W Taylor & Francis
`
`~
`
`Taylor&.Franc1~Group
`
`Expert Opinion on Drug Delivery
`
`ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20
`
`Dose accuracy and injection force dynamics of a
`novel disposable insulin pen
`
`Alastair Clarke & Geralyn Spollett
`
`To cite this article: Alastair Clarke & Geralyn Spollett (2007) Dose accuracy and injection force
`dynamics of a novel disposable insulin pen, Expert Opinion on Drug Delivery, 4:2, 165-174, DOI:
`10.1517/17425247.4.2.165
`
`To link to this article: https://doi.org/10.1517 /17425247.4.2.165
`
`Ii) Published on line: 05 Mar 2007.
`
`~~ Submit your article to this journal C?
`
`I 1111 Article views: 417
`
`~ Citing articles: 51 View citing articles C?
`
`Full Terms & Conditions of access and use can be found at
`https://www.tandfonline.com/action/journal1nformation?journa1Code=iedd20
`
`Sanofi Exhibit 2144.001
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Technology Evaluation
`
`Exp_ert
`Opinion
`
`Dose accuracy and injection force
`dynamics of a novel disposable
`insulin pen
`
`1.
`
`Introduction
`
`2. The evolution of insulin pens
`
`3. SoloStar pen
`
`4. Technical testing of the SoloStar
`pen
`
`5. Conclusions
`
`6. Expert opinion
`
`For reprint orders, please
`contact:
`Ben.Fisher@informa.com
`
`informa
`
`healthcare
`
`Alastair Clarke t & Geralyn Spollett
`t Sjte Frankfurt Devkes/Devke Desjgn & lndustda]jsaaon, SanofJ-Avenas Deutschland GmbH,
`Frankfurt am Majn, lndustdepark Hoechst, Buj]djng K607, D-65926 Frankfurt am Majn, Germany
`
`SoloStar® (sanofi-aventis) is a new, disposable insulin pen for the administration
`of insulin glargine (Lantus®, sanofi-aventis) or insulin glulisine (Apidra®,
`sanofi-aventis). SoloStar was developed to address a wide range of patient needs
`and demonstrates advancement over previous devices, owing to its appropriate
`combination of ergonomically-tested and mechanically improved features. The
`authors report the results of key investigations carried out by sanofi-aventis as
`part of the SoloStar development plan, including dose accuracy and injection
`force testing. Comparisons between SoloStar and two commonly used pens,
`FlexPen® (Novo Nordisk) and the Humulin®/Humalog® pen (Eli Lilly) establish
`SoloStar as a state of the art pen that is suitable for most patients with diabetes.
`
`Keywords: delivery device, FlexPen®, insulin, insulin delivery, insulin pen, Lilly
`Humu!in®/Humalog® pen, medical device, SoioStar®, Type 1 diabetes , Type 2 diabetes
`
`Expert Opjn_ Drug Delh. (2007) 4(2):165-174
`
`1.
`
`Introduction
`
`In the 60 years following the introduction of insulin for diabetes (in approximately
`1922), the mainstay of insulin administration was the vial and syringe. The first
`insulin pumps appeared in the mid- l 970s, and pump use today is a small, but
`important segment of diabetes care. The first insulin pen (NovoPen® , Novo
`Nordisk) was launched in 1985. Over 20 years later, insulin pens now account for
`just over 50% of insulin use worldwide [!]. Figure IA shows that insulin pens are now
`the predominant form of insulin delivery in many countries, with the notable
`exception of the US , where the vial and syringe is most commonly used by people
`with diabetes. Also noteworthy, Figure 1B shows that the use of disposable pens is
`increasing, driven by the simplicity and ease of use of these devices. Interestingly,
`although the use of insulin pens is relatively low in the US , the vast majority of the
`pens that are used in the US are disposable.
