(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`
`%&\
`
`International Bureau
`
`(10) International Publication Number
`
`WO 2015/069773 A1
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(43) International Publication Date
`14 May 2015 (14.05.2015)
`
`WI PC I P C T
`
`(51)
`
`International Patent Classification:
`A61M 37/00 (2006.01)
`A61K 9/22 (2006.01)
`A61C 7/08 (2006.01)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/US2014/064137
`
`(22)
`
`International Filing Date:
`
`5 November 2014 (05.11.2014)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`61/899,979
`61/926,022
`61/987,899
`62/042,553
`
`5 November 2013 (05.11.2013)
`10 January 2014 (10.01.2014)
`2 May 2014 (02.05.2014)
`27 August 2014 (27.08.2014)
`
`English
`
`English
`
`US
`US
`US
`US
`
`Applicant: SYNAGILE CORPORATION [US/US];
`3465 N. Pines Way, Suite 104, Pmb 218, Wilson, WY
`83014 (US).
`
`Inventors: HELLER, Ephraim; 3465 N. Pines Way,
`Suite 104, Pmb 218, Wilson, WY 83014 (US). HELLER,
`Adam; 1801 Lavava Street, Apt. 11E, Austin, TX 78701
`(US). REHLAENDER, Bruce; 18051 Kelok Rd, Lake Os-
`wego, OR 97034 (US). SPIRIDIGLOZZI, John; 9 W
`Broadway - Unit 609, Boston, MA 02127 (US).
`
`(74)
`
`Agents: BIEKER-BRADY, Kristina et a1.; Clark & E1-
`bing LLP, 101 Federal Street, 15th Floor, Boston, MA
`02110 (US).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM, ML, MR, NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`as to applicant’s entitlement to applyfor and be granted a
`patent (Rule 4.1 7(ii))
`
`as to the applicant’s entitlement to claim the priority ofthe
`earlier application (Rule 4. l 7(iii))
`Published:
`
`with international search report (Art. 21(3))
`
`[Continued on nextpage]
`
`(54) Title: DEVICES AND METHODS FOR CONTINUOUS DRUG DELIVERY VIA THE MOUTH
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`
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`(57) Abstract: The invention features a drug delivery device held in the mouth and continuously administering either a fluid com-
`prising drug dissolved and/or dispersed in water or in a non-toxic liquid, or a drug in solid fonn.
`
`
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`— before the expiration of the time limitfnr amending the
`claims and to be republished in the event of receipt of
`amendments (Ru/e 48.2(h))
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`DEVICES AND METHODS FOR CONTINUOUS DRUG DELIVERY VIA THE MOUTH
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`The invention features a drug delivery device anchored in the mouth for continuously
`
`administering a drug in solid form or a fluid in which a drug is dissolved or suspended.
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`FIELD OF THE INVENTION
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`BACKGROUND
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`This invention relates to devices and methods for continuous or semi-continuous drug
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`administration via the oral route.
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`It is an aim of this invention to solve several problems related to drugs
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`with short physiological half-lives of drugs (e.g., shorter than 8 hours, 6 hours, 4 hours, 2 hours, 1 hour,
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`30 min, 20 min or 10 min) and/or narrow therapeutic windows of drugs that are currently dosed multiple
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`times per day: it is inconvenient to take a drug that must be dosed multiple times per day or at night, the
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`drug’s pharmacokinetics and efficacy may be sub-optimal, and side effects may increase in frequency
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`and/or severity. Continuous or semi-continuous administration is particularly beneficial for drugs with a
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`short half—life and/or a narrow therapeutic window, such as levodopa (LD), anti—epileptics (e.g.,
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`oxcarbazepine, topiramate, lamotrigine, gabapentin, carbamazepine, valproic acid, levetiracetam,
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`pregabalin), and sleep medications (e.g., zaleplon). Continuous or semi-continuous infusion in the mouth
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`can provide for lesser fluctuation in the concentration of a drug in an organ or fluid, for example in the
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`blood or plasma. Convenient, automatic administration of a drug can also increase patient compliance
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`with their drug regimen, particularly for patients who must take medications at night and for patients with
`dementia.
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`Medical conditions managed by continuously orally administered drugs include Parkinson’s
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`disease, bacterial infections, cancer, pain, organ transplantation, disordered sleep, epilepsy and seizures,
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`anxiety, mood disorders, post-traumatic stress disorder, cancer, arrhythmia, hypertension, heart failure,
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`spasticity, dementia, and diabetic nephropathy.
