral anatomy would mechanically interfere with and prevent the removal of the drug delivery device from the pocket when the retainer is attached to the surface of the patient’s mouth. The drug delivery device can be positioned within the pocket such that the outlet of the delivery tube through which the drug-containing fluid (e.g., drug-containing suspension, emulsion, or paste) leaves the assembly is on or near the lingual side of the teeth, meaning that drug-containing fluid from the device residing in the cheek pocket, or buccal pocket, is delivered to the saliva-rich lingual side of the teeth, near the salivary glands. In a preferred embodiment, the pocket of the retainer is located on the buccal side of the upper molars and/or bicuspids and holds the drug delivery device such that the delivery tube of the drug delivery device delivers drug on the lingual side of the teeth. The drug device can be inserted (e.g., pushed) into the pocket before the retainer is inserted into the mouth and the drug delivery device may be removed from the pocket by pushing on the device (e.g., when the device is outside of the mouth of a patient, such as after the retainer is removed from the mouth). In some embodiments, the retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer (e.g., the drug delivery device is pushed into the pocket from behind, such that the drug delivery device moves toward an anterior portion of the retainer as it is inserted into the pocket). In other embodiments, the retainer is configured such that the drug delivery device is inserted into the pocket from below an occlusal plane of the retainer (e.g., the drug delivery device is pushed into the pocket from below, such that the drug delivery device moves toward the top of the retainer (the top of the pocket) as it is inserted into the pocket). The retainer may also be configured such that the drug delivery device is inserted into the pocket from a side of the retainer (e.g., from the buccal side, e.g., in a direction that would be away from the cheek and toward the buccal surface of a tooth that is adjacent to the pocket when the retainer is worn).

The retainer can position the drug delivery device coplanar with the occlusal plane of a molar, such as the first molar or second molar. The retainer can be worn over some or all of the bicuspids and molars and can position the drug delivery device such that the device spans only the first and second molars, with its midline on the occlusal plane of the molars (e.g., the occlusal plane of the first or second molar), and its posterior end between the midline and the posterior of the first or second molar. The drug delivery device can also be positioned within the retainer (e.g., in the pocket) such that it is set on the Wilson plane. This set of constraints ensures that the device is comfortable, as positioning the device too far up into the buccal vestibule can cause discomfort and pain. Positioning the drug delivery device on the first and second molars ensures that the device remains planar with only two teeth, which limits its protrusion outward toward the cheek. The retainer and drug delivery device can be matched to the dentition of the patient.

The retainer may cover at least one bicuspid (e.g., may cover a buccal, lingual, and occlusal surface of a first and second bicuspid, such as an upper first and second bicuspid or a lower first and second bicuspid) and at least one molar (e.g., may cover a buccal, lingual, and occlusal surface of a first molar, a first and second molar, or a first, second, and third molar, such as an upper first and second molar or an upper first, second, and third molar or a lower first and second molar or a lower and first, second, and third molar) in at least one quadrant of the mouth. The retainer is configured to allow a delivery tube in fluid communication with a drug reservoir positioned on the buccal side of the teeth to deliver a pharmaceutical composition from the drug reservoir to or near the lingual side of the teeth by passing across the occlusal surface (the biting surface) of the teeth. In some embodiments, the retainer covers an occlusal surface of a first tooth and leaves at least a portion of an occlusal surface of a second tooth uncovered. In some embodiments, the thickness of the retainer where it covers the occlusal surface of the first tooth is equal to or greater than the external diameter of the delivery tube, and thereby provides space for the delivery tube to extend across the portion of the second tooth that is uncovered (e.g., from the buccal side of the tooth to or toward the lingual side of the tooth) without being compressed or crushed between the teeth (e.g., between the occlusal surfaces of the upper and lower teeth) when a patient wearing the retainer bites down. For example, the thickness of the retainer where it covers the occlusal surface of the first tooth is about 1 .0 mm to about 2.5 mm (e.g., about 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4, or 2.5 mm, e.g., about 1 .5 mm) and the external diameter of the delivery tube is about 1 .0 mm to about 2.25 mm (e.g., 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.25 mm, e.g., about 1 .5 mm). In some embodiments, the thickness of the retainer and the external diameter of the delivery tube are both about 1 .5 mm. The separation between the teeth (e.g.., between the portion of the second tooth that is uncovered and the opposing tooth that would otherwise meet the second tooth when the patient bites down) that is provided by the thickness of the retainer where it covers the occlusal surface of the first tooth provides a space for the delivery tube to pass over the occlusal surface of the teeth. The first tooth may be a bicuspid or a molar and the second tooth may be a bicuspid or a molar. For example, the first tooth may be an upper first molar and the second tooth may be an upper second molar, or the first tooth may be an upper second molar and the second tooth may be an upper third molar. In some embodiments, the second tooth (e.g., the tooth that is at least partially uncovered, the occlusal surface of which the delivery tube passes over) is a second molar (e.g., an upper or lower second molar). In some embodiments, the retainer is configured such that the occlusal surface covered by the retainer is positioned in front of (i.e. , anterior to or on the mesial side of) the delivery tube and the occlusal surface that is left uncovered extends from said delivery tube (e.g., from just anterior to the delivery tube or from the anterior side of said delivery tube) to a rear (i.e., a distal side) of said patient’s rearmost tooth (i.e., the most distal tooth or back tooth) in a quadrant of the mouth containing the delivery tube when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient (e.g., all of the occlusal surfaces starting from the location of the delivery tube and extending distally to the distal side of the rearmost tooth are uncovered). An example of this configuration is shown in FIG. 4A. Depending on the location of the delivery tube, the occlusal surface of one or more teeth (e.g., one, two, three, or more teeth, such as the third molar, the second and third molar, or the first, second, and third molar) may be left uncovered by the retainer. In some embodiments, only the portion of the occlusal surface over which the delivery tube is designed to pass is left uncovered by the retainer (e.g., the retainer is configured to cover the surrounding occlusal surfaces and to only leave a gap for the passage of the delivery tube). In some embodiments, the retainer covers an occlusal surface of a first tooth and contains a recess that leaves a portion of an occlusal surface of a second tooth uncovered (i.e., uncovered by the retainer), as shown in FIGS. 1A-1 B and 3A-3C. The recess may correspond to a cut-out or gap in the portion of the retainer that is configured to cover the occlusal surface of the second tooth and may leave at least a portion of the occlusal surface of the second tooth exposed. The recess can have a depth and width that is equal to or greater than an external diameter of the delivery tube, which allows the delivery tube to fit inside the recess. For example, the depth and width of the recess may be about 1 .0 mm to about 2.5 mm (e.g., about 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4, or 2.5 mm, e.g., about 1 .5 mm) and the external diameter of the delivery tube can be about 1 .0 mm to about 2.25 mm (e.g., 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.25 mm, e.g., about 1 .5 mm). In some embodiments, the depth and width of the recess and the external diameter of the delivery tube are about 1 .5 mm. In this embodiment, the delivery tube can pass across the occlusal surface of the second tooth by extending through the recess from the buccal side of the second tooth to or near the lingual side of the second tooth, which allows the delivery tube to avoid being compressed or crushed when a patient wearing the retainer bites down. The first tooth may be a bicuspid or a molar and the second tooth may be a bicuspid or a molar. For example, the first tooth may be an upper first molar and the second tooth may be an upper second molar, or the first tooth may be an upper second molar and the second tooth may be an upper third molar. In some embodiments, the second tooth (e.g., the tooth that is at least partially uncovered by the recess, the occlusal surface of which the delivery tube passes over when positioned in the recess) is a second molar (e.g., an upper or lower second molar). In some embodiments, the recess is positioned between two teeth (e.g., between two adjacent molars or between a molar and a bicuspid). In some embodiments, the recess may span an interproximal space between two teeth, such as an interproximal space between the upper second and third molars or the interproximal space between the first and second molars. In some embodiments, the recess extends from the buccal side of the second tooth to the lingual side of the second tooth (e.g., as shown in FIGS. 1 A, 3A, and 3C). Preventing the delivery tube from being compressed or crushed allows the continuous or semi-continuous administration of the pharmaceutical composition to be maintained (e.g., at a constant rate) when the delivery tube extends across the occlusal surface of the teeth since compression or crushing of the delivery tube by the teeth (e.g., between the upper and lower teeth, as is shown in FIGS. 2C-2D) could cause administration of the pharmaceutical composition to be slowed or stopped. In any of the above embodiments, the delivery tube may be configured to extend all the way across the occlusal surface of a tooth (i.e., the delivery tube terminates at or beyond the lingual side of the tooth over which it extends when the drug delivery device is positioned in the retainer pocket and the retainer is positioned on the teeth). Alternatively, the delivery tube may be configured such that the distal end of the delivery tube is positioned on the occlusal surface of the tooth over which it extends (i.e., the delivery tube does not extend all the way across the occlusal surface of the tooth when the drug delivery device is positioned in the retainer pocket and the retainer is positioned on the teeth but is still capable of delivering drug to the lingual side of the patient’s teeth). For example, the delivery tube may be configured to terminate about halfway across the occlusal surface of the tooth over which it extends (e.g., about halfway across the occlusal surface of a second molar), or may be configured to terminate closer to the lingual side of the tooth (e.g., the delivery tube may terminate about two thirds of the way across the occlusal surface of the tooth, three quarters of the way across the occlusal surface of the tooth, or more without reaching the lingual side of the tooth when the drug delivery device is positioned in the retainer pocket, as shown in FIGS. 3B and 3D in which the distal end of the delivery tube is configured to be near the lingual side of the tooth it extends across but not to extend all the way to the lingual side of the tooth).

In one example, for a subject having upper and lower third molars, the retainer covers the upper first and second bicuspids and upper first and second molars on both the right and left sides of the mouth (e.g., covers the buccal, lingual, and occlusal surfaces of the first and second bicuspids and molars) and leaves the upper third molars uncovered. The retainer contains a pocket for positioning a drug delivery device on the buccal side of the first and/or second upper molar on one side of the mouth (e.g., on the right side of the mouth) such that when the drug delivery device is inserted into the pocket, the delivery tube extends from the drug delivery device on the buccal side of the teeth across the occlusal surface of the uncovered upper third molar (e.g., the right upper third molar) to or toward the lingual side of the teeth. The thickness of the retainer where it covers the occlusal surface of the second molar is equal to or greater than the external diameter of the delivery tube, which provides a space for the delivery tube to pass over the occlusal surface of the third molar without being compressed when the patient wearing the retainer bites down. The retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer (e.g., the drug delivery device is pushed into the pocket from behind (e.g., from the back or distal edge of the pocket), such that the drug delivery device moves toward an anterior portion of the retainer (e.g., toward an anterior edge of the pocket) as it is inserted into the pocket). In a second example, the retainer covers the upper first and second bicuspids and upper first molars on both the right and left sides of the mouth (e.g., covers the buccal, lingual, and occlusal surfaces of the first and second bicuspids and first molars) and leaves at least a portion of one or both of the upper second molars uncovered. If the subject has upper third molars (a left upper third molar, a right upper third molar, or both), they may be covered by the retainer or left uncovered. The retainer contains a pocket for positioning a drug delivery device on the buccal side of the upper bicuspids and/or molars (e.g., the buccal side of the second bicuspid and/or first molar) on one side of the mouth (e.g., on the right side of the mouth) such that when the drug delivery device is inserted into the pocket, the delivery tube extends from the drug delivery device on the buccal side of the teeth across the uncovered occlusal surface of the upper second molar (e.g., the right upper second molar) to or toward the lingual side of the teeth. The thickness of the retainer where it covers the occlusal surface of the first molar is equal to or greater than the external diameter of the delivery tube, which provides a space for the delivery tube to pass over the occlusal surface of the second molar without being compressed when the patient wearing the retainer bites down. The retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer (e.g., the drug delivery device is pushed into the pocket from behind (e.g., from the back or distal edge of the pocket), such that the drug delivery device moves toward an anterior portion of the retainer (e.g., toward an anterior edge of the pocket) as it is inserted into the pocket), or such that the drug delivery device is inserted into the pocket from a side of the retainer (e.g., from the buccal side, e.g., in a direction that would be away from the cheek and toward the buccal surface of a tooth that is adjacent to the pocket when the retainer is worn).

In another example, for a subject having upper and lower third molars, the retainer covers the upper first and second bicuspids and first, second, and third molars on both the right and left sides of the mouth (e.g., covers the buccal, lingual, and occlusal surfaces of the first and second bicuspids and first, second, and third molars). The retainer contains a recess spanning the interproximal space between the second and third molars (e.g., the right upper second and third molars) and a pocket for positioning a drug delivery device on the buccal side of the first and/or second upper molar (e.g., the upper right first and second molars) such that when the drug delivery device is inserted into the pocket, the delivery tube extends from the drug delivery device on the buccal side of the teeth through the recess to or near the lingual side of the teeth. The recess has a width and depth that is greater than or equal to the external diameter of the delivery tube, which allows the delivery tube to fit within the recess and avoid being compressed when the patient wearing the retainer bites down. In some embodiments, the recess also exposes a portion of one or both of the second and third molars (e.g., a portion of an occlusal surface of the second molar or the third molar, or a portion of an occlusal surface of each of the second and third molars). The retainer is configured such that the drug delivery device is inserted into the pocket from below an occlusal plane of the retainer (e.g., the drug delivery device is pushed into the pocket from below, such that the drug delivery device moves toward the top of the retainer (e.g., the top of the pocket) as it is inserted into the pocket) or such that the drug delivery device is inserted into the pocket from a side of the retainer (e.g., from the buccal side, e.g., in a direction that would be away from the cheek and toward the buccal surface of a tooth that is adjacent to the pocket when the retainer is worn). In yet another example, the retainer covers the upper first and second bicuspids and first and second molars on both the right and left sides of the mouth (e.g., covers the buccal, lingual, and occlusal surfaces of the first and second bicuspids and first and second molars). The retainer may optionally cover the upper third molar(s), if present. The retainer contains a recess spanning an occlusal surface of the second molar (e.g., the right upper second molar) and a pocket for positioning a drug delivery device on the buccal side of the teeth (e.g., the upper molars or bicuspids, such as the upper right second bicuspid and/or first molar) such that when the drug delivery device is inserted into the pocket, the delivery tube extends from the drug delivery device on the buccal side of the teeth through the recess to or near the lingual side of the teeth. The recess has a width and depth that is greater than or equal to the external diameter of the delivery tube, which allows the delivery tube to fit within the recess and avoid being compressed when the patient wearing the retainer bites down. The retainer can be configured such that the drug delivery device is inserted into the pocket from below an occlusal plane of the retainer (e.g., the drug delivery device is pushed into the pocket from below, such that the drug delivery device moves toward the top of the retainer (e.g., the top of the pocket) as it is inserted into the pocket), or such that the drug delivery device is inserted into the pocket from a side of the retainer (e.g., from the buccal side, e.g., in a direction that would be away from the cheek and toward the buccal surface of a tooth that is adjacent to the pocket when the retainer is worn).

