Drug delivery device with intravesical tolerability
Intravesical devices are provided that are wholly deployable within the bladder of a patient in need of treatment and are well tolerated by the patient. The device may include an elastic body having a retention shape having (i) dimensions that provide intravesical mobility and that prevent voiding of the medical device through the urethra, and (ii) dimensions, buoyancy, or both, that exclude the medical device from entering the orifices of the ureters. The elastic body may exert a maximum acting force less than 1 N when compressed to a shape with a maximum dimension in any dimension of 3 cm. The device may include a drug for controlled release within the bladder, for treatment of the bladder or a regional tissue. Methods of treatment are also provided that include selecting a patient in need of treatment in the bladder where tolerability of the treatment is a primary concern.
1 . An intravesical drug delivery system comprising:
a device body which comprises two integrally formed silicone tubes that are substantially aligned and adjoined along a longitudinal edge, the two tubes respectively defining a drug reservoir lumen and a retention frame lumen, and the drug reservoir lumen having a first end and an opposed second end, wherein the first end and the second end of the drug reservoir lumen are sealed;
a plurality of mini-tablets which are disposed in the drug reservoir lumen and which comprise at least 75% by weight of a drug which comprises gemcitabine or a salt form thereof, with the remainder of the weight of the mini-tablets being one or more excipients;
a retention frame which is disposed in the retention frame lumen and which comprises an elastic wire formed from nitinol,
wherein:
the intravesical drug delivery system is configured to enable the mini-tablets to be solubilized in vivo and to release the gemcitabine, driven by osmotic pressure, through an aperture in a sidewall of the silicone tube defining the drug reservoir lumen,
the device body is elastically deformable between a retention shape and a deployment shape for insertion through a patient's urethra, the retention shape comprising two smaller arches sharing a common larger arch, and
the device body exerts a maximum acting force less than 1 N when the device body is compressed from the retention shape to a shape having a maximum dimension in any direction of 3 cm or less.
2 . The intravesical drug delivery system of claim 1 , wherein the plurality of mini-tablets is between 10 and 100 mini-tablets, and wherein the plurality of mini-tablets are aligned in a row in the drug reservoir lumen.
3 . The intravesical drug delivery system of claim 1 , wherein the device body exerts a maximum acting force less than 1 N when the device is compressed from the retention shape to a shape with a maximum dimension in any direction of 1.5 cm.
4 . The intravesical drug delivery system of claim 1 , wherein the retention shape has a maximum dimension in any direction of 6 cm or less when in an uncompressed state.
5 . The intravesical drug delivery system of claim 1 , wherein the one or more excipients comprise lubricants and binders.
6 . The intravesical drug delivery system of claim 1 , wherein the plurality of mini-tablets comprise at least 80% or more by weight of the drug.
7 . The intravesical drug delivery system of claim 1 , wherein the drug reservoir lumen has a cylindrical shape.
8 . An intravesical drug delivery system comprising:
a device body which comprises two integrally formed polymeric tubes that are substantially aligned and adjoined along a longitudinal edge, the two tubes respectively defining a drug reservoir lumen and a retention frame lumen, and the drug reservoir lumen having a first end and an opposed second end, wherein the first end and the second end of the drug reservoir lumen are sealed;
a plurality of mini-tablets which are disposed in the drug reservoir lumen and which comprise (i) a drug which comprises a kinase inhibitor, and (ii) one or more excipients;
a retention frame which is disposed in the retention frame lumen and which comprises an elastic wire formed from nitinol,
wherein:
the intravesical drug delivery system is configured to enable the mini-tablets to be solubilized in vivo and to release the kinase inhibitor, driven by diffusion through a wall of the polymeric tube defining the drug reservoir lumen,
the device body is elastically deformable between a retention shape and a deployment shape for insertion through a patient's urethra, the retention shape comprising two smaller arches sharing a common larger arch, and
the device body exerts a maximum acting force less than 1 N when the device body is compressed from the retention shape to a shape having a maximum dimension in any direction of 3 cm or less.
9 . The intravesical drug delivery system of claim 8 , wherein the plurality of mini-tablets is between 10 and 100 mini-tablets, and wherein the plurality of mini-tablets are aligned in a row in the drug reservoir lumen.
10 . The intravesical drug delivery system of claim 8 , wherein the device body exerts a maximum acting force less than 1 N when the device is compressed from the retention shape to a shape with a maximum dimension in any direction of 1.5 cm.
11 . The intravesical drug delivery system of claim 8 , wherein the retention shape has a maximum dimension in any direction of 6 cm or less when in an uncompressed state.
12 . The intravesical drug delivery system of claim 8 , wherein the one or more excipients comprise lubricants and binders.
13 . The intravesical drug delivery system of claim 8 , wherein the plurality of mini-tablets comprise at least 50% by weight of the drug.
14 . The intravesical drug delivery system of claim 8 , wherein the drug reservoir lumen has a cylindrical shape.
15 . The intravesical drug delivery system of claim 8 , wherein the polymeric tube defining the drug reservoir lumen is formed of a water permeable, biocompatible elastomeric material.
16 . The intravesical drug delivery system of claim 8 , wherein the drug comprises a fibroblast growth factor receptor-3 (FGFR3)-selective tyrosine kinase inhibitor.
17 . An intravesical drug delivery system comprising:
a device body which comprises two integrally formed polymeric tubes that are substantially aligned and adjoined along a longitudinal edge, the two tubes respectively defining a drug reservoir lumen and a retention frame lumen, and the drug reservoir lumen having a first end and an opposed second end, wherein the first end and the second end of the drug reservoir lumen are sealed;
a plurality of mini-tablets which are disposed in the drug reservoir lumen and which comprise a drug and one or more excipients;
a retention frame which is disposed in the retention frame lumen and which comprises an elastic wire formed from nitinol,
wherein:
the intravesical drug delivery system is configured to enable the mini-tablets to be solubilized in vivo and to release the drug, driven by (i) osmotic pressure through an aperture in a sidewall of the tube defining the drug reservoir lumen, or (ii) diffusion through a wall of the tube defining the drug reservoir lumen,
the device body is elastically deformable between a retention shape and a deployment shape for insertion through a patient's urethra,
the retention shape comprises two smaller arches sharing a common larger arch, wherein upon compression the smaller arches overlap, and subsequently, all three of the arches resist compression of the device body to impede collapse of the retention shape and voiding of the intravesical drug delivery system as the bladder contracts during urination, and
the device body exerts a maximum acting force less than 1 N when the device body is compressed from the retention shape to a shape having a maximum dimension in any direction of 3 cm or less.
18 . The intravesical drug delivery system of claim 17 , wherein the device body exerts a maximum acting force less than 1 N when the device is compressed from the retention shape to a shape with a maximum dimension in any direction of 1.5 cm.
19 . The intravesical drug delivery system of claim 17 , wherein the retention shape has a maximum dimension in any direction of 6 cm or less when in an uncompressed state.
20 . The intravesical drug delivery system of claim 17 , wherein the drug comprises a fibroblast growth factor receptor-3 (FGFR3)-selective tyrosine kinase inhibitor.
21 . The intravesical drug delivery system of claim 17 , wherein the drug comprises gemcitabine or a salt form thereof.