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`A challenge with most drug delivery devices in the prior art is that they are not designed for
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`placement and operation in the mouth. Devices must be designed to be small, comfortable, and non—
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`irritating, and to not interfere with speech, swallowing, drinking and/or eating.
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`In the mouth saliva, food or
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`drink may penetrate into the drug reservoir and/or the pump, thereby potentially unpredictably extracting
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`and delivering the drug, or reacting with the drug, or clogging the delivery device. Pumps that have been
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`suggested for operation in the mouth, such as osmotic tablets and mucoadhesive patches, often do not
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`reliably provide constant rate drug delivery for extended periods of time under the conditions in the
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`mouth. Drinking of hot or cold beverages may cause undesirable changes in drug delivery, e.g., delivery
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`of a drug bolus. Likewise, sucking on the device may cause delivery of an unwanted bolus. Exposure to
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`foods and liquids such as oils, alcohols, and acids may temporarily or permanently increase or decrease
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`the drug delivery rate from the device.
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`lntra-oral drug delivery devices must also administer the drug into
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`a suitable location in the mouth, e.g., into a location where the drug does not accumulate in an unwanted
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`manner or to a location where it is immediately swallowed. There is, therefore, a need for improved drug
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`delivery devices that can operate comfortably, safely and reliably in the mouth over extended periods of
`time.
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`lntra-oral pumps have previously been proposed in inconvenient formats, e.g., wherein the device
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`is located within a replacement tooth. There is a need for improved intra-oral drug delivery devices that
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`can conveniently be inserted and removed by the patient, without requiring the insertion or removal of a
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`replacement tooth, dental bridge, or denture. A problem with these and other pumps that reside in the
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`mouth and that can continuously deliver drug in the mouth, such as controlled release osmotic tablets and
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`muco-adhesive drug delivery patches, is that once drug delivery has begun it cannot be temporarily
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`stopped. Temporarily stopping the drug delivery is desirable so that drug is not wasted and, more
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`importantly, so that dispensed drug does not accumulate on the surface of the device while the device is
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`removed from the mouth. Such an unquantified accumulation of drug on the surface of the device might
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`lead to the undesired delivery of a bolus of an unknown quantity of drug to the patient when the device is
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`placed back into the mouth. Maintenance of accurate rate of drug delivery when the ambient atmospheric
`
`pressure changes, e.g., during air-travel or at elevated locations, can also be challenging.
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`The pumps of the invention can provide constant rate, continuous administration of drugs in the
`
`mouth, and can be temporarily stopped when the devices are removed from the mouth.
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`Most drugs intended for oral administration are formulated as solids (e.g., pills, tablets), solutions
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`or suspensions that are administered once or several times per day. Such drugs are not formulated to
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`meet the requirements of continuous or semi-continuous, constant-rate, intra-oral administration. For
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`example, many suspensions and solutions are formulated in relatively large daily volumes and/or in
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`formulations that are physically or chemically unstable over the course of a day at body temperature; and
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`pills and tablets are rarely formulated in units and dosage amounts appropriate for dosing frequently
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`throughout the day.
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`Large quantities of drug must be administered to treat some diseases. For example, 1,000 mg of
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`levodopa is a typical daily dose administered to patients with advanced Parkinson’s disease.
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`In order to
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`continuously administer such large quantities of drug into the mouth in a fluid volume that will fit
`
`comfortably in the mouth (typically less than 5 mL) for many hours, it is sometimes necessary to employ
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`concentrated, often viscous, fluid formulations of the drug. Use of viscous fluids can provide the small
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`volumes, high concentrations, uniform drug dispersion, storage stability, and operational stability desired
`
`for the drugs and methods of the invention. Consequently, it is often necessary to employ miniaturized
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`pumps tailored to provide the high pressures required to pump the viscous fluids. The drug devices and
`formulations of the invention address these unmet needs.
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`As a specific example, Parkinson’s disease (PD) is characterized by the inability of the
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`dopaminergic neurons in the substantia nigra to produce the neurotransmitter dopamine. PD impairs
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`motor skills, cognitive processes, autonomic functions and sleep. Motor symptoms include tremor,
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`rigidity, slow movement (bradykinesia), and loss of the ability to initiate movement (akinesia) (collectively,
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`the “off” state). Non-motor symptoms of PD include dementia, dysphagia (difficulty swallowing), slurred
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`speech, orthostatic hypotension, seborrheic dermatitis, urinary incontinence, constipation, mood
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`alterations, sexual dysfunction, and sleep issues (e.g., daytime somnolence, insomnia).