In some embodiments, the retainer is unilateral and only covers teeth on one side of the mouth (e.g., 2, 3, 4, 5, or more teeth in a single quadrant, such as teeth of the upper right or upper left quadrant, or teeth of the lower right or lower left quadrant). The retainer may cover, for example, some or all of the first and second bicuspid and first, second, and, if present, third molar (e.g., in a single quadrant, such as a buccal, lingual, and occlusal surface of at least two or more of these teeth in a single quadrant).

In some embodiments, the retainer is bilateral and covers teeth on both sides of the mouth (e.g., 2, 3, 4, 5, or more teeth in both upper quadrants or both lower quadrants). In this embodiment, the retainer can cover some or all of the first and second bicuspid and first, second, and third molars on both the left and right sides (e.g., a buccal, lingual, and occlusal surface of a first and second bicuspid and first, second, and, if present, third molar on the right and left side of the mouth). The retainer may include a single recess on one side (e.g., a recess spanning an interproximal space between an upper second and third molar or an upper first and second molar on the left or right side or a recess spanning an occlusal surface of a second molar) or it may include a recess on both the left and right sides (i.e., for a total of two recesses, one on each side). In embodiments in which the retainer contains a single recess, the retainer pocket is positioned on the same side of the retainer (e.g., on the right or left side) as the recess. In embodiments in which the retainer contains two recesses (e.g., one for the teeth on the left side and one for the teeth on the right side), the retainer may contain a pocket adjacent to each recess.

In embodiments in which the retainer is bilateral, portions of the retainer covering teeth on the right and left sides (e.g., some or all of the first and second bicuspid and first, second, and third molars on both the left and right sides) may be joined by a palatal strap (exemplified in FIGS. 3A-3D and FIG. 4A) or palatal bar, by an incisor connector (i.e., a strap covering the incisors, which is observed in an aligner style retainer), or by a lingual connector (i.e., a strap located behind the lingual surface of the teeth that are not covered by the retainer, such as the incisors and, optionally, the canines, which is observed in a partial aligner style retainer and exemplified in FIGS. 1 A-1 B).

A partial aligner style retainer includes a lingual connector that contacts the lingual surface of all intervening teeth (e.g., in a bilateral retainer worn on the upper teeth, it may run behind all of the teeth in the upper arch between the right and left bicuspids). An aligner style retainer may cover one or more of a labial/buccal surface, an incisal/occlusal surface, and a lingual surface of all intervening teeth (e.g., an incisor connector joins the portions of the retainer covering the bicuspids and/or molars, e.g., in an aligner style retainer worn on the upper teeth, the retainer covers all of the upper teeth). In the palatal bar or palatal strap style, the strap can be positioned to span approximately halfway the hard and soft palates (e.g., approximately half of the hard palate and half of the soft palate is covered by the palatal strap of the retainer) to improve comfort and minimize the disruption of speech. The hard palate is only partially covered by the retainer to ensure that speech is not affected, and the soft palate is only partially covered by the retainer to prevent discomfort and/or gag reflex.

In some embodiments, the retainer is configured to maintain a neutrocentric occlusion (e.g., a bite-neutral occlusion), in which the occlusal surfaces of all teeth contact each other or the retainer when the patient wearing the retainer bites down. This prevents eruption of teeth and may be particularly beneficial if the retainer will be worn overnight or while eating.

An exemplary retainer is shown in FIGS. 1 A-1 B. The retainer can be made of a plastic, such as an acrylate-containing polymer. In some embodiments, the retainer is made of Essix® PLUS™ plastic. In some embodiments, the retainer is 3D printed (e.g., made of a 3D printable resin). As shown in FIGS.

1 A-1 B, the bilateral, partial aligner style retainer includes a right and left portion, each of which covers the buccal, lingual, and occlusal surface of the first and second bicuspids and the first, second, and third molars. The left and right sides are joined by a lingual connector that contacts the lingual surface of all intervening teeth (e.g., the canines and incisors). Both the left and right sides of the retainer contain recesses that span the interproximal space between the upper second and third molars, as shown in FIG.

1 A. The retainer contains a single pocket for securing the drug delivery device in the buccal vestibule (e.g., attaching the drug delivery device to the surface of an upper molar, such as an upper first molar), which is located on the right side of the retainer. The retainer pocket is an integral part of the retainer. The delivery tube is in fluid communication with the drug reservoir of the drug delivery device, which is located on the buccal side of the teeth. The delivery tube extends from the buccal side of the teeth across the occlusal surface of the teeth (e.g., across a surface of the teeth exposed by the recess) to release a pharmaceutical composition from the drug reservoir on the lingual side of the teeth (e.g., near the back of the mouth where it can be swallowed). As shown in FIG. 1 B, the recess in the retainer provides a space for the delivery tube to cross from the buccal side of the teeth to the lingual side of the teeth by passing over the occlusal surface of the third molar without being crushed by the teeth when a patient wearing the retainer bites down. This is possible because the distance between the occlusal surface of the third molar and the outer surface of the recess (e.g., the vertical distance between these surfaces) is equal to or greater than the diameter of the delivery tube (e.g., the outer diameter of the delivery tube, e.g., the depth of the recess is equal to or greater than the outer diameter of the delivery tube). The width of the recess is also greater than the diameter of the delivery tube. In the absence of a recess in the retainer, the delivery tube would be crushed between the teeth, as shown in FIGS. 2A-2D. The drug delivery device can be removed from the retainer when needed (e.g., to replace a drug delivery device that has been used continuously for 4 or more hours with a fresh drug delivery device, e.g., when more than half of the drug-containing fluid in the first drug delivery device has been delivered). The drug delivery device may be removed by first removing the retainer from the mouth and then pushing the drug delivery device out of the retainer pocket.

Another exemplary retainer is shown in FIGS. 3A-3D. The retainer can be made of a plastic, such as an acrylate-containing polymer. In some embodiments, the retainer is made of Essix® PLUS™ plastic. In some embodiments, the retainer is 3D printed (e.g., made of a 3D printable resin). As shown in FIGS. 3A-3B, the bilateral retainer includes a right and left portion, each of which covers the buccal, lingual, and occlusal surface of the first and second bicuspids and the first and second molars. The left and right sides are joined by a palatal strap. Only one side of the retainer contains a recess that spans the interproximal space between the upper first and second molars. The retainer contains a single pocket for securing the drug delivery device in the buccal vestibule (e.g., attaching the drug delivery device to the surface of an upper tooth, such as an upper second bicuspid and/or first molar), which is located on the same side of the retainer as the recess. The retainer pocket is an integral part of the retainer. The delivery tube is in fluid communication with the drug reservoir of the drug delivery device, which is located on the buccal side of the teeth. The delivery tube extends from the buccal side of the teeth across the occlusal surface of the teeth (e.g., across a surface of the teeth exposed by the recess) to release a pharmaceutical composition from the drug reservoir on the lingual side of the teeth (e.g., near the back of the mouth where it can be swallowed). As shown in FIGS. 3B and 3D, the delivery tube is fully contained within the recess. This is possible because the depth and width of the recess are equal to or greater than the diameter of the delivery tube (e.g., the outer diameter of the delivery tube). The delivery tube is straight and is connected to a nozzle adaptor that is L-shaped (i.e. , the nozzle adaptor extends from the drug delivery device, e.g., from a drug reservoir, on the buccal side of the teeth and makes a single 90 degree turn to direct the straight delivery tube through the recess and toward the lingual side of the teeth) and does not extend beyond the edge of the recess (e.g., terminates before reaching the lingual side of the teeth). The retainer is configured such that the drug delivery device can be inserted into the pocket from a side of the retainer (e.g., from the buccal side, e.g., in a direction that would be away from the cheek and toward the buccal surface of a tooth that is adjacent to the pocket when the retainer is worn). The drug delivery device can be removed from the retainer when needed (e.g., to replace a drug delivery device that has been used continuously for 4 or more hours with a fresh drug delivery device, e.g., when more than half of the drug-containing fluid in the first drug delivery device has been delivered). The drug delivery device may be removed by first removing the retainer from the mouth and then pushing the drug delivery device out of the retainer pocket.

Another additional retainer is shown in FIGS. 4A-4B. The retainer can be made of a plastic, such as an acrylate-containing polymer. In some embodiments, the retainer is made of Essix® PLUS™ plastic. In some embodiments, the retainer is 3D printed (e.g., made of a 3D printable resin). As shown in FIG. 4A, the bilateral retainer includes a right and left portion, each of which covers the buccal, lingual, and occlusal surface of the first and second bicuspids and the first and second molars. The left and right sides are joined by a palatal strap. The third molar is left uncovered by the retainer. The retainer contains a single pocket for securing the drug delivery device in the buccal vestibule (e.g., attaching the drug delivery device to the surface of an upper first molar). The retainer pocket is an integral part of the retainer. The delivery tube is in fluid communication with the drug reservoir of the drug delivery device, which is located on the buccal side of the teeth. The delivery tube extends from the buccal side of the teeth across the occlusal surface of the teeth (e.g., across the occlusal surface of the uncovered third molar) to release a pharmaceutical composition from the drug reservoir on the lingual side of the teeth (e.g., near the back of the mouth where it can be swallowed). As shown in FIG. 4B, the delivery tube can extend across the occlusal surface of the uncovered third molar (e.g., between the upper and lower third molars) without being compressed when the patient wearing the retainer bites down. This is possible because the thickness of the retainer where it covers the occlusal surface of one or more of the molars or bicuspids is equal to or greater than an outer diameter of the delivery tube. The retainer is configured such that the drug delivery device can be inserted into the pocket from a rear of the retainer (e.g., the drug delivery device can be pushed into the pocket from behind (e.g., from the back or distal edge of the pocket toward the anterior edge of the pocket), such that the drug delivery device moves toward an anterior portion of the retainer as it is inserted into the pocket). The drug delivery device can be removed from the retainer when needed (e.g., to replace a drug delivery device that has been used continuously for 4 or more hours with a fresh drug delivery device, e.g., when more than half of the drug-containing fluid in the first drug delivery device has been delivered) by first removing the retainer from the mouth and then pushing the drug delivery device out of the retainer pocket.

A retainer described herein can be used with any drug delivery device sized to fit within the mouth, such as drug delivery devices described in U.S. Publication Nos. US20160278899A1 and US20170172961 A1 and International Application Publication No. W02022/060909, which are incorporated herein by reference in their entirety.

Pumps

The pumps for the drug delivery devices are suitable for miniature devices carried safely and comfortably in the mouth. Any suitable pump may be used. The pump can be a mechanical pump, e.g., a propellant-driven pump, a spring-driven pump, an elastomer-driven pump, or a compressed gas-driven pump; an osmotic pump; or a battery-driven pump. The pump and the drug reservoir may be distinct. Miniature pumps are advantageous for placement in the mouth. For example, the extruded fluid including the drug may occupy more than 33%, 50%, 66%, or 75% of the total volume of the drug delivery device.

Pumps that do not require a battery can be smaller and have fewer moving parts than batteryrequiring electrical pumps. One group of nonelectric disposable pumps is based on the physical principle that mechanical restriction within the flow path by a flow restrictor can determine the flow rate of a pressurized fluid. The restriction of flow may be provided by an orifice (e.g., in the drug reservoir), by narrow-bore tubing (such as a metal, glass or plastic pipe), by a channel, by a capillary, or by a flowcontrolling nozzle. Optionally, the flow-controlling nozzles, channels, or tubes can be made of a plastic such as an engineering plastic or made of a metal or a ceramic such as a glass. The flow restrictor can have an internal diameter smaller than 1 mm or 2 mm and larger than 0.05 mm and a length between 0.25 cm and 10 cm (e.g., an internal diameter smaller than 0.7 mm and larger than 0.2 mm). Preferred internal diameters are 0.1 - 2 mm and preferred lengths are 0.25 - 5 cm.

Flow rate can be affected by the pressure gradient across the flow restrictor and by fluid viscosity. A significant source of inaccuracy in existing pump products can be that viscosity is strongly affected by temperature. An important benefit of carrying within the mouth the drug delivery devices is that the temperature is held nearly constant at about 37 °C, thereby minimizing variations in the rheological properties (such as viscosity and slip rate) and therefore in the infusion rate. The nearly constant about 37 °C is also advantageous in maintaining a stable pumping pressure when a gas, such as from a liquid propellant, is used to drive the pump.

The formulations used in the devices attached to a retainer described herein can be viscous suspensions. Use of viscous suspensions is often desired to achieve the small volumes, high concentrations, uniform drug dispersion, storage stability, and operational stability desired for continuous or semi-continuous intraoral drug delivery using a removable intraoral drug delivery device.

Consequently, it is often desired to employ pump mechanisms that can provide the pressures required to pump the viscous fluids.

The pressure difference required to extrude the viscous fluid, typically a paste, can be between 2 and 20 bar, such as between 3 and 12 bar, or such as between 4 and 8 bar. Any pump that can provide sufficient pressure can be used in the drug delivery device.

Any of the drug delivery devices described herein can include a pump and/or a drug reservoir described in U.S. Application Publication Nos. US20160278899A1 and US20170172961 A1 and International Application Publication No. W02022/060909, which are incorporated herein by reference in their entirety.

Propellant-driven pumps

In some embodiments, the drug delivery device is a device containing a propellant-driven pump that includes two or more compartments, with a propellant in at least one compartment and the pharmaceutical composition to be administered (e.g., a drug-containing paste, suspension, or emulsion) in at least one separate drug reservoir. The propellant provides the driving force. The two compartments are separated by a movable member (such as a flexible and/or deformable diaphragm) that transmits the force from the propellant compartment to the drug compartment. In one embodiment, the device for continuous or semi-continuous intraoral drug administration includes a chamber containing a propellant, a chamber containing a drug-including fluid such as a paste, and a flexible and/or deformable diaphragm separating the propellant chamber from the drug chamber. The housing of the device can be rigid and can be gas and liquid impermeable, for example impermeable to gaseous and liquid propellant, air, water vapor, liquid water, saliva and/or gaseous helium. In a preferred embodiment, the rigid housing forms a wall of a chamber containing the drug-including fluid and a wall of a chamber containing the propellant, and the two chambers are separated by a diaphragm. The diaphragm can include a wall of the first chamber and a wall of the second chamber. The diaphragm can be shaped to substantially conform to the interior housing wall of the first chamber and/or the interior housing wall of the second chamber. The device dispenses at least 50% (e.g., at least 50%, 60%, 70%, 80%, 90%, 99%, or more) of the weight of the drug-including fluid (e.g., paste) in the chamber, preferably while the rate of drug delivery, meaning the flow rate or extrusion rate, varies by less than ±20% (e.g., less than ±15%, less than ±10%, or less than ±5%) over a period of greater than or equal to 4, 8, 16, or 24 hours.