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`After more than 40 years of clinical use levodopa therapy remains the most effective method for
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`managing PD and provides the greatest improvement in motor function. Consequently, LD administration
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`is the primary treatment for PD. LD is usually orally administered. The orally administered LD enters the
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`blood and part of the LD in the blood crosses the blood brain barrier.
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`It is metabolized, in part, in the
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`brain to dopamine which temporarily diminishes the motor symptoms of PD. As the neurodegeneration
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`underlying PD progresses, the patients require increasing doses of LD and the fluctuations of brain
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`dopamine levels increase. When too much LD is transported to the brain, dyskinesia sets in (uncontrolled
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`movements such as writhing, twitching and shaking); when too little is transported, the patient re-enters
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`the off state. As PD progresses, the therapeutic window for oral formulations of LD narrows, and it
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`becomes increasingly difficult to control PD motor symptoms without inducing motor complications.
`
`In
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`addition, most PD patients develop response fluctuations to intermittent oral LD therapy, such as end of
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`dose wearing off, sudden on/off’s, delayed time to on, and response failures.
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`The devices, formulations and methods of the invention provide improved therapies for patients
`with PD.
`
`SUMMARY OF THE INVENTION
`
`The invention features a drug delivery device, configured and arranged to be removably inserted
`
`in a patient’s mouth by the patient.
`
`In a first aspect, the invention features a drug delivery device configured to be removably inserted
`
`in a patient’s mouth and for continuous or semi-continuous intraoral administration of a pharmaceutical
`
`composition including a drug, the device including: (i) a fastener to removably secure the drug delivery
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`device to a surface of the patient’s mouth; (ii) an electrical or mechanical pump; (iii) an oral liquid
`
`impermeable drug reservoir, the volume of the drug reservoir being from 0.1 mL to 5 mL (e.g., 0.1 mL to 1
`
`mL,
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`1 mL to 2 mL, 2 mL to 3.5 mL, or 3.5 mL to 5 mL); and (iv) an automatic stop/start. The drug delivery
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`device can be configured to be automatically stopped upon one or more of the following: (a) the drug
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`delivery device, the pump, and/or the oral liquid impermeable reservoir are removed from the mouth; (b)
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`the drug delivery device, the pump, and/or the oral liquid impermeable reservoir are disconnected from
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`the fastener; or (c) the oral liquid impermeable reservoir is disconnected from the pump. The drug
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`delivery device can be configured to be automatically started upon one or more of the following: (a) the
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`drug delivery device, the pump, and/or the oral liquid impermeable reservoir are inserted into the mouth;
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`(b) the drug delivery device, the pump, and/or the oral liquid impermeable reservoir are connected to the
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`fastener; or (c) the oral liquid impermeable reservoir is connected to the pump.
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`In particular
`
`embodiments, the automatic stop/start is selected from: a pressure sensitive switch, a clip, a fluidic
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`channel that kinks, a clutch, a sensor, or a cap. The device optionally further includes a suction-induced
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`flow limiter, a temperature-induced flow limiter, bite-resistant structural supports, or a pressure-invariant
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`mechanical pump, or a combination thereof.
`
`The invention further features a drug delivery device configured to be removably inserted in a
`
`patient’s mouth and for continuous or semi-continuous intraoral administration of a pharmaceutical
`
`composition including a drug, the device including:
`
`(i) a fastener to removably secure the drug delivery
`
`device to a surface of the patient’s mouth; (ii) an electrical or mechanical pump; (iii) an oral liquid
`
`impermeable drug reservoir, the volume of the drug reservoir being from 0.1 mL to 5 mL (e.g., 0.1 mL to 1
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`mL,
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`1 mL to 2 mL, 2 mL to 3.5 mL, or 3.5 mL to 5 mL); and (iv) a suction-induced flow limiter.
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`In certain
`
`embodiments, the suction-induced flow limiter includes pressurized surfaces that are in fluidic (gas and/or
`
`liquid) contact with the ambient atmosphere via one or more ports or openings in the housing of the drug
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`delivery device.
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`In other embodiments, the suction-induced flow limiter is selected from a deformable
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`channel, a deflectable diaphragm, a compliant accumulator, an inline vacuum-relief valve, and a float
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`valve. The suction—induced flow limiter can be configured to prevent the delivery of a bolus greater than
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`about 5%, 3%, or 1% of the contents of a fresh drug reservoir, when the ambient pressure drops by 6 psi,
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`4 psi, 2 psi, or 1 psi for a period of 20 second, 40 seconds, one minute, or two minutes. The device
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`optionally further includes an automatic stop/start, a temperature-induced flow limiter, bite-resistant
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`structural supports, or a pressure—invariant mechanical pump.
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`The invention also features a drug delivery device configured to be removably inserted in a
`
`patient’s mouth and for continuous or semi-continuous intraoral administration of a pharmaceutical
`
`composition including a drug, the device including: (i) a fastener to removably secure the drug delivery
`
`device to a surface of the patient’s mouth; (ii) an electrical or mechanical pump; (iii) an oral liquid
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`impermeable drug reservoir, the volume of the drug reservoir being from 0.1 mL to 5 mL (e.g., 0.1 mL to 1
`
`mL,
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`1 mL to 2 mL, 2 mL to 3.5 mL, or 3.5 mL to 5 mL); and (iv) a temperature-induced flow limiter.
`
`In
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`certain embodiments, the temperature-induced flow limiter includes insulation with a material of low
`
`thermal conductivity proximate the drug reservoir and/or the pump.
`
`In certain embodiments, the pump is
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`elastomeric and the temperature-induced flow limiter includes an elastomer selected from a natural
`
`rubber or a synthetic elastomer. The temperature-induced flow limiter can include an elastomer whose
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`force in a fresh reservoir increases by less than 30%, 20%, or 10% when the oral temperature is raised
`
`from 37 to 55 °C for a period of one minute.
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`In other embodiments, the pump includes a spring and the
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`temperature-induced flow limiter includes a spring configured to produce a force in a fresh reservoir that
`
`increases by less than 30%, 20%, or 10% when the oral temperature is raised from 37 to 55 °C for a
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`period of one minute. The temperature—induced flow limiter can include a spring including a 300 series
`
`stainless steel, titanium, lnconel (Le, a family of austenitic nickel-chromium-based superalloys), and fully
`
`austenitic Nitinol.
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`In still other embodiments, the pump is gas-driven and the temperature-induced flow
`
`limiter includes a gas having a volume of less than 40%, 30%, 20% or 10% of the volume of filled drug
`
`reservoir in a fresh reservoir at 37 °C and 13 psia. For example, the pump can be propellant—driven and
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`the temperature-induced flow limiter includes a propellant having a pressure that increases by less than
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`about 80%, 60%, or 40% when the oral temperature is raised from 37 to 55 °C for a period of one minute.
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`The device optionally further includes a suction-induced flow limiter, an automatic stop/start, bite-resistant
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`structural supports, or a pressure—invariant mechanical pump.
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`The invention further features a drug delivery device configured to be removably inserted in a
`
`patient’s mouth and for continuous or semi-continuous intraoral administration of a pharmaceutical
`
`composition including a drug, the device including: (i) a fastener to removably secure the drug delivery
`
`device to a surface of the patient’s mouth; (ii) an electrical or mechanical pump; (iii) an oral liquid
`
`impermeable drug reservoir, the volume of the drug reservoir being from 0.1 mL to 5 mL (e.g., 0.1 mL to 1
`
`mL,
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`1 mL to 2 mL, 2 mL to 3.5 mL, or 3.5 mL to 5 mL); and (iv) bite-resistant structural supports.
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`In
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`certain embodiments, the bite-resistant structural supports are selected from: a housing that encapsulates
`
`the entire drug reservoir and pump components; posts; ribs; or a potting material. The device optionally
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`further includes a suction-induced flow limiter, an automatic stop/start, a temperature-induced flow limiter,
`
`or a pressure-invariant mechanical pump.