The housing containing the two compartments is typically constructed to have a fixed volume that does not vary significantly as the drug is dispensed. In a preferred embodiment, the propellant and a solid or fluid drug are contained within a rigid metal-walled housing, for example of titanium or titanium alloy or iron alloy or stainless steel, that does not significantly deform under the pressure of the propellant. The rigid wall of the drug and the propellant including chambers (which can comprise part of the housing) can be strong, dense and it can be metallic. The rigid housing of the chamber wall can be strong and includes a metal, ceramic, or a composite of a polymer reinforced by fibers. The fibers reinforcing the polymer can include, for example, carbon fibers, glass fibers, or metal fibers. When metallic, the metal of the housing can be selected from the group titanium, iron, aluminum, molybdenum, or tungsten, or an alloy of titanium, iron, molybdenum, or tungsten; it can be formed of, for example, titanium or an alloy of titanium or of a steel, e.g., a stainless steel, such as an austenitic stainless steel or a ductile stainless steel like 304, 308 or 316L stainless steel. Each of the propellant housing and the drug housing can have a wall thickness between 0.25 mm and 0.5 mm.

The propellant and the drug are separated within the housing by a deformable diaphragm, transmitting the pressure of the propellant vapor to the drug comprising fluid, typically a deformable semirigid paste. For hermeticity, the rims of the propellant housing and the metal diaphragm may be welded and residual pinholes in the weld, if any, may be sealed by applying a sealant on the exterior of the weld. The sealant can be polymeric, for example polysiloxane-comprising. Alternatively, the compartment separating deformable diaphragm can comprise a metalized polymer, such as three-layered polymer- aluminum-polymer. It can be adhered to the rim of the propellant compartment and/or to the rim of the drug comprising fluid compartment using an adhesive, such as an epoxy, polyurethane or polyacrylate adhesive.

In some embodiments, the propellant (e.g., a liquid propellant) boils at sea level atmospheric pressure at a temperature less than about 37 °C. At this temperature, the vapor-pressure of the liquefied propellant is typically greater than 2 bar pressure. Because upon its evaporation the volume of the liquid propellant increases greatly, the volume of the propellant compartment is small relative to the drug comprising fluid volume, typically less than 1/4, 1 /5^th, or 1 /8^th of the drug comprising fluid (e.g., paste) volume. Exemplary volatile propellant compounds for use in the devices include hydrocarbons (e.g., 2- methylpropane; pentane; 1 -pentene; trans-2-pentene; trans-dimethylcyclopropane; ethylcyclopropane; 1 ,4 -pentadiene; 2-methyl-1 ,3-butadiene; and methyl-1 -butane; 2-butyne); halocarbons (e.g., trichlorofluoromethane; difluoromethane; 1 ,1 -dichloro-1 -fluoroethane; 2,2-dichloro-1 ,1 ,1 -trifluoroethane; 1 - fluorobutane; 2-fluorobutane; perfluoropentane; 1 ,1 -dichloroethylene; cis-1 -chloropropene; and 2- chloropropene); esters (e.g., methyl formate); ethers (e.g., dimethyl ether), and hydrofluoroalkanes. In some embodiments, the propellant is trifluorochloromethane, dichlorofluoromethane, 1 ,2-difluoroethane, 2-butene, n-butane, 1 -fluoropropane, 1 -butene, 2-fluoropropane, 1 ,1 -difluoroethane, cyclopropene, propane, propene, or diethyl ether. Preferred propellants are those approved by the FDA for use in medication inhalers, such as 1 ,1 -difluoroethane (HFC-152a); 1 ,1 ,1 ,2 tetrafluoroethane (R-134a); and 1 ,1 ,1 ,2, 3, 3, 3 heptafluoropropane, sold as R-227ea. Also preferred are propellants approved by the FDA for topical applications, such as 1 ,1 ,1 ,3,3,3 hexafluoropropane (sold as R-236fa); and propellants approved for use in food and over the counter drug products, such as octafluorocyclobutane or isopentane. The propellant can have a vapor pressure of greater than 1 .5 bar and less than 20 bar at 37 °C, such as a vapor pressure of greater than 2.0 bar and less than 15 bar at 37 °C, or a vapor pressure of greater than 3.0 bar and less than 10 bar at 37 °C. In some embodiments, the propellant has a vapor pressure of about 4 atm or greater at 37 °C. The pump can maintain an internal pressure of greater than or equal to about 2 bar on the pharmaceutical composition.

Exemplary pressurized liquid propellants and their vapor pressures at 37 ^eC are listed in Table 1 . Table 1 .

The diaphragm separating the chamber containing the drug-including fluid from the chamber containing the propellant can be a deformable metal foil or it can include a flexible and/or deformable metal foil. In a preferred embodiment, the diaphragm separating the chamber containing the drug- including fluid from the chamber containing the propellant can be metallic. It can be a deformable, pinhole-free, metal foil or it can comprise a metal layer. The diaphragm may comprise a pinhole free a ductile metal foil, such as a titanium foil, a silver foil, or a foil of an austenitic stainless steel, typically of a thickness between 10 pm and about 1 mm, e.g., between 10 pm and 250 pm, 10 pm and 75 pm, such as between 25 pm and 75 pm. In some embodiments, the diaphragm includes a rim that is thicker than the center of the diaphragm. In one embodiment, the metallic diaphragm is uniformly thick. The thickness and the associated rigidity of the diaphragm, meaning its resistance to change of shape under stress, can vary by less than ±25 % across the diaphragm, such as by less than ±10 %. The metallic diaphragm can include, for example, a silver or an alloy of silver; or it can include aluminum or an alloy of aluminum; or it can include magnesium or an alloy of magnesium; or it can include titanium or an alloy of titanium; or it can include tin or an alloy of tin; or it can include copper or an alloy of copper; or it can include steel such as stainless steel. For example, the metallic diaphragm can be a foil of annealed silver, or of an annealed austenitic stainless steel, such as 304, 308 or 316L stainless steel. The metal foil (e.g., silver or stainless steel) diaphragm can be pinhole-free; the metal layer (e.g., of titanium, aluminum, or magnesium) can have pinholes when in contact with a polymer layer, optionally on both of its sides. In some embodiments, for example when both the housing wall and the diaphragm are of similar metals such as stainless steels, the rims of the diaphragm can be attached to the rims of either or both the propellant and drug housings by welding. When the diaphragm comprises metal and polymer layers, its rim can be adhered to those of the housings using an adhesive, such as a two-part epoxy, a polyacrylate or a polyurethane.

The housing wall of the propellant chamber can include a sealable port (e.g., containing a grommet, septum, or similar resealable member) for filling the propellant chamber with propellant (e.g., for injecting the propellant, e.g., using a needle). The sealable port may contain a septum eyelet, which may be made of metal, such as titanium or titanium alloy, and a septum (e.g., an elastomeric and compressible septum, such as a rubber septum, e.g., a septum containing nitrile rubber) that can be inserted into the eyelet (e.g., to form a hermetic seal).

The housing wall of the drug chamber can include one or more sealable or sealed ports that allow for the introduction of a pharmaceutical composition. The port may be temporarily or permanently sealed prior to or after the filling process, e.g., by a plug, grommet, or septum. A port may also be used for delivery of the drug during operation of the device, e.g., by attaching a plugged drug delivery tube. In combination with a chamber wall thickness of about 0.015 inches, the plugged port can sustain a pressure of about 12 bar.

Patient compliance depends on the drug delivery device and retainer being comfortable when worn in the mouth. Preferably, the system does not substantially affect the appearance of the wearer, impede speech, or impede swallowing and drinking. In general, it is preferred that the pump and/or its drug outlet be located such that the likelihood of excessive drug accumulation in the buccal vestibule is avoided. To avoid irritation of tissue the surfaces of the pump are smooth. For example, pump surfaces contacting buccal tissue may have protrusions that are less than about 100 pm, e.g., less than about 30 pm, 10 pm, 5 pm, or 1 pm.

The pump can be, for example, substantially obround shaped or it can be substantially flattened teardrop shaped. The dimensions of the substantially obround-shaped pump are width, measured from the vestibular surface of the teeth outward, height measured in the direction of tooth eruption, and length measured along the direction of a series of teeth, typically including a molar. The width (outer dimension, OD) of the pump housing can be between about 3 mm and about 10 mm; its height (OD) can be between about 5 mm and about 18 mm; its length (OD) can be between about 10 mm and about 30 mm. Preferably, the length of the pump housing can be such that the pump housing spans one or two teeth, but not three teeth. The thickness of the wall of the rigid housing can be between about 0.2 mm and about 2 mm, such as between about 0.3 mm and about 1 .0 mm.

When stored, the pump can be hermetically sealed. When in use, the drug can flow or be extruded through the one, two, or more drug delivery ports.

The drug delivery device may contain one or more (e.g., one, two, three, or more) flow restrictors. The flow restrictors regulate flux (e.g., control the administration rate) of the drug-containing fluid, and can be mounted in coupling adaptor connected to the delivery tube. The flow restrictors (e.g., nozzles, channels, tubes, or orifices) can be made of a plastic, such as an engineering plastic. The engineering plastic can include a polyamide, a polyester, a polycarbonate, a polyetheretherketone, a polyetherketone, a polyimide, a polyoxymethylene, or polyphenylene sulfide, a polyphenylene oxide, a polysulfone, a polytetrafluoroethylene, a polyvinylidene difluoride, an ultra-high-molecular-weight polyethylene, or a strong elastomer. In a device containing two or more flow restrictors, the flow restrictors may be of the same length or of different lengths and may have the same internal diameter or different internal diameters. The flow restrictor may be made of metal, glass, or plastic and, in embodiments in which the device contains two or more flow restrictors, the flow restrictors may be made of the same or of different material. Preferably, in embodiments in which the drug delivery device contains two or more flow restrictors, all of the flow restrictors are made of the same material. The flow restrictor may be made of any polymer that has a low water permeability and that is chemically inert. In some embodiments, the flow restrictor is made of a thermoplastic polymer, such as polypropylene, polyethylene, polyvinyl chloride, polystyrene, acrylic, polyamide (nylon), acrylonitrile butadiene styrene, polycarbonate, or polyvinylidene fluoride. In some embodiments, the flow restrictor is made of a thermoset polymer. In some embodiments, the flow restrictor is made of a thermoplastic polyester, such as polybutylene terephthalate (PBT), polyethylene terephthalate (PET), or polyethylene furanoate (PEF). In some embodiments, the flow restrictor is made of PET. In embodiments in which the drug delivery device contains two or more flow restrictors, the flux (e.g., flow rate or administration rate) through the two or more flow restrictors may be about the same or it may be different. Preferably, in embodiments in which the drug delivery device contains two or more flow restrictors, the flux (e.g., flow rate) through each flow restrictor will be about the same. When two or more flow restrictors of different lengths (e.g., two flow restrictors of different lengths that extend into different regions of the drug chamber) are included in the device, each flow restrictor can deliver drug-containing fluid from a different part of the drug chamber. When the device contains two or more flow restrictors (e.g., two flow restrictors), the lengths of the flow restrictors are such that each flow restrictor targets (e.g., terminates at) a different location in the drug chamber on one end and does not extend into the bend of the delivery tube on the other end. The internal diameters of the two or more flow restrictors can be selected to achieve a desired flow rate, and the internal diameter of each flow restrictor can be sized such that the flow rate between the two or more flow restrictors is matched as closely as possible (e.g., the flow rate through each flow restrictor is approximately the same) to prevent different regions of the drug chamber from emptying at different rates (e.g., to ensure that the regions of the drug chamber in which the two or more flow restrictors terminate empty at approximately the same rate). A pump may contain two flow restrictors fluidically connected to the drug reservoir, in which the first flow restrictor has a length of 6 - 12 mm and an internal diameter of 0.0100 - 0.0120 inches (e.g., 0.0115 inches), and the second flow restrictor has a length of 14 - 24 mm and an internal diameter of 0.0130 - 0.0145 inches (e.g., 0.0130 or 0.0135 inches).