`
`The invention also features a drug delivery device configured to be removably inserted in a
`
`patient’s mouth and for continuous or semi-continuous intraoral administration of a pharmaceutical
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`composition including a drug, the device including: (i) a fastener to removably secure the drug delivery
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`device to a surface of the patient’s mouth; (ii) a pressure-invariant mechanical pump; and (iii) an oral
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`liquid impermeable drug reservoir, the volume of the drug reservoir being from 0.1 mL to 5 mL (e.g., 0.1
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`mL to 1 mL,1 mL to 2 mL, 2 mL to 3.5 mL, or 3.5 mL to 5 mL). The pressure-invariant mechanical pump
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`can be selected from a spring, an elastomer, compressed gas, and a propellant.
`
`In certain embodiments,
`
`the pressure-invariant mechanical pump includes pressurized surfaces that are in fluidic (gas and/or
`
`liquid) contact with the ambient atmosphere via one or more ports or openings in the housing of the drug
`
`delivery device. The pressure-invariant mechanical pump can be configured to maintain an internal
`
`pressure of greater than or equal to about 4 atm.
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`In other embodiments, the pressure-invariant
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`mechanical pump is configured such that the average rate of drug delivery increases or decreases by
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`less than about 20%, 10%, or 5% at 14.7 psia and at 11.3 psia, as compared to the average rate of
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`delivery at 13.0 psia. The device optionally further includes a suction-induced flow limiter, an automatic
`
`stop/start, a temperature-induced flow limiter, or bite-resistant structural supports.
`
`The invention further features a drug delivery device configured to be removably inserted in a
`
`patient’s mouth and for continuous or semi-continuous intraoral administration of a pharmaceutical
`
`composition including a drug, the device including:
`
`(i) a fastener to removably secure the drug delivery
`
`device to a surface of the patient’s mouth; (ii) a mechanical pump; and (iii) an oral liquid impermeable
`
`drug reservoir, the volume of the drug reservoir being from 0.1 mL to 5 mL (e.g., 0.1 mL to 1 mL, 1 mL to
`
`2 mL, 2 mL to 3.5 mL, or 3.5 mL to 5 mL).
`
`In one particular embodiment, the mechanical pump is
`
`selected from: a spring, an elastomer, compressed gas, and a propellant.
`
`In still other embodiments, the
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`oral liquid impermeable reservoir includes one or more of: metal reservoirs, plastic reservoirs, elastomeric
`
`reservoirs, metallic barrier layers, valves, squeegees, baffles, rotating augers, rotating drums, propellants,
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`pneumatic pumps, diaphragm pumps, hydrophobic materials, and/or hydrophobic fluids.
`
`In some
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`embodiments, the device is configured such that 4 hours after inserting a drug delivery device including a
`
`fresh reservoir in a patient’s mouth and initiating the administration, less than 5%, 3%, or 1% by weight of
`
`the drug—including solid or drug—including fluid in the reservoir includes an oral liquid.
`
`In still other
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`embodiments, the oral liquid impermeable drug reservoir includes a fluidic channel in a spiral
`
`configuration. The device optionally further includes a suction-induced flow limiter, an automatic
`
`stop/start, a temperature-induced flow limiter, a pressure-invariant mechanical pump, or bite-resistant
`
`structural supports.
`
`In an embodiment of any of the above devices, the pump is an electrical pump (e.g., a
`
`piezoelectric pump or an electroosmotic pump). For example, the electrical pump can be a piezoelectric
`
`pump configured to operate at a frequency of less than about 20,000 Hz, 10,000 Hz, 5,000 Hz.
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`Optionally, the electrical pump includes a motor.
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`In another embodiment of any of the above devices, the pump is a mechanical pump. The
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`mechanical pump can be an elastomeric drug pump. The elastomeric drug pump can include an
`
`elastomeric balloon, an elastomeric band, or a compressed elastomer. The mechanical pump can be a
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`spring-driven pump. The spring-driven pump can include a constant force spring. The spring-driven
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`pump can include a spring that retracts upon relaxation. The mechanical pump can be a negative
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`pressure pump (e.g., a pneumatic pump or a gas-driven pump). For example, a gas driven pump can
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`include a gas in a first compartment and the drug in a second compartment, the gas providing a pressure
`
`exceeding 1 atm, 1.2 atm, or 1.5 atm. The gas-driven pump can include a compressed gas cartridge.
`
`In
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`particular embodiments, the gas driven pump includes a gas, the volume of the gas being less than 35%,
`
`25%, 15%, or 10% of the volume of the pharmaceutical composition.
`
`In other embodiments, the gas
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`driven pump includes a gas generator.