The drug delivery devices can release the drug-containing fluid contained within the device (e.g., within the drug reservoir) into the mouth via a polymeric fluidic channel. The polymeric fluidic channel can be attached to the housing of the drug reservoir and in fluidic communication with the pharmaceutical composition. The polymeric fluidic channel may also contain a bend of 45 to 135 degrees (e.g., a bend of 80 to 100 degrees, e.g., a 90-degree bend). This bend may direct the polymeric fluidic channel toward a lingual side of the patient’s teeth when the drug delivery device is worn on a buccal side of the patient’s teeth. In embodiments in which the polymeric fluidic channel contains a bend, the bend can be located in the portion of the polymeric channel that is closest to the drug reservoir (e.g., the bend in the polymeric fluidic channel may be less than 0.5, 1 .0, 1 .5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or 7.5 mm from the exterior of the drug reservoir) and the remaining portion of the polymeric fluidic channel can be straight. In some embodiments, a majority of the length of the polymeric fluidic channel is straight (e.g., at least 50%, 60%. 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more of the length of the polymeric fluidic channel is straight). In some embodiments, the polymeric fluidic channel includes a delivery tube, which is fluidically connected to the drug reservoir. The delivery tube, also termed outlet tube, can have a length of 0.5 cm to 5 cm and an internal diameter of 0.010 inches to 0.08 inches. The delivery tube can be multilayered and is shaped and located in the mouth so as not to interfere with speech. In some embodiments, the delivery tube is straight. In some embodiments, the straight delivery tube has a length of about 5 mm to about 15 mm (e.g., about 5 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 mm, e.g., a length of about 10 mm). In some embodiments, the delivery tube has an external (outer) diameter of about 1 .0 mm to about 2.25 mm (e.g., about 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.25 mm, e.g., an external diameter of about 1 .5 mm). The delivery tube may have an internal diameter of about 0.7 mm to about 2 mm (e.g., about 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, or 2.0 mm, e.g., an external diameter of about 1 .2 mm). In some embodiments, the polymeric fluidic channel further includes a nozzle adaptor, which may be the part of the polymeric fluidic channel that contains a bend of 45 to 135 degrees (e.g., a bend of 80 to 100 degrees, e.g., a bend of 90 degrees). In some embodiments, the polymeric fluidic channel is L-shaped (e.g., the polymeric fluidic channel contains a straight delivery tube fluidically connected to a nozzle adaptor that extends from the drug delivery device and makes a single 90 degree turn to ensure that the straight delivery tube can extend across the occlusal surface of a tooth when the drug delivery device is worn on a buccal side of the teeth). The nozzle adaptor can be connected to the drug delivery device (e.g., connected directly to the drug reservoir or drug chamber so the pharmaceutical composition flows out of the drug reservoir and into the nozzle adaptor) and can direct the pharmaceutical composition from a drug reservoir located on the buccal side of a patient’s teeth toward the lingual side of the teeth (e.g., by creating a 90-degree turn in the fluid path of the pharmaceutical composition that can direct it into a delivery tube that extends across the occlusal surface of a tooth to or near the lingual side of the teeth when the drug delivery device is worn on a buccal side of the teeth). In some embodiments, the bend in the polymeric fluidic channel (e.g., the nozzle adaptor containing a bend) is upstream of (e.g., closer to the drug reservoir than) the delivery tube. In some embodiments, the distal end of the delivery tube (i.e., the end of the delivery tube from which the pharmaceutical composition is released) is on the lingual side of the patient’s teeth (e.g., the delivery tube extends all the way across the occlusal surface of the tooth over which it passes and terminates at the lingual side of the tooth or extends beyond the lingual side of the tooth). In other embodiments, the distal end of the delivery tube is on an occlusal surface of the teeth (e.g., on the occlusal surface of the tooth it extends across, meaning that the delivery tube does not extend all the way across the occlusal surface, e.g., the delivery tube terminates before reaching the lingual side of the tooth) while still allowing drug to be delivered on the lingual side of the patient’s teeth (e.g., the distal end of the delivery tube is near the lingual side of the tooth it extends across but does not reach or extend beyond the lingual side of the tooth, as shown in FIGS. 3B and 3D). In some embodiments, the distal end of the delivery tube is positioned in the middle of the occlusal surface of the tooth (e.g., the delivery tube terminates about halfway across the occlusal surface of the tooth, such as halfway across the occlusal surface of a second molar). In some embodiments, the delivery tube is configured to terminate on the occlusal surface of the tooth closer to the lingual side of the tooth (e.g., the distal end of the delivery tube may be positioned about two thirds of the way across the occlusal surface of the tooth, three quarters of the way across the occlusal surface of the tooth, or closer to the lingual side of the tooth without reaching the lingual side of the tooth when the drug delivery device is positioned in the retainer pocket and the retainer is placed on the teeth). Including an L-shaped polymeric fluidic channel containing a delivery tube fluidically connected to a nozzle adaptor in which the distal end of the delivery tube is on an occlusal surface of the teeth (e.g., doesn’t extend beyond the lingual side of the tooth it extends across, such as terminating about halfway across the occlusal surface of the tooth it extends across) has the benefit of reducing or eliminating interference of the delivery tube with the tongue, which may improve comfort and reduce disruption of speech for a patient using the drug delivery device. In some embodiments, the polymeric fluidic channel also contains an external flow restrictor, which may be positioned between the nozzle adaptor and the delivery tube. In some embodiments, the external flow restrictor and delivery tube are combined to form a single component that is connected to the nozzle adaptor (which may be referred to as an external flow restrictor tube). The external flow restrictor may modify the flow rate of the pharmaceutical composition. The delivery tube can contain two laminated polymer layers: an outer layer, typically made of an elastomeric biocompatible (e.g., compatible with living tissue, for example, the material does not cause sensitivity or irritation of the oral mucosa and does not cause systemic toxicity or cytotoxicity) polymer, such as a polyurethane or a crosslinked polyethylene glycol (PEG) derivative, such as polyethylene glycol) diacrylate or poly(lactide-co-glycolide) (PLGA), and an inner, mechanically strong polymer layer that reduces the permeation of water and is compatible with the components of the drugcontaining fluid (e.g., its water, oil, and surfactant), such as polyethylene terephthalate (PET), high density polyethylene (HDPE), polyvinylidene chloride (PVDC), polytetrafluoroethylene (PTFE), or polymeric fluorinated ethylene propylene (FEP). In some embodiments, the delivery tube contains a single layer of a biocompatible thermoplastic elastomer, such as a thermoplastic polyurethane elastomer, e.g., Pellethane®. When the drug delivery device is located in the cheek pocket and contains a fluid pharmaceutical composition (e.g., a suspension, emulsion, or paste) containing a drug in the drug chamber, also referred to herein as the drug reservoir, the drug-containing fluid is extruded through the delivery tube into the salivated oral cavity on the lingual side of the teeth, avoiding accumulation of the drug-containing fluid in the cheek pocket or in a nearby buccal region. The delivery tube is designed such that the components of the drug-containing fluid are neither absorbed by the tube nor diffuse through the wall of the tube during storage (e.g., during the shelf life before use).

In a preferred embodiment, greater than 60% (e.g., 75% - 85%, 86% - 95%, or greater than 95%) of the drug-including fluid can be dispensed while the delivery rate varies by less than ±20% (e.g., less than ±15%, ±10%, or ±5%) over a period of greater than or equal to 4 hours (e.g., greater than or equal to 8, 16, or 24 hours).

In order to obtain the desired rate of delivery of the pharmaceutical composition without clogging the flow restrictor (e.g., the nozzle) the apparent viscosity and the particle size of the pharmaceutical composition, the vapor pressure, as well as the diameter and length of the flow restrictor are simultaneously controlled. Table 3 provides exemplary ranges for these simultaneously controlled parameters for an intra-oral drug delivery device and formulation.

Table 3: Exemplary parameter ranges for continuous intra-oral drug delivery devices and formulations

*Measured by light scattering when the particles are suspended in a non-solvent, e.g., with a Malvern Ltd (UK) Mastersizer.

**Typically, the compositions contain solid drug particles and/or excipient particles and can be semirigid deformable pastes

The term “Dso” refers to the median for a volume distribution of the particles. Particle size can be measured by conventional particle size measuring techniques well known to those skilled in the art (e.g., optical microscopy, electron microscopy, sedimentation, field flow fractionation, photon correlation spectroscopy, light scattering, laser diffraction, and centrifugation. Dso values are commonly derived of particle size distributions of particles suspended in a non-solvent, the distributions measured by light scattering.

The oral device can continuously or semi-continuously extrude a semisolid drug-comprising composition into the mouth, the composition deforming under pressure; it can also comprise a mechanical pump comprising, for example, a spring, pressurized gas, or propellant. The device can comprise a flow restrictor such as a nozzle, a channel, a tube or any other flow or extrusion restricting component. The rate of extrusion through the nozzle can depend on its internal diameter, on its length, and on the vapor pressure of the liquefied propellant. The oral device can comprise a semisolid deformable drug-comprising paste, solution, or suspension, extruded into the mouth at a rate that can be between 0.001 mL/hour and 1 .25 mL/hour (e.g., 0.015 - 1 .25 mL/hour). The viscosity of the paste, the solution or the suspension can be greater than 100 poise and less than 100,000 poise at about 37°C (e.g., greater than 100 poise and less than 50,000 poise at about 37°C). The device may include a mechanical pump (e.g., a propellant-driven pump) including a flow restrictor, the flow restrictor including an internal diameter between 0.05 mm and 3.00 mm and a length between 0.25 cm and 20 cm. The device can comprise a propellant having a vapor pressure at about 37°C greater than 2 bar and less than 50 bar (e.g., 3 - 10 bar). When a paste comprising drug particles and/or excipient particles is extruded into the mouth, the particle size distribution, measured by light scattering (e.g., with a Malvern Mastersizer after dispersing the paste in a liquid non-solvent) can have a D90 less than 200 pm (e.g., between 0.1 pm and 200 pm) and a D50 between 0.1 pm and 50 pm (e.g., between about 0.5 pm and about 30 pm). In some embodiments, the administration rate is greater than 0.05 mL/hour and less than 0.2 mL/hour, the viscosity is greater than 500 poise and less than 100,000 poise, the flow restrictor has an internal diameter between 0.2 mm and 0.5 mm and a length between 1 cm and 2.5 cm; and the propellant has a vapor pressure at about 37°C greater than 4 bar and less than 10 bar. In particular embodiments, the solid drug particles and/or excipient particles have a D90 between 3 pm and 30 pm and a D50 between 2 pm and 20 pm.

A typical device can comprise a viscous drug-comprising paste, or a viscous orally infused drugcomprising solution, or a viscous orally infused drug-comprising suspension, extruded or infused into the mouth at a rate that can be between 0.03 mL/hour and 0.5 mL/hour. The typical viscosity of the paste, solution or suspension can be greater than 200 poise and less than 100,000 poise at about 37°C; its extrusion rate or flow rate can be controlled mostly by a flow restrictor (e.g., nozzle) which can have an internal diameter between 0.1 mm and 0.7 mm and can be between 1 cm and 5 cm long; the typical device can also comprise a mechanical pump. A semirigid deformable drug-comprising paste can be administered at an extrusion rate between 0.001 mL/hour and 1 .25 mL/hour; the paste, can have at low shear rate a viscosity greater than 2,000 poise and less than 50,000 poise; the extrusion rate or the flow rate can be controlled mostly by a flow restrictor or pair of flow restrictors; the extrusion or infusion can be driven by a mechanical pump. The mechanical pump can comprise a propellant, the propellant can have a vapor pressure at about 37°C greater than 2 bar and less than 50 bar. The paste or the suspension or the solution can comprise solid drug and/or excipient particles whose particle size distribution (when dispersed in a non-solvent and when measured by light scattering) can have a D90 less than 200 pm and a D50 between 0.1 pm and 50 pm.

DRUG FORMULATIONS

Formulations of drugs to be delivered via an intraoral drug delivery device mounted to a retainer (such as LD, LD prodrugs, DOPA decarboxylase (DDC) inhibitors, and any other drugs described herein) may include non-toxic aqueous or non-aqueous carrier liquids, such as water, and edible oils such as vegetable oils, lipids, triglycerides, paraffin oil, and their mixtures. In some embodiments, the formulation to be delivered includes a drug and one or more excipients (e.g., excipients such as water, oil, and a surfactant). The formulation can include solid drug particles and/or solid excipient particles. In some embodiments, the formulation may include a mucoadhesive polymer and, optionally, a permeation enhancer (e.g., to aid transport across the sublingual or buccal mucosa).

Formulations that can be delivered include those described in U.S. Patent Publication No. US20170172961 A1 , which is incorporated by reference herein in its entirety.

THERAPY

The devices and methods of the invention are suitable for the administration of a variety of drugs that have a short half-life and/or a narrow therapeutic range. Complementary drugs may be coadministered or co-infused with these drugs. Such complementary drugs may improve the pharmacokinetics, improve the efficacy, and/or reduce the side effects of the primary drugs.

Gastroparesis, or delayed gastric emptying, is common in people with Parkinson’s disease (PD). Drugs for the treatment of gastroparesis may be delivered using the devices and methods of the invention. In one embodiment, drugs for the treatment of gastroparesis are co-administered (administered or infused into the mouth simultaneously or within less than 60, 30, 15, or 5 minutes) with the LD or CD, using the drug delivery devices and methods of the invention. In another embodiment, drugs for the treatment of gastroparesis are administered using other methods of drug delivery known in the art (i.e. , they are not administered via continuous or frequent intra-oral delivery) while LD or CD are infused intra-orally. Examples of drugs for the treatment of gastroparesis are Metoclopramide, Cisapride, Erythromycin, Domperidone, Sildenafil Citrate, Mirtazapine, Nizatidine, Acotiamide, Ghrelin, Levosulpiride, Tegaserod, Buspirone, Clonidine, Relamorelin, Serotonin 5-HT4 agonists and dopamine D2 or D3 antagonists.

Because administration is into the mouth, it is preferred that the drugs selected for administration are those whose taste is neutral or pleasant, as perceived by a majority of patients. Taste masking or modifying excipients may be added to the formulations of drugs whose taste is unpleasant, as perceived by a majority of patients.

Other drugs that may usefully be delivered in accordance with the invention include methylphenidate, prostaglandins, prostacyclin, treprostinil, beraprost, nimodipine, pyridostigmine or a pyridostigmine prodrug, pilocarpine or a pilocarpine prodrug, levodopa or a levodopa prodrug, baclofen or a baclofen prodrug, furosemide or a furosemide prodrug, and testosterone. Levodopa prodrug formulations of are provided in U.S. Patent No. 5,607,969, and in patent applications WO 2012/079072 and WO 2013/184646, each incorporated herein by reference. The preferred LD prodrugs for administration into the mouth include highly soluble levodopa amides, levodopa esters, levodopa carboxamides, levodopa sulfonamide, levodopa phosphate prodrugs (e.g., foslevodopa, also known as levodopa 4'-monophosphate, see, e.g., Huters et al., J Org. Chem. 2021 and Rosebraugh et al., Ann Neurol. 90:52-61 , 2021 ), levodopa ethyl ester, levodopa methyl ester, and their salts. An exemplary baclofen prodrug is arbaclofen placarbil. Exemplary pilocarpine prodrugs include alkyl and aralkyl esters of pilocarpic acid, pilocarpic acid diesters, and other pilocarpic acid derivatives, such as those described in Bundgaard et al., J Pharm Sci 75:36-43, 1986, Bundgaard et al., J Pharm Sci 75:775-83, 1986, and U.S. Patent No. US4742073A, which are incorporated herein by reference. Exemplary furosemide prodrugs include furosemide esters, such as the neutral alkyl ester, alkyl esters containing an amino group, glycolamide esters and O-acyloxymethyl ester described in Mork et al., International Journal of Pharmaceutics 60:163-169, 1990, acyloxymethyl esters of furosemide described in Prandi et al., Farmaco 47:249-63, 1992 and Prandi et al., Farmaco 47:1225-34, 1992, and the furosemide analogs and prodrugs described in International Patent Application Publication No. WO2014039454A2, which are incorporated herein by reference.

Examples of drugs that are often prescribed to be dosed four times per day include:

• Amoxicillin - infection

• Cephalexin (Keflex) - infection

• Chlorpromazine (Thorazine) - neuroleptic for migraine

• Diazepam (Valium) - anxiety and sleep

• Diclofenac (Voltaren) - arthritis

• Diltiazem - calcium channel blocker

• Erythromycin - infection

• Haloperidol (Haldol) - neuroleptic for migraine

• Impramine - psychotropic

• Ipratropium (Atrovent) - Anticholinergic

• Metoclopramide (Reglan) - gastroesophageal reflux, migraine

• Nifedipine - calcium channel blocker

• Olanzapine (Zyprexa) - neuroleptic for migraine

• Prochlorperazine (Compazine) - neuroleptic for migraine

• Promethazine (Phenergan) - neuroleptic for migraine

• Salbutamol - asthma

• Tetracycline - infection

• Theophylline (Theolair) - COPD, asthma

• Trazodone - psychotropic

• Vaccines— immunotherapy

• Zaleplon— insomnia, disordered sleep

• Zolpidem— insomnia, disordered sleep

Drugs delivered as solids may be formulated with excipients to increase disintegration or dispersion.

Many types of drugs may be delivered in accordance with the invention. Drugs which may in principle be used for treatment according to the invention are any known drugs, wherein the drugs may be present in the form according to the invention as such, or in the form of the active ingredient, optionally in the form of a pharmaceutically acceptable salt of the active ingredient, or in the form of a prodrug that is rapidly converted to the active drug. Drugs which may be delivered in accordance with the invention include, without limitation, analgesics and anti-inflammatory agents (e.g., aloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac), anthelmintics (e.g., albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate, thiabendazole), anti-arrhythmic agents (e.g., amiodarone HCI, disopyramide, flecainide acetate, quinidine sulphate, anti-bacterial agents (e.g., benethamine penicillin, cinoxacin, ciprofloxacin HCI, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim), anti-coagulants (e.g., dicoumarol, dipyridamole, nicoumalone, phenindione), antidepressants (e.g., amoxapine, maprotiline HCI, mianserin HCI, nortriptyline HCI, trazodone HCI, trimipramine maleate), antidiabetics (e.g., acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide), antiepileptics (e.g., beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide, methylphenobarbitone (methylphenobarbital), oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, valproic acid, topiramate, lamotrigine, gabapentin, levetiracetam, pregabalin), antifungal agents (e.g., amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCI, terconazole, tioconazole, undecenoic acid), antigout agents (e.g., allopurinol, probenecid, sulphin-pyrazone), antihypertensive agents (e.g., amlodipine, benidipine, darodipine, diltiazem HCI, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine HCI, nifedipine, nimodipine, phenoxybenzamine HCI, prazosin HCI, reserpine, terazosin HCI), antimalarials (e.g., amodiaquine, chloroquine, chlorproguanil HCI, halofantrine HCI, mefloquine HCI, proguanil HCI, pyrimethamine, quinine sulphate), anti-migraine agents (e.g., dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate), anti-muscarinic agents (e.g., atropine, benzhexol HCI, biperiden, ethopropazine HCI, hyoscyamine, mepenzolate bromide, oxyphencyclimine HCI, tropicamide), anti-neoplastic agents and immunosuppressants (e.g., aminoglutethimide, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone (mitozantrone), procarbazine HCI, tamoxifen citrate, testolactone), anti-protozoal agents (e.g., benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole), antithyroid agents (e.g., carbimazole, propylthiouracil), anxiolytic, sedatives, hypnotics and neuroleptics (e.g., alprazolam, amobarbital (amylobarbitone), barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, fluanisone, flunitrazepam, fluopromazine, flupentixol (flupenthixol) decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone), p-Blockers (e.g., acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol), cardiac inotropic agents (e.g., amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin), corticosteroids (e.g., beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone), diuretics (e.g., acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide (frusemide), metolazone, spironolactone, triamterene), anti-parkinsonian agents (e.g., bromocriptine mesylate, lisuride (lysuride) maleate), gastrointestinal agents (e.g., bisacodyl, cimetidine, cisapride, diphenoxylate HCI, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCI, ranitidine HCI, sulphasalazine), histamine H, -receptor antagonists (e.g., acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCI, dimenhydrinate, flunarizine HCI, loratadine, meclozine HCI, oxatomide, terfenadine), lipid regulating agents (e.g., bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol), nitrates and other anti-anginal agents (e.g., amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate), opioid analgesics (e.g., codeine, dextropropoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine), sex hormones (e.g., clomiphene citrate, danazol, ethinyl estradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, conjugated oestrogens, progesterone, stanozolol, stilbesterol, testosterone, tibolone), and stimulants (e.g., amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol). In some embodiments, the pharmaceutical composition included in a drug delivery device described herein may include one or more of levodopa or a levodopa prodrug, baclofen or a baclofen prodrug, pyridostigmine or a pyridostigmine prodrug, pilocarpine or a pilocarpine prodrug, furosemide or a furosemide prodrug, methylphenidate, a prostaglandin, prostacyclin, treprostinil, beraprost, nimodipine, and testosterone. In some embodiments, the drug can be an analgesic (e.g., lidocaine, bupivacaine, mepivacaine, ropivacaine, tetracaine, etidocaine, chloroprocaine, prilocaine, procaine, benzocaine, dibucaine, dyclonine hydrochloride, pramoxine hydrochloride, benzocaine, proparacaine, or a pharmaceutically acceptable salt thereof) or an opioid (e.g., buprenorphine, nor-buprenorphine, fentanyl, methadone, levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone, hydrocodone, or a pharmaceutically acceptable salt thereof) administered for the treatment of pain. The above-stated compounds are predominantly stated by their international nonproprietary name (INN) and are known to the person skilled in the art. Further details may be found, for example, by referring to International Nonproprietary Names (INN) for Pharmaceutical Substances, World Health Organization (WHO).

Gastroparesis, delayed or erratic gastric emptying, and other abnormalities or diseases of the stomach, intestine, pylorus, jejunum, duodenum impact the transport of food and medication from the stomach to the duodenum and through the small and large intestines. Such conditions of the Gl tract are commonly caused by or associated with various diseases and conditions, including Parkinson’s disease, diabetes, autonomic neuropathy, and cancer treatments. Reduced, delayed, or erratic transport of medication from the stomach to the duodenum and through the small and large intestines decreases the benefits or effectiveness of many drugs, including levodopa. It is for this reason that the Duopa™ (also known as Duodopa™) LD/CD delivery system infuses a LD/CD suspension into the jejunum or duodenum, even though intrajejunal delivery requires surgical implantation of a PEG tube and suffers from a high rate of PEG tube related complications. The inventors discovered that the oral intake of an aqueous solution of L-DOPA and carbidopa at frequency of about 6 - 12 times/hour also stabilizes the plasma concentration of L-DOPA and reduces by about 43% the OFF time of PD patients. Without limiting the scope of this invention by a theory or model, the inventors have observed that the reported gastric delay of drugs does not necessarily apply when the drugs are continuously orally infused and are dissolved. Thus, it can be advantageous to infuse into the mouths of patients a suspension or paste including solid drug particles at a rate that equals or is slower than the rate of dissolution of the solid drug particles in body fluids secreted in the mouth, such that the drug passing through the esophagus to the stomach is already substantially dissolved, such that the remaining solid drug particles are substantially dissolved in fluid secreted in the stomach, and/or such that the still remaining drug particles are substantially dissolved in fluid secreted in the duodenum, then, if solid drug particles still remain, these are substantially dissolved in fluids secreted in the jejunum, then if still present, substantially dissolved in fluids secreted in the ileum, and eventually if still present, substantially dissolved in fluids secreted in the colon. The secreted body fluid in which the solid drug may dissolve can be, for example, saliva secreted in the mouth (e.g., by the submandibular and parotid glands) mostly in the awake hours. In healthy persons the rate of secretion can be between about 50 mL/hour and about 100 mL/hour. Considering that the solubility of LD can be about 50 mg/mL and considering that even if a patient would require as much as 200 mg LD per hour, as little as about 4 mL/hour of saliva could dissolve the orally delivered solid LD. The drug could not only be dissolved, but its solution might be diluted before reaching the stomach even in patients (e.g., patients with PD or xerostomia) secreting less saliva than healthy people. For rapid dissolution in saliva, it could be advantageous to disperse the drug particles (e.g., by administering their surfactant-including suspension) where the size of the drug particles could be small (e.g., typically less than about 100 pm in average diameter, such as less than 50 pm in average diameter, such as less than 20 pm in average diameter, such as less than10 pm in average diameter).

Other drugs, such as baclofen or pyridostigmine, that are administered in lesser daily amounts than LD could be adsorbed on small particles of a solid excipient, such as an amino acid like tyrosine. For continuous oral delivery, the paste of the drug-containing excipient could be extruded into the mouth where the excreted saliva would dissolve the sorbed drug as well as any solid drug particles, if present.

The drug delivery devices can be mounted in a retainer of the invention and used to orally administer drugs to patients in therapeutically effective amounts. For example, an amount is administered which prevents, delays, reduces, or eliminates the symptoms of a disease, such as PD, mucositis, a bacterial infection, a viral infection, a fungal infection, a parasite caused disease, cancer, pain, organ transplantation, disordered sleep, epilepsy or a seizure, anxiety, a mood disorder, post- traumatic stress disorder, arrhythmia, hypertension, heart failure, spasticity, muscle weakness, an immune disease, anesthesia, diabetic nephropathy, or allergy. They can also be used to manage allergies, for example, to peanuts, e.g., by delivering agents, such as fractions or whole allergy causing antigens, for sublingual immunotherapy such that the delivered agents contact a mucous membrane or tissue of the mouth. Using the drug delivery devices, a drug appropriate for the treatment of a given disease to be treated can be formulated and administered using the methods, compositions, and devices described herein. The methods described herein can also be used to treat multiple sclerosis, cerebral palsy, spasticity, neurogenic orthostatic hypotension, Wilson’s disease, cystinuria, rheumatoid arthritis, Alzheimer’s disease, myasthenia gravis, Type-1 Gaucher disease, Type C Niemann-Pick disease, eosinophilic gastroenteritis, chronic mastocytosis, ulcerative colitis, gastro-oesophageal reflux, gastroenteritis, hyperemesis gravidarum, glioblastoma multiforme, anaplastic astrocytoma, pulmonary hypertension, coronary heart disease, congestive heart failure, angina, Type 2 diabetes, COPD, asthma, irritable bowel syndrome, overactive bladder, or urinary urge incontinence. For treating myasthenia gravis, the pharmaceutical composition can include pyridostigmine, or a pharmaceutically acceptable salt thereof. For treating Parkinson’s disease, the pharmaceutical composition can include levodopa or a levodopa prodrug. In some embodiments, the pharmaceutical composition for treating Parkinson’s disease further includes carbidopa or a carbidopa prodrug and/or benserazide. For treating spasticity (e.g., in a subject having multiple sclerosis or a spinal cord injury), the pharmaceutical composition can include baclofen or a baclofen prodrug. For treating dry mouth (e.g., dry mouth associated with or caused by Sjogren’s syndrome or radiation therapy), the pharmaceutical composition can include pilocarpine or a pilocarpine prodrug. For treating high blood pressure (hypertension) or edema (e.g., edema associated with or caused by heart failure (e.g., congestive heart failure), kidney disease, or liver disease (e.g., cirrhosis or liver fibrosis)), the pharmaceutical composition can include furosemide or a furosemide prodrug.

Many drugs with narrow therapeutic indices benefit from drug delivery devices and methods that result in small fluctuation indices. For example, Table 4 summarizes the fluctuation indices of extended- release tablet formulations of anti-epileptic drugs reported in various studies (from “Extended-release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate-release formulations”, lie E. Leppik and Collin A. Hovinga, Epilepsia, 54(1 ):28— 35, 2013).

Table 4. Fluctuation indices of anti-epileptic drug extended release tablets.

The invention includes a method of treating a disease or medical condition using any of the devices, drugs, formulations, and methods disclosed herein, wherein the fluctuation index is less than or equal to 2.0, 1 .5, 1 .0, 0.75, 0.50, 0.25, or 0.15. The term “fluctuation index” refers to the magnitude of the rise and fall of drug level in plasma relative to the average plasma concentration, is defined as [Cmax- Cmin]/ Cavg , and is measured over a specified period of time. The time period can begin, for example, after the drug’s plasma concentration: has reached the steady-state concentration; or has reached 90% of the steady-state concentration; or 30, 60, or 120 minutes after a drug delivery device has been inserted into the mouth and begun to deliver drug. The time period can end, for example: at the end of the use period specified in the instructions for use of the drug delivery device; when the drug reservoir is 90% depleted or substantially depleted; or about 4, 8, 16, 24, 72, or 168 hours after the start of the time period.

Drug dosages administered using the methods of the invention may be higher or lower than those administered using traditional, infrequent dosing regimens. A lower daily dose is possible without loss of efficacy when continuous or semi-continuous administration reduces troughs in the drug’s steady state circulating plasma concentration, enabling the drug’s plasma concentration to remain above the minimum effective plasma concentration without the need for high peak concentrations. A higher daily dose is possible without increased side effects when continuous or semi-continuous administration reduces peaks in the drug’s steady state circulating plasma concentration, enabling an increase in the drug’s average plasma concentration without the need for high peak concentrations.

The devices and methods of the invention provide a dosing regimen having an improved safety profile as adverse events associated with peak plasma concentrations (i.e., a Cmax characteristic of oral unit dosage forms) are eliminated. Thus, the devices and methods of the invention can be used to deliver drugs having a narrow therapeutic window in the patient population being treated (i.e., patients refractory to standard therapeutic regimens). Details provided below for the treatment of PD can be applicable to the formulation and administration of drugs for the treatment of other diseases.