`
`In some embodiments, the gas driven pump is a propellant—driven
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`pump. The propellant-driven pump can include a fluid propellant, the fluid propellant having a boiling
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`point of less than 37 °C at 1 atm. The fluid propellant can be a hydrocarbon, a halocarbon, a
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`hydrofluoralkane, an ester, or an ether (e.g., 1-fluorobutane, 2-fluorobutane, 1,2-difluoroethane, methyl
`
`ethyl ether, 2—butene, butane, 1—fluoropropane, 1—butene, 2—fluoropropane, 1,1—difluoroethane,
`
`cyclopropene, propane, propene, diethyl ether, 1,1,1,2 tetrafluoroethane, 1,1,1,2,3,3,3
`
`heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, octafluorocyclobutane or isopentane).
`
`In an embodiment of any of the above devices, the drug delivery device can include two or more
`
`drug pumps and/or two or more drug reservoirs.
`
`In particular embodiments, the oral liquid impermeable
`
`reservoir is substantially impermeable to oxygen gas.
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`In another embodiment of any of the above devices, the drug reservoir includes a pharmaceutical
`
`composition and the pharmaceutical composition occupies greater than 33% (e.g., 33% to 70%, 50% to
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`80%, 66% to 90%) of the total volume of the drug reservoir and pump. The total volume of the one or
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`more drug reservoirs and the one or more drug pumps can be less than 5 mL, 3 mL, or 2 mL.
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`In an embodiment of any of the above devices, the device is configured to be secured to the
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`surface of one or more teeth of the patient. The fastener can include a band, a bracket, a clasp, a splint,
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`or a retainer.
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`In particular embodiments, the fastener includes a transparent retainer. For example, the
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`fastener can include a partial retainer attached to fewer than 5 teeth, 4 teeth, or 3 teeth.
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`In another embodiment of any of the above devices, the drug delivery device includes one or
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`more drug reservoirs and one or more pumps, and the drug reservoirs or the pumps are configured to be
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`worn in the buccal vestibule.
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`In one embodiment of any of the above devices, the drug delivery device includes one or more
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`drug reservoirs and one or more pumps, and the drug reservoirs or the pumps are configured to be worn
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`on the lingual side of the teeth.
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`In still another embodiment of any of the above devices, the drug delivery device includes one or
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`more drug reservoirs and one or more pumps, and the drug reservoirs or the pumps are configured to be
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`worn simultaneously in the buccal vestibule and on the lingual side of the teeth.
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`In another embodiment of any of the above devices, the drug delivery device includes one or
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`more drug reservoirs and one or more pumps, and the drug reservoirs or the pumps are configured
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`bilaterally.
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`In still another embodiment of any of the above devices, the drug delivery device includes one or
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`more drug reservoirs and one or more pumps, and the drug reservoirs or the pumps are configured to
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`administer the pharmaceutical composition into the mouth of the patient on the lingual side of the teeth.
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`For example, the drug delivery device can include a fluidic channel from the buccal side to the lingual side
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`of the patient’s teeth for dispensing the pharmaceutical composition.
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`In another embodiment of any of the above devices, the drug delivery device includes a fluidic
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`channel in the fastener through which the pharmaceutical composition is administered into the mouth of
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`the patient. For example, the drug delivery device can include a leak-free fluidic connector for direct or
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`indirect fluidic connection of the fastener to the one or more drug reservoirs. The drug delivery device
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`can include a flow restrictor in the fastener for controlling the flow of the pharmaceutical composition.
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`In another embodiment of any of the above devices, the drug delivery device includes a pump or
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`a power source.
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`In an embodiment of any of the above devices, the drug reservoir is in fluid communication with a
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`tube, channel, or orifice of less than 4 cm, 3 cm, 2 cm, 1 cm, 0.5 cm, or 0.2 cm length and the shear
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`viscosity of the pharmaceutical composition is greater than about 50, 500, 5,000, or 50,000 cP (e.g., from
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`50 to 5000 cP or from 5,000 to 50,000 cP, or from 50,000 to 200,000 cP), and where the device is
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`configured to administer the drug via the tube, channel, or orifice.
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`In particular embodiments, the tube,
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`channel, or orifice has a minimum internal diameter of greater than about 1 mm, 2 mm, 3 mm, 4mm, or
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`5mm (e.g., 1 to 3 mm, 2 to 4 mm, 3 to 6 mm, or 5 to 15 mm).