For the treatment of PD, typical administered dose ranges are from about 20 pmole/kg to about 200 pmole/kg of LD or LD prodrug per day. The typical daily dose of the optionally co-administered DDC inhibitor is between about 5 pmole/kg and about 50 pmole/kg. For example, the typical daily dose for a patient weighing 75 kg is from about 1 .5 millimoles to about 15 millimoles of LD or LD prodrug. Optionally, a molar amount of a DDC inhibitor between about 10% and about 40% of the molar amount of the LD or LD prodrug, for example between 15% and 30%, may be added. Optionally, catechol-O-methyl transferase (COMT) inhibitors such as entacapone, tolcapone, or opicapone may be administered using the devices of the invention. Exemplary LD prodrug formulations of the prior art are provided in U.S. Patent No. 5,607,969, and in patent applications WO 2012/079072 and WO 2013/184646, each incorporated herein by reference. The preferred prodrugs for administration into the mouth include highly soluble levodopa amides, levodopa esters, levodopa carboxamides, levodopa sulfonamide, levodopa phosphate prodrugs (e.g., foslevodopa, also known as levodopa 4'-monophosphate, see, e.g., Huters et al., J Org. Chem. 2021 and Rosebraugh et al., Ann Neurol. 90:52-61 , 2021 ), levodopa ethyl ester, levodopa methyl ester, and their salts, which can be rapidly hydrolyzed in the body, typically in an enzyme catalyzed reaction, to form LD, yet can be stored at least for the duration of the intended administration period, for example at least 8 hours, 16 hours, 24 hours, 48 hours, 72 hours, in a reservoir of the drug delivery device. Additional examples of levodopa prodrugs, including LD ester prodrugs, LD amide prodrugs, LD dimeric amide prodrugs, carrier-mediated prodrugs, peptide transport-mediated prodrugs, and cyclic prodrugs, are described in Haddad et al., Molecules 23:40, 2018, which is incorporated herein by reference.

The administration into the mouth can be for 24 hours daily or it can be limited to the awake period, typically about 16 hours. When limited to the awake period it can be advantageous to administer a morning bolus to more rapidly raise the plasma concentration of the LD than a constant rate administration would. The morning bolus can be delivered, for example, through an orally taken pill or pills of LD and a DDC inhibitor or it can be through administration of a solid or fluid drug into the mouth using the drug devices of the invention. Alternatively, the exterior of the drug delivery device may include a drug, such that a bolus of the drug is delivered into the mouth when the device is first inserted into the mouth.

The invention includes methods of administering into the mouth one or more drugs (e.g., LD and CD) from one or more drug reservoirs residing in the cavity of the mouth (e.g., attached to a retainer described herein) including a total volume of 0.1 - 10 mL of drugs (e.g., 0.1 -1 .0 mL, 1 .0-2.0 mL, 2.0-3.0 mL, 3.0-4.0 mL, 4.0-5.0 mL). The invention includes methods of administering the one or more drugs (in either solid or fluid form) at a rate in the range of 0.001 - 1 .25 mL/hour (e.g., 0.001 - 0.10 mL/hour, 0.10- 0.20 mL/hour, 0.015-0.25 mL/hour, 0.20-0.30 mL/hour, 0.25-0.5 mL/hour, 0.30-0.40 mL/hour, 0.40-0.50 mL/hour, 0.50-0.60 mL/hour, 0.5-0.75 mL/hour; 0.60-0.70 mL/hour, 0.70-0.80 mL/hour, 0.75-1 .0 mL/hour, 0.80-0.90 mL/hour, 0.90-1 .0 mL/hour, 1 .0-1 .1 mL/hour, or 1 .1 -1 .25 mL/hour). The invention includes methods of administering the one or more drugs at an average rate of less than 1 mg per hour, 1 -10 mg per hour, 10 - 25 mg per hour, 25 - 50 mg per hour, 50 - 75 mg per hour, 75 - 100 mg per hour, 100 - 125 mg per hour, or greater than 125 mg per hour. For treating Parkinson’s disease, the method may include administration of a pharmaceutical composition containing levodopa or a levodopa prodrug using a drug delivery device mounted to a retainer described herein at a rate of 10 mg/hour to 200 mg/hour (e.g., 30 mg/hour to 150 mg/hour or 50 mg/hour to 125 mg/hour) for a period of about 4 hours to about 168 hours. The invention includes methods of administering one or more drugs via continuous and/or semi-continuous administration. In a preferred embodiment, the method includes holding the average administration rate constant or near constant for a period of 4, 8, 12, 16, or 24 hours during the day. For example, the volume administered every hour may vary from the average hourly administration rate during the infusion period by less than ±10% or ±20% per hour, or by ±10% or ±20% per 15-minute period. The average hourly rate may vary by less than ± 20% or ± 10% per hour over a period of 4 or more hours (e.g., 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 168 hours, or more). The administering may be performed over a period of from about 4 hours to about 168 hours at about 37 ^eC and a constant pressure of about 1 .013 bar. In some embodiments, the fluctuation index of the drug is reduced to less than or equal to 2.0, 1 .5, 1 .0, 0.75, 0.50, 0.25, or 0.15 during the delivery period. The pharmaceutical composition can be administered to the patient over a delivery period of about 4 or more hours (e.g., 4, 8, 10, 12, 14, 16, 18, 20, 24, or more hours).

Continuous or semi-continuous administration using the drug delivery devices and formulations of the invention can reduce concentration fluctuations of the therapeutic drug in body fluid, for example in blood, plasma, or serum. It can provide, for example, a plasma concentration profile where the difference between peak concentrations and nadir concentrations of the therapeutic drug is less than ±70% of the average concentration through a period in which the drug is administered, for example it can be less than ±50%, less than ±30%, less than ±20%, or less than ±10% of the time averaged concentration over a period of greater than or equal to 4 hours (e.g., 8, 12, 16, or 24 hours). In some embodiments, during the administration the circulating drug plasma concentration varies by less than +/- 20% or +/- 10% from its mean for a period of at least 1 , 2, or 4 hours.

The invention features a method of treating a disease in a patient, the method including: (a) inserting a drug delivery device (e.g., a drug delivery device attached to a retainer described herein) into the patient’s mouth; (b) starting a drug administration from the device; (c) administering into the patient’s mouth one or more drugs, using continuous or semi-continuous administration, for a period of 4 hours to 7 days at an hourly rate in the range of 0.015 - 1 .25 mL/hour or 1 -125 mg/hour; and (d) removing the drug delivery device from the mouth; wherein the drug delivery device includes a drug reservoir of 0.1 -5 mL volume (e.g., 0.1 -1 mL, 0.5-3 mL, or 3-5 mL), and the reservoir includes a solid or fluid including a drug. Optionally, the method may also include the step of: (e) stopping the drug delivery from the device. The invention further includes a method wherein steps a, b, c, and d (and e, if included) are performed at least twice over a period of 4 hours to 7 days. The drug may include a total of greater than 1 millimole of LD.

The methods of the invention can further include treating Parkinson’s disease in a patient (including in patients with scores of 4 and 5 on the Hoehn and Yahr scale), the method including: (a) removably inserting a drug delivery device of the invention into the patient’s mouth (e.g., a drug delivery device attached to a retainer described herein), the drug delivery device including a reservoir of 0.1 -5 mL volume (e.g., 0.1 -1 mL, 0.5-3 mL, or 3-5 mL), and the reservoir including a solid or fluid including a total of greater than 1 millimole of LD; (b) administering into the patient’s mouth the solid or fluid for a period of at least 8 hours at an hourly rate in the range of 0.03 - 1 .25 mL/hour or 30 - 150 mg/hour, such that a circulating plasma LD concentration greater than 400 ng/mL and less than 7,500 ng/mL is continuously maintained for a period of at least 8 hours during the administration; and (c) removing the drug delivery device from the patient’s mouth. In certain embodiments, the LD suspension is administered into the mouth at such a rate that a circulating plasma LD concentration greater than 800 ng/mL, 1 ,200 ng/mL, 1 ,600 ng/mL, or 2,000 ng/mL (e.g., from 800 to 1 ,500, from 1 ,000 to 2,000, from 1 ,600 to 2,500, or from

1 .500 to 3,000 ng/mL, depending upon the condition of the patient) is continuously maintained for a period of at least 2 hours, 3 hours, 4 hours, 8 hours, 16 hours, or 24 hours during the administration. In particular embodiments, the LD suspension is administered into the mouth at such a rate that a circulating plasma LD concentration greater than 400 ng/mL, 800 ng/mL, 1 ,200 ng/mL, 1 ,600 ng/mL, or 2,000 is achieved within 60 minutes of the initiation of the infusion. The LD suspension can be administered into the mouth at such a rate that a circulating plasma LD concentration less than 7,500 ng/mL, 5,000 ng/mL,

3.500 ng/mL, 3,000 ng/mL, 2,500 ng/mL, or 2,000 ng/mL is continuously maintained for a period of at least 8 hours during the administration. In particular embodiments, the patient receives an average daily dose of less than 10 mL, 7.5 mL, 5 mL, 3 mL, or 2 mL of the LD suspension. The LD suspension can be administered into the mouth at such a rate that the circulating LD plasma concentration varies by less than ±20%, ±15%, or ±10% from its mean for a period of at least 1 hour, 2 hours, 3 hours, or 4 hours.

In some embodiments, the method includes treating a patient having Parkinson’s disease using a drug delivery device containing levodopa or a levodopa prodrug, in which the method includes administering into the patient’s mouth the levodopa or a levodopa prodrug for a period of at least 4 hours at an hourly rate in the range of 30 mg/hour to 150 mg/hour. The method can include intraoral administration such that a circulating plasma levodopa concentration greater than 1 ,200 ng/mL and less than 2,500 ng/mL is continuously maintained for a period of at least 4 hours during the administration. The patient can have a score of 4 or 5 on the Hoehn and Yahr scale.

In any of the methods described herein for the treatment of Parkinson’s disease, the fluctuation index of levodopa may be less than or equal to 2.0, 1 .5, 1 .0, 0.75, 0.50, 0.25, or 0.15 for a period of at least 4 hours (e.g., at least 6 hours, at least 8 hours, or longer) during the administration. In some embodiments, during administration the circulating levodopa plasma concentration varies by less than +/- 20% or +/- 10% from its mean for a period of at least 1 hour (e.g., 2 hours, 3 hours, 4 hours, or more hours). The method can further include the co-administration of an effective amount of a DDC inhibitor such as benserazide, carbidopa or carbidopa prodrug. Carbidopa can be co-administered as a solid, suspension or emulsion, or as a solution of one of its highly water-soluble prodrug salts, exemplified by carbidopa ethyl ester hydrochloride, by carbidopa methyl ester hydrochloride, by carbidopa amide hydrochloride, or by carbidopa phosphate prodrugs (e.g., foscarbidopa, also known as carbidopa 4'- monophosphate, see, e.g., Huters et al., J Org. Chem. 2021 and Rosebraugh et al., Ann Neurol. 90:52- 61 , 2021 ). The molar amount of the co-administered DDC inhibitor can be between one-tenth and one- half of the molar amount of LD, preferably about 1 /4^th ± 1 /8^th of the molar amount of LD. Preparations of the carbidopa prodrugs, recognized to be LD decarboxylase inhibitors, are described, for example, in U.S. Patent Nos. 3,895,052 and 7,101 ,912, and Patent Publication Nos. DE2062285A and FR2052983A1. In one particular embodiment, a LD suspension includes a greater than 0.5 M LD. In particular embodiments, the LD and the DDC inhibitor are co-administered separately, or are contained in a single solid or fluid and administered into the patient.

The method can alleviate a motor or non-motor complication in a patient afflicted with Parkinson’s disease, such as tremor, akinesia, bradykinesia, dyskinesia, dystonia, cognitive impairment, or disordered sleep.

EXAMPLES

The following examples are meant to illustrate the invention. They are not meant to limit the invention in any way.

EXAMPLE 1. Testing of different retainer configurations

A human subject tested different retainers for attaching a drug delivery device to a buccal surface of the teeth. One retainer tested was the retainer shown in FIGS. 1 A-1 B, which covered the buccal, lingual, and occlusal surfaces of the upper bicuspids and molars on both sides of the mouth and included a lingual connector that contacted the lingual surface of all intervening teeth between the bicuspids. The retainer was a bite neutral device that separated the teeth so that when the subject bit down the teeth contacted each other or the retainer. The retainer contained bilateral recesses spanning the interproximal space of the upper second and third molars (indicated with an arrow in FIG. 1 A). The retainer also included a pocket for attaching the drug delivery device to the buccal surface of one or more teeth on the right side of the mouth (e.g., an upper first molar) where the subject had upper and lower third molars. A drug delivery device containing a delivery tube was inserted into the pocket and the retainer was placed on the teeth. The subject found that, when biting down while wearing the retainer, the drug delivery tube could cross from the buccal side of the teeth to the lingual side of the teeth by extending through the recess across the occlusal surface of the teeth without being compressed or crushed. The subject reported that the retainer fit comfortably and that it was easy to open and close the mouth during wear. The drug delivery device and retainer pocket could be felt during lateral movements of the mandible and salivation increased during wear. It was possible for others to tell that the subject had something in his mouth when speaking as it interfered slightly with speech.

The subject also tested a retainer that covered the buccal, lingual, and occlusal surfaces of the upper bicuspids and molars on both sides of the mouth and included aa lingual connector that contacted the lingual surface of all intervening teeth between the bicuspids. This retainer is shown in FIGS. 2A-2D. The retainer was a bite neutral device that separated the teeth so that when the subject bit down the teeth contacted each other or the retainer. This retainer did not contain any recesses. The retainer included a pocket for attaching the drug delivery device to the buccal surface of one or more teeth (e.g., an upper first molar) on the side of the mouth on which the subject had upper and lower third molars. A drug delivery device containing a drug delivery tube was inserted into the pocket and the retainer was placed on the teeth. The subject found that, when biting down while wearing the retainer, the drug delivery tube was bitten by the teeth, which caused it to become crushed. The subject reported that the retainer fit comfortably and that it was easy to open and close the mouth during wear. Salivation increased during wear and speech was impacted. The subject also reported that he could feel the delivery tube hitting the side of his tongue and moving alongside the tongue when his mouth opened and closed and was concerned that this could cause soft tissue abrasion over time.

The subject also tested a version of the retainer that only covered teeth in the upper left quadrant (the bicuspids and molars) of the mouth. This retainer also had a pocket for attaching a drug delivery device to the buccal surface of one or more teeth (e.g., an upper first molar). The retainer tested by the subject was fitted to the left side of the mouth, where the subject lacked an upper third molar. The subject found this retainer to be more comfortable and not to interfere with speech or increase salivation. However, the subject noted that the retainer could easily be removed from the teeth with slight pressure from the cheek, which could make it a choking hazard.

Finally, the subject tested a version of the retainer that covered the buccal, lingual, and occlusal surfaces of the upper bicuspids and the upper first and second molars on both sides of the mouth and included a palatal strap to connect the portion of the retainer covering the upper left bicuspids and molars to the portion of the retainer covering the upper right bicuspids and molars (shown in FIG. 4A). The retainer was not bite neutral and did not cover the third molar. The retainer included a pocket for attaching the drug delivery device to the buccal surface of one or more teeth (e.g., an upper first molar). A drug delivery device containing a drug delivery tube was inserted into the pocket and the retainer was placed on the teeth. The subject found that, when biting down while wearing the retainer, the drug delivery tube could cross from the buccal side of the teeth to the lingual side of the teeth between the upper and lower third molars without being compressed or crushed by extending across the occlusal surface of the upper third molar that was left uncovered by the retainer. The subject reported that this design interfered less with speech although it did initially trigger the subject’s gag reflex. However, because the retainer was not bite neutral, it would be possible for teeth to erupt, and, therefore, would not be suitable for use at night (e.g., while sleeping).