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`In another embodiment of any of the above devices, the drug delivery device includes a flow
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`restrictor that sets the administration rate of the pharmaceutical composition. For example, the length of
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`the flow restrictor can set the administration rate of the pharmaceutical composition.
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`In particular
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`embodiments, the flow restrictor is flared.
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`In an embodiment of any of the above devices, the drug delivery device is configured to deliver
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`an average rate of volume of from about 0.015 mL/hour to about 1.25 mL/hour over a period of from
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`about 4 hours to about 168 hours at 37 9C and a constant pressure of 13 psia, wherein the average rate
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`varies by less than i 20% or i 10% per hour over a period of 4 or more hours. The drug delivery device
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`can include oral fluid contacting surfaces that are compatible with the oral fluids, such that the average
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`rate of delivery of the drug increases or decreases by less than i 20% or i 10% per hour after the device
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`is immersed for five minutes in a stirred physiological saline solution at about 37 °C including any one of
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`the following conditions, as compared to an identical drug delivery device immersed for five minutes in a
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`physiological saline solution of pH 7 at 37 °C: (a) pH of about 2.5; (b) pH of about 9.0; (c) 5% by weight
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`olive oil; and (d) 5% by weight ethanol.
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`In an embodiment of any of the above devices, the drug delivery device is configured to deliver
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`an average rate of volume of from about 0.015 mL/hour to about 1.25 mL/hour over a period of from
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`about 4 hours to about 168 hours at 37 9C and a constant pressure of 13 psia, wherein the volume is
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`administered at the average rate in less than about 60, 30, or 10 minutes after the first insertion of the
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`device into the patient’s mouth.
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`In an embodiment of any of the above devices, the drug reservoir includes a suspension including
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`at 37 ”0 solid particles of the drug, a concentration of the drug greater than about 2 M (e.g., 2 to 5 M),
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`and a viscosity of the pharmaceutical composition in the drug reservoir of greater than about 1,000 cP
`
`(e.g., 1,000 cP to 200,000 cP). The drug delivery device can further include a suspension flow-
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`enhancement element. The suspension flow enhancement element can be selected from: a drug with a
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`multimodal particle size distribution wherein the ratio of the average particle diameters for the peaks is in
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`the range of 3:1 to 7:1; a drug with a packing density in the range of 0.64 — 0.70; lubricants, glidants, anti-
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`adhesives, or wetting agents; and modification of the surface properties of the fluidic channel to enhance
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`the flow of particles.
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`In particular embodiments, the suspension flow enhancement element includes a
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`flared orifice, tube, or flow restrictor.
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`In other embodiments, the suspension flow enhancement element
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`includes an orifice, tube or flow restrictor minimum inner diameter at least 10 times greater than the
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`maximum effective particle size.
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`In certain embodiments, the suspension flow enhancement element
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`includes pumping the suspension at a pressure of less than 10 bars. The viscosity of the suspension can
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`be greater than about 10,000 cP.
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`In certain embodiments, the suspension includes a fluid carrier
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`including an oil.
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`In an embodiment of any of the above devices, the drug reservoir includes a pharmaceutical
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`composition and the pharmaceutical composition includes a drug. For example, the drug reservoir can
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`include a pill, tablet, pellet, capsule, particle, microparticle, granule, or powder.
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`In particular
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`embodiments, the drug reservoir includes extruded and spheronized particles, or particles generated by
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`spray drying, Wurster coating, or granulation and milling.
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`The solid optionally further includes a disintegrant.
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`In particular embodiments, the pharmaceutical
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`composition includes from 50% to 100% or from 75% to 100% (w/w) drug.
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`In one embodiment, the drug
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`reservoir does not include a fluid.
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`In another embodiment, the drug reservoir includes a solid drug
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`pharmaceutical composition and an aqueous or non-aqueous liquid (e.g., an edible non-aqueous liquid,
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`such as a lubricant or oil). The non-aqeous, edible liquid can substantially reduce contact of the solid
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`drug in the drug reservoir with saliva when the device resides in the mouth of a patient.
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`In another embodiment of any of the above devices, the drug reservoir includes a fluid including a
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`drug (e.g., where the shear viscosity of the fluid is between about 10 cP and about 50,000 cP at 37 °C, for
`
`example between about 10 cP and about 1,000 cP at 37 °C, or between about 1,000-10,000 cP at 37 °C,
`
`or between about 10,000