These tests demonstrated that incorporating a recess into the portion of the retainer spanning the interproximal space between the upper second and third molars allowed a subject with upper and lower third molars to use a retainer-mounted drug delivery device located on the buccal side of the teeth containing a delivery tube that crossed the occlusal surface of the teeth to administer drug on the lingual side of the teeth. In the absence of a recess, the delivery tube was crushed. The delivery tube could also cross the occlusal surface of the teeth without being crushed or compressed when a patient wearing the retainer bit down if the delivery tube extended across an occlusal surface of a tooth that was not covered by the retainer and if the thickness of the retainer where it covered an occlusal surface of a different tooth (e.g., an adjacent tooth) was at least as thick as the external diameter of the delivery tube. These tests also provided insights into modifications that could be made to a retainer containing a recess, such as using a palatal strap rather than a lingual connector to connect the left and right quadrant portions of the retainer (as shown in FIGS. 3A-3D and FIG. 4A), and modifications that could be made to increase comfort when the drug delivery device is worn in the mouth, such as using an L-shaped polymeric fluidic channel containing a nozzle adaptor (e.g., a nozzle adaptor that contains a 90-degree bend) connected to the drug reservoir and fluidically connected to a straight delivery tube (e.g., a configuration that allows the delivery tube to extend across the occlusal surface of a tooth to or near the lingual side of the teeth when the drug delivery device is worn on the buccal side of the teeth) to reduce contact of the delivery tube with the tongue and the risk of soft tissue abrasion.

EXAMPLE 2. Use of a drug delivery device to treat Parkinson’s disease in a subject having upper and lower third molars

A human patient having Parkinson’s disease can insert a single-use drug delivery device into the pocket of a reusable custom retainer for continuous intraoral administration of a paste containing suspended particles of micronized LD and CD at a controlled rate. The retainer is configured to cover the lingual, buccal, and occlusal surface of the patient’s first, second, and third upper molars and first and second upper bicuspids on both the left and right side of the mouth and includes a lingual connector connecting the left and right sides of the retainer that contacts the lingual surface of all the intervening teeth. The pocket is molded on one side of the retainer to attach the drug delivery device to a buccal surface of one or more of the patient’s molars and can position the drug delivery device coplanar with the occlusal surface of the first or second molar. Since the patient has upper and lower third molars, the retainer includes a recess that spans the interproximal space of the patient’s second and third molars on the same side of the retainer as the pocket.

The drug delivery device is pre-filled with the LD/CD paste (e.g., a paste containing LD:CD in a ratio of 4:1 ). An exemplary paste includes about 49.5 w/w% LD, about 13.4 w/w% CD, about 5.0 w/w% poloxamer 188, about 25.3 w/w% medium chain triglycerides (e.g., Miglyol 812), about 6.5 w/w% water, about 0.3 w/w% benzoic acid, and about 0.1 w/w% sodium edetate (EDTA). The drug delivery device can include a propellant chamber and a drug chamber separated by a deformable metallic diaphragm. The LD/CD paste leaves the drug delivery device through two flow restrictors of different lengths before it is extruded into a delivery tube. The delivery tube is in fluid communication with the drug chamber and is configured to administer the LD/CD paste at the back of the mouth on the lingual side of the teeth. When the drug delivery device is positioned in the pocket and the retainer is inserted into the patient’s mouth for use (e.g., by the patient or a caregiver), the delivery tube passes from the buccal side of the teeth through the recess of the retainer and over the occlusal surface of the teeth to the lingual side of the teeth. Due to the recess in the retainer, the delivery tube is not crushed when the patient wearing the retainer bites down. Once the drug delivery device is inserted into the retainer pocket, the retainer can be inserted into the mouth for continuous administration of the LD/CD paste (e.g., for a period of one or more hours, e.g., 1 , 2, 3, 4, 5, 6, or more hours). The retainer can be removed for eating or brushing teeth and to replace the drug delivery device with a fresh, prefilled drug delivery device. When not in use, the retainermounted drug delivery device can be placed into a storage case, which may contain a mechanism to pause the flow of LD/CD paste from the drug delivery device when the retainer-mounted drug delivery device is placed into the case and the case is closed.

A practitioner of skill in the art can monitor the patient’s improvement in response to this therapy by a variety of methods. For example, a physician can monitor the patient’s plasma LD levels to assess LD fluctuation (e.g., using a blood test) and can monitor the patient’s Off time and motor symptoms based on patient reports or observation (e.g., during a neurological examination). A finding that the patient exhibits reduced plasma levodopa variability (e.g., reduced fluctuation of plasma LD levels), reduced Off time, and/or improved motor symptoms indicates that the patient is responding favorably to the treatment and can continue use of the intraoral drug delivery system.

EXAMPLE 3. Use of a drug delivery device to treat Parkinson’s disease via attachment to a retainer containing a recess

A human patient having Parkinson’s disease can insert a single-use drug delivery device into the pocket of a reusable custom retainer for continuous or semi-continuous intraoral administration of a paste containing suspended particles of micronized LD and CD at a controlled rate. The retainer is configured to cover the patient’s first and second upper molars and first and second upper bicuspids on both the left and right side of the mouth and includes a palatal strap connecting the left and right sides of the retainer. If the patient has upper third molars on the right or left side of the mouth, the retainer may also be configured to cover the third molars. The pocket is molded on one side of the retainer to attach the drug delivery device to a buccal surface of one or more of the patient’s upper molars and/or bicuspids (e.g., a buccal surface of the patient’s upper first molar). The retainer is 3D printed and designed to leave at least a portion of an occlusal surface of an upper second molar of the patient uncovered. For example, the retainer may contain a recess configured to span a portion of an upper second molar of the patient from the buccal side to the lingual side of the upper second molar that leaves the portion of the occlusal surface of the second molar uncovered. The recess is on the same side of the retainer as the pocket (e.g., both the retainer and the pocket are on the right side of the retainer, for example, the recess is configured to span a portion of an upper second molar on the right side of the patient’s mouth and the pocket is configured to attach the drug delivery device to an upper first molar on the right side of the patient’s mouth).

The drug delivery device is pre-filled with the LD/CD paste (e.g., a paste containing LD:CD in a ratio of 4:1 ). An exemplary paste includes about 49.5 w/w% LD, about 13.4 w/w% CD, about 5.0 w/w% poloxamer 188, about 25.3 w/w% medium chain triglycerides (e.g., Miglyol 812), about 6.5 w/w% water, about 0.3 w/w% benzoic acid, and about 0.1 w/w% sodium edetate (EDTA). The drug delivery device can include a propellant chamber and a drug chamber separated by a deformable metallic diaphragm. The LD/CD paste leaves the drug delivery device through a polymeric fluidic channel in fluid communication with the drug chamber. The polymeric fluidic channel can contain an L-shaped nozzle adaptor (i.e., a nozzle adaptor that makes a 90-degree turn) and a delivery tube that is substantially straight. The polymeric fluidic channel is configured to transport the drug from the buccal side of the teeth to or toward the lingual side of the teeth by extending across the occlusal surface of the teeth so the LD/CD paste can be administered at the back of the mouth on the lingual side of the teeth. When the drug delivery device is positioned in the pocket and the retainer is inserted into the patient’s mouth for use (e.g., by the patient or a caregiver), the delivery tube extends across the portion of the occlusal surface of the upper second molar that is uncovered by the retainer from the buccal side of the tooth to or toward the lingual side of the tooth. The distal end of the delivery tube may be positioned on the occlusal surface of the upper second molar when the drug delivery device is inserted into the pocket and the retainer is positioned on the teeth (e.g., the delivery tube does not extend all the way from the buccal side of the upper second molar to the lingual side of the upper second molar, but instead terminates on the occlusal surface of the upper second molar, such as about halfway across the upper second molar). Despite extending across the occlusal surface of the upper second molar, the delivery tube is not crushed when the patient wearing the retainer bites down (e.g., in a retainer containing a recess, the delivery tube fits within the recess, which may occur when the recess has a depth and width greater than or equal to the external diameter of the delivery tube, which prevents the delivery tube from being crushed when the patient bites down).

Once the drug delivery device is inserted into the retainer pocket, the retainer can be inserted into the mouth for continuous administration of the LD/CD paste (e.g., for a period of one or more hours, e.g., 1 , 2, 3, 4, 5, 6, or more hours). The retainer can be removed for eating or brushing teeth and to replace the drug delivery device with a fresh, prefilled drug delivery device. When not in use, the retainermounted drug delivery device can be placed into a storage case, which may contain a mechanism to pause the flow of LD/CD paste from the drug delivery device when the retainer-mounted drug delivery device is placed into the case and the case is closed.

Other Embodiments

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

What is claimed is: CLAIMS

1 . A retainer configured to removably secure a drug delivery device comprising a delivery tube to a buccal side of one or more teeth of a patient, wherein the retainer:

(i) is configured to cover an occlusal surface of at least a first tooth and to leave at least a portion of an occlusal surface of a second tooth uncovered; and

(ii) comprises a pocket for securing the drug delivery device to the buccal side of the one or more teeth of the patient, wherein said pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into a mouth of the patient the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the thickness of the retainer where it is configured to cover the occlusal surface of at least the first tooth is equal to or greater than an external diameter of the delivery tube or (b) wherein the thickness of the retainer where it is configured to cover the occlusal surface of at least the first tooth is equal to or greater than 50% of an external diameter of the delivery tube.

2. The retainer of claim 1 , wherein the retainer is configured such that said occlusal surface of at least the first tooth covered by the retainer is positioned in front of the delivery tube and said occlusal surface of the second tooth that is left uncovered extends from said delivery tube to a rear of said patient’s rearmost tooth in a quadrant of the mouth containing the delivery tube when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient.

3. The retainer of claim 1 or 2, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer.

4. The retainer of claim 1 , wherein the retainer comprises a recess that is configured to leave the portion of the occlusal surface of the second tooth uncovered having a depth and width equal to or greater than the external diameter of the delivery tube.

5. The retainer of claim 4, wherein said pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to or toward the lingual side of the tooth.

6. A retainer configured to removably secure a drug delivery device comprising a delivery tube to a buccal side of one or more teeth of a patient, wherein the retainer:

(i) is configured to cover an occlusal surface of at least a first tooth and comprises a recess configured to leave at least a portion of an occlusal surface of a second tooth uncovered; and (ii) comprises a pocket for securing the drug delivery device to the buccal side of one or more teeth of the patient, wherein said pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into a mouth of a patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the recess has a depth and width equal to or greater than an external diameter of the delivery tube or (b) wherein the recess has a depth and width equal to or greater than 50% of an external diameter of the delivery tube.

7. The retainer of claim 6, wherein the thickness of the retainer where it is configured to cover the occlusal surface of at least the first tooth is equal to or greater than the external diameter of the delivery tube.

8. The retainer of any one of claims 4-7, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from below an occlusal plane of the retainer.

9. The retainer of any one of claims 4-7, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from a side of the retainer.

10. The retainer of any one of claims 4-9, wherein the recess is configured to span an interproximal space between two teeth.

11 . The retainer of any one of claims 1 -10, wherein the second tooth is a second molar.

12. The retainer of any one of claims 1 -11 , wherein the patient has upper and lower third molars.

13. The retainer of any one of claims 1 -12, wherein the retainer is unilateral.

14. The retainer of any one of claims 1 -12, wherein the retainer is bilateral.

15. The retainer of claim 14, wherein the retainer comprises a palatal strap or bar.

16. The retainer of claim 14, wherein the retainer comprises an aligner-style design.

17. The retainer of claim 14, wherein the retainer comprises a partial aligner-style design.

18. The retainer of any one of claims 1 -17, wherein the retainer is configured to be worn on the upper teeth of the patient.

19. The retainer of claim 18, wherein the recess is configured to span an interproximal space between the upper second and third molars.

20. The retainer of any one of claims 1 -17, wherein the retainer is configured to be worn on the lower teeth of the patient.

21 . The retainer of any one of claims 1 -20, wherein the first tooth is a molar.

22. The retainer of any one of claims 1 -21 , wherein the pocket is fabricated as an integral part of the retainer.

23. The retainer of any one of claims 1 -22, wherein the retainer is configured to maintain a neutrocentric occlusion.

24. The retainer of any one of claims 1 -23, wherein the pocket is configured to position the drug delivery device coplanar with an occlusal plane of a molar.

25. The retainer of any one of claims 1 -24, wherein the pocket is configured to position the drug delivery device such that it is set on the Wilson plane.

26. The retainer of any one of claims 1 -25, wherein the retainer is configured such that the patient’s oral anatomy would mechanically interfere with and prevent the removal of the drug delivery device from the retainer when the drug delivery device is inserted into the pocket and the retainer is being worn by the patient.

27. The retainer of any one of claims 1 -26, wherein the pocket is configured such that it has a friction fit with the drug delivery device and thereby prevents the drug delivery device from being dislodged from the pocket during insertion of the retainer into the mouth or administration of drug.

28. The retainer of any one of claims 1 -27, wherein the retainer is made of a plastic.

29. The retainer of claim 28, wherein said retainer is 3D-printed or milled.

30. The retainer of claim 28 or 29, wherein the plastic is an acrylate-containing polymer, a thermoplastic polyolefin, or nylon.

31 . The retainer of any one of claims 1 -30, wherein the delivery tube is fl uidical ly connected to an L-shaped nozzle adaptor, optionally wherein the delivery tube is straight.

32. The retainer of any one of claims 1 -31 , wherein the delivery tube that extends across the portion of the occlusal surface of the second tooth that is uncovered is not compressed when the patient wearing the retainer bites down.

33. The retainer of any one of claims 1 -31 , wherein the delivery tube that extends across the portion of the occlusal surface of the second tooth that is uncovered is partially and reversibly compressed when the patient wearing the retainer bites down.

34. The retainer of any one of claims 1 -33, wherein said drug delivery device comprises a pump and a drug reservoir, wherein said drug reservoir comprises a pharmaceutical composition and is in fluid communication with said delivery tube.

35. The retainer of any one of claims 1 -34, wherein when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to the lingual side of the tooth and terminates at or beyond the lingual side of the tooth.

36. The retainer of any one of claims 1 -34, wherein when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth toward the lingual side of the tooth and terminates on the occlusal surface of the second tooth.

37. The retainer of claim 36, wherein the delivery tube terminates about halfway across the occlusal surface of the second tooth.

38. A method of administering a pharmaceutical composition on a lingual side of a patient’s teeth, the method comprising:

(i) inserting a drug delivery device into the pocket of the retainer of any one of claims 1 -37, wherein the drug delivery device comprises a drug reservoir comprising a pharmaceutical composition in fluid communication with a delivery tube configured to deliver said pharmaceutical composition from a buccal side to the lingual side of the patient’s teeth;

(ii) inserting the retainer comprising the drug delivery device into a mouth of the patient;

(iii) administering said pharmaceutical composition to the patient; and

(iv) removing the retainer from the mouth of the patient.

39. The method of claim 38, wherein the drug delivery device is inserted into the pocket from the rear of the retainer.

40. The method of claim 38, wherein the drug delivery device is inserted into the pocket from below the occlusal plane of the retainer.

41 . The method of claim 38, wherein the drug delivery device is inserted into the pocket from the side of the retainer.

42. A system comprising a retainer and a drug delivery device configured to be removably secured to one or more teeth of a patient, wherein:

(i) said retainer is configured to cover an occlusal surface of at least a first tooth of the patient and to leave at least a portion of an occlusal surface of a second tooth of the patient uncovered, wherein said retainer comprises a pocket on a buccal side of the retainer that is configured to secure the drug delivery device to a buccal side of the one or more teeth of said patient when the retainer is worn; and

(ii) said drug delivery device is suitable for insertion into the retainer pocket and comprises a delivery tube, wherein the delivery tube is configured such that when the drug delivery device is inserted into the retainer pocket and the retainer is inserted into a mouth of the patient, the delivery tube extends across the portion of the occlusal surface of the second tooth that is left uncovered by the retainer from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the thickness of the retainer where it is configured to cover the occlusal surface of at least the first tooth is equal to or greater than an external diameter of the delivery tube or (b) wherein the thickness of the retainer where it is configured to cover the occlusal surface of at least the first tooth is equal to or greater than 50% of an external diameter of the delivery tube.

43. The system of claim 42, wherein the retainer is configured such that said occlusal surface of at least the first tooth covered by the retainer is positioned in front of the delivery tube and said occlusal surface of the second tooth that is left uncovered extends from said delivery tube to a rear of said patient’s rearmost tooth in a quadrant of the mouth containing the delivery tube when the drug delivery device is inserted into the retainer pocket and the retainer is inserted into the mouth of the patient.

44. The system of claim 42 or 43, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer.

45. The system of claim 42, wherein the retainer comprises a recess that is configured to leave the portion of the occlusal surface of the second tooth uncovered having a depth and width equal to or greater than the external diameter of the delivery tube.

46. The system of claim 45, wherein said pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to or toward the lingual side of the tooth.

47. A system comprising a retainer and a drug delivery device configured to be removably secured to one or more teeth of a patient, wherein: (i) said retainer is configured to cover an occlusal surface of at least a first tooth of the patient and comprises a recess configured to leave at least a portion of an occlusal surface of a second tooth of the patient uncovered, wherein said retainer comprises a pocket on a buccal side of the retainer that is configured to secure the drug delivery device to a buccal side of the one or more teeth of said patient when the retainer is worn; and

(ii) said drug delivery device is suitable for insertion into the retainer pocket and comprises a delivery tube, wherein the delivery tube is configured such that when the drug delivery device is inserted into the retainer pocket and the retainer is inserted into a mouth of the patient, the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is left uncovered from a buccal side of the tooth to or toward a lingual side of the tooth, and wherein (a) the recess has a depth and width equal to or greater than an external diameter of the delivery tube or (b) the recess has a depth and width equal to or greater than 50% of an external diameter of the delivery tube.

48. The system of claim 47, wherein the thickness of the retainer where it covers the occlusal surface of at least the first tooth is equal to or greater than the external diameter of the delivery tube.

49. The system of any one of claims 45-48, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from below an occlusal plane of the retainer.

50. The system of any one of claims 45-48, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from a side of the retainer.

51 . The system of any one of claims 45-50, wherein the recess is configured to span an interproximal space between two teeth.

52. The system of any one of claims 42-51 , wherein the second tooth is a second molar.

53. The system of any one of claims 42-52, wherein the patient has upper and lower third molars.

54. The system of any one of claims 42-53, wherein the retainer is unilateral.

55. The system of any one of claims 42-53, wherein the retainer is bilateral.

56. The system of claim 55, wherein the retainer comprises a palatal strap or bar.

57. The system of claim 55, wherein the retainer comprises an aligner-style design.

58. The system of claim 55, wherein the retainer comprises a partial aligner-style design.

59. The system of any one of claims 42-58, wherein the retainer is configured to be worn on the upper teeth of the patient.

60. The system of claim 59, wherein the recess is configured to span an interproximal space between the upper second and third molars.

61 . The system of any one of claims 42-58, wherein the retainer is configured to be worn on the lower teeth of the patient.

62. The system of any one of claims 42-61 , wherein the first tooth is a molar.

63. The system of any one of claims 42-62, wherein the pocket is fabricated as an integral part of the retainer.

64. The system of any one of claims 42-63, wherein the retainer is configured to maintain a neutrocentric occlusion.

65. The system of any one of claims 42-64, wherein the pocket is configured to position the drug delivery device coplanar with an occlusal plane of a molar.

66. The system of any one of claims 42-65, wherein the pocket is configured to position the drug delivery device such that it is set on the Wilson plane.

67. The system of any one of claims 42-66, wherein the retainer is configured such that the patient’s oral anatomy would mechanically interfere with and prevent the removal of the drug delivery device from the retainer when the drug delivery device is inserted into the pocket and the retainer is being worn by the patient.

68. The system of any one of claims 42-67, wherein the pocket is configured such that it has a friction fit with the drug delivery device and thereby prevents the drug delivery device from being dislodged from the pocket during insertion of the retainer into the mouth or administration of drug.

69. The system of any one of claims 42-68, wherein the retainer is made of a plastic.

70. The system of claim 69, wherein said retainer is 3D-printed or milled.

71 . The system of claim 69 or 70, wherein the plastic is an acrylate-containing polymer, a thermoplastic polyolefin, or nylon.

72. The system of any one of claims 42-71 , wherein the delivery tube is fluid ically connected to an L-shaped nozzle adaptor, optionally wherein the delivery tube is straight.

73. The system of any one of claims 42-72, wherein the delivery tube that extends across the portion of the occlusal surface of the second tooth that is left uncovered is not compressed when the patient wearing the retainer bites down.

74. The system of any one of claims 42-72, where the delivery tube is partially and reversibly compressed when the patient wearing the retainer bites down.

75. The system of any one of claims 42-74, wherein said drug delivery device comprises a pump and a drug reservoir, wherein said drug reservoir comprises a pharmaceutical composition and is in fluid communication with said delivery tube.

76. The system of any one of claims 42-75, wherein when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient, the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to the lingual side of the tooth and terminates at or beyond the lingual side of the tooth.

77. The system of any one of claims 42-75, wherein when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient, the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth toward the lingual side of the tooth and terminates on the occlusal surface of the second tooth.

78. The system of claim 77, wherein the delivery tube terminates about halfway across the occlusal surface of the second tooth.

79. A method of administering a pharmaceutical composition on a lingual side of a patient’s teeth, the method comprising:

(i) inserting the system of any one of claims 42-78 into a mouth of the patient, wherein the drug delivery device is inserted into the retainer pocket and comprises a drug reservoir comprising a pharmaceutical composition in fluid communication with the delivery tube;

(ii) administering said pharmaceutical composition to the patient; and

(iii) removing the retainer from the mouth of the patient.

80. A method of administering a pharmaceutical composition to a patient on a lingual side of said patient’s teeth, comprising:

(i) inserting into a mouth of the patient a retainer-mounted drug delivery device comprising a drug reservoir comprising said pharmaceutical composition in fluid communication with a delivery tube, wherein the drug delivery device is inserted into a pocket in the retainer that secures the drug delivery device to a buccal side of one or more teeth of the patient, wherein the retainer covers an occlusal surface of at least a first tooth of the patient and leaves at least a portion of an occlusal surface of a second tooth of the patient uncovered, wherein (a) the thickness of the retainer where it covers the occlusal surface of at least the first tooth is equal to or greater than an external diameter of the delivery tube or (b) wherein the thickness of the retainer where it covers the occlusal surface of at least the first tooth is equal to or greater than 50% of an external diameter of the delivery tube, and wherein the delivery tube extends across the portion of the occlusal surface of the second tooth that is left uncovered by the retainer from a buccal side of the tooth to or toward a lingual side of the tooth;

(ii) administering said pharmaceutical composition on the lingual side of said patient’s teeth via said delivery tube; and

(iii) removing the retainer-mounted drug delivery device from the mouth of said patient after said administering.

81 . The method of claim 80, wherein the retainer is configured such that said occlusal surface of at least the first tooth covered by the retainer is positioned in front of the delivery tube and said occlusal surface of the second tooth that is left uncovered extends from said delivery tube to a rear of said patient’s rearmost tooth in a quadrant of the mouth containing the delivery tube when the retainermounted drug delivery device is inserted into the mouth of the patient.

82. The method of claim 80 or 81 , wherein the retainer is configured such that the drug delivery device is inserted into the pocket from a rear of the retainer.

83. The method of claim 80, wherein the retainer comprises a recess that leaves the portion of the occlusal surface of the second tooth uncovered having a depth and width equal to or greater than the external diameter of the delivery tube.

84. The method of claim 83, wherein said pocket is configured to position the drug delivery device such that when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to or toward the lingual side of the tooth.

85. A method of administering a pharmaceutical composition to a patient on a lingual side of said patient’s teeth, comprising:

(i) inserting into a mouth of the patient a retainer-mounted drug delivery device comprising a drug reservoir comprising said pharmaceutical composition in fluid communication with a delivery tube, wherein the drug delivery device is inserted into a pocket in the retainer that secures the drug delivery device to a buccal side of one or more teeth of the patient, wherein the retainer covers an occlusal surface of at least a first tooth of the patient and comprises a recess that leaves at least a portion of an occlusal surface of a second tooth of the patient uncovered, wherein (a) the recess has a depth and width equal to or greater than an external diameter of the delivery tube or (b) the recess has a depth and width equal to or greater than 50% of an external diameter of the delivery tube, and wherein the delivery tube extends through the recess across the portion of the occlusal surface of the second tooth that is left uncovered by the retainer from a buccal side of the tooth to or toward a lingual side of the tooth; (ii) administering said pharmaceutical composition on the lingual side of said patient’s teeth via said delivery tube; and

86. The method of claim 85, wherein the thickness of the retainer where it covers the occlusal surface of at least the first tooth is equal to or greater than the external diameter of the delivery tube.

87. The method of any one of claims 83-86, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from below an occlusal plane of the retainer.

88. The method of any one of claims 83-86, wherein the retainer is configured such that the drug delivery device is inserted into the pocket from a side of the retainer.

89. The method of any one of claims 83-88, wherein the recess spans an interproximal space between two teeth.

90. The method of any one of claims 80-89, wherein the second tooth is a second molar.

91 . The method of any one of claims 80-90, wherein the patient has upper and lower third molars.

92. The method of any one of claims 80-91 , wherein the retainer is unilateral.

93. The method of any one of claims 80-91 , wherein the retainer is bilateral.

94. The method of claim 93, wherein the retainer comprises a palatal strap or bar.

95. The method of claim 93, wherein the retainer comprises an aligner-style design.

96. The method of claim 93, wherein the retainer comprises a partial aligner-style design.

97. The method of any one of claims 80-96, wherein the retainer is configured to be worn on the upper teeth of the patient.

98. The method of claim 97, wherein the recess spans an interproximal space between the upper second and third molars.

99. The method of any one of claims 80-96, wherein the retainer is configured to be worn on the lower teeth of the patient.

100. The method of any one of claims 80-99, wherein the first tooth is a molar.

101 . The method of any one of claims 80-100, wherein the pocket is fabricated as an integral part of the retainer.

102. The method of any one of claims 80-101 , wherein the retainer is configured to maintain a neutrocentric occlusion.

103. The method of any one of claims 80-102, wherein the pocket is configured to position the drug delivery device coplanar with an occlusal plane of a molar.

104. The method of any one of claims 80-103, wherein the pocket is configured to position the drug delivery device such that it is set on the Wilson plane.

105. The method of any one of claims 80-104, wherein the retainer is configured such that the patient’s oral anatomy would mechanically interfere with and prevent the removal of the drug delivery device from the retainer when the drug delivery device is inserted into the pocket and the retainer is being worn by the patient.

106. The method of any one of claims 80-105, wherein the pocket is configured such that it has a friction fit with the drug delivery device and thereby prevents the drug delivery device from being dislodged from the pocket during insertion of the retainer into the mouth or administration of drug.

107. The method of any one of claims 80-106, wherein the retainer is made of a plastic.

108. The method of claim 107, wherein said retainer is 3D-printed or milled.

109. The method of claim 107 or 108, wherein the plastic is an acrylate-containing polymer, a thermoplastic polyolefin, or nylon.

110. The method of any one of claims 80-109, wherein the delivery tube is fluidically connected to an L-shaped nozzle adaptor, optionally wherein the delivery tube is straight.

111. The method of any one of claims 80-110, wherein the delivery tube that extends across the portion of the occlusal surface of the second tooth that is left uncovered is not compressed when the patient wearing the retainer bites down.

112. The method of any one of claims 80-110, wherein the delivery tube that extends across the portion of the occlusal surface of the second tooth that is left uncovered is partially and reversibly compressed when the patient wearing the retainer bites down.

113. The method of any one of claims 80-112, wherein said drug delivery device comprises a pump and a drug reservoir, wherein said drug reservoir comprises a pharmaceutical composition and is in fluid communication with said delivery tube.

114. The method of any one of claims 80-113, wherein when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient, the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth to the lingual side of the tooth and terminates at or beyond the lingual side of the tooth.

115. The method of any one of claims 80-113, wherein when the drug delivery device is inserted into the pocket and the retainer is inserted into the mouth of the patient, the delivery tube extends across the portion of the occlusal surface of the second tooth that is uncovered from the buccal side of the tooth toward the lingual side of the tooth and terminates on the occlusal surface of the second tooth.

116. The method of claim 115, wherein the delivery tube terminates about halfway across the occlusal surface of the second tooth.