`A study of US patient records has demonstrated that converting from the vial and
`syringe method to insulin pens is associated with improved medication adherence
`and a reduced likelihood of experiencing a hypoglycemic event (odds ratio = 0.50;
`95% CI = 0.37 - 0.68; p < 0.05) [2]. Furthermore, all-cause annual treatment costs
`were reduced by $1590 per patient (from $16,359 to $14 ,769; p < 0.01). Therefore ,
`the use of insulin pens will not only benefit the patient in terms of health and
`lifestyle, but also the healthcare provider by reducing overall costs per patient [2].
`SoloStar® (sanofi-aventis) is a new disposable insulin pen. The presently available
`disposable pens, while addressing many user needs, still leave certain needs unmet.
`With this in mind, sanofi-aventis has developed a new insulin pen device that will
`retain the best features of previous pen devices, and improve or incorporate new
`features in order to meet the needs of a larger audience of pen users. SoloStar
`addresses a wider combination of user needs than previous individual devices,
`including the simplicity of use, the force required to deliver the injection, the length
`to which the pen extends when the dose has been dialed (dial extension) , the
`
`10.1517/17425247.4.2.165 © 2007 lnforma UK Ltd ISSN 1742-5247
`
`165
`
`Sanofi Exhibit 2144.002
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Dose accuracy and injection force dynamics of a novel disposable insulin pen
`
`A
`
`--0-- Worldwide
`
`----- Europe
`
`--D-- USA
`
`---- Japan
`
`---&- ROW
`
`100
`
`rn ?fl. ~- • •
`
`• ■ ■
`
`■ ■
`
`■ ■ ■ ■ ■ ■ ■
`
`----■ ■ ■
`__________.--• • •
`
`■ ■ ■ ■ ■ ■ ■ ■ ■ 94%
`86%
`
`.--
`
`·-· • •
`
`0
`0
`0
`N
`"
`----
`
`0
`0
`N
`----
`st
`
`N
`0
`0
`N
`----
`
`N
`0
`0
`N
`----
`0
`
`(V)
`0
`0
`N
`"
`----
`Period (month/year)
`
`st
`0
`0
`N
`----
`st
`
`LI"\
`0
`0
`N
`----
`
`LI"\
`0
`0
`N
`----
`0
`
`'°
`0
`0
`N
`"
`----
`
`--0-- Worldwide
`
`----- Europe
`
`--D-- USA
`
`---- Japan
`
`---&- ROW
`
`56%
`
`47%
`
`14%
`
`73%
`73%
`
`47%
`46%
`
`28%
`
`90
`
`- 80
`
`C: -
`rn
`GJ
`C. "C
`C: 0
`rn ·- ..c:
`:!::: :i ii
`§ ~ E
`C •- aj
`·- >..c:
`:i.C ...
`rn -c o
`C: GJ =
`a:;
`-
`.::: rn
`::I
`Gi
`rn
`"C a;
`>
`
`(0
`
`B
`
`rn
`C:
`GJ -c.-;fl.
`GJ -
`GJ
`-
`!!l ~ gi
`·- rn c:
`C: 0 GJ
`::I ~ C.
`,§ '6 iii
`~ ..c .s
`::I >, ...
`-c rn
`-
`GJ
`::I
`... rn
`GJ
`
`... > GJ = >
`
`GJ
`"C
`
`70
`
`60
`so
`
`40
`
`30
`
`20
`
`10
`
`0
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`0
`0
`~
`r---
`
`~
`
`0
`0
`~
`st
`
`N
`0
`0
`~
`
`N
`0
`0
`~
`0
`
`C')
`0
`0
`~
`r---
`
`st
`0
`0
`~
`st
`
`LO
`0
`0
`~
`
`LO
`0
`0
`
`~
`
`co
`0
`0
`
`~
`
`Period (month/year)
`
`Figure 1. The increasing use of insulin pen devices to administer insulin worldwide and in selected regions (Europe, USA,
`Japan and rest of the world), between July 2000 and July 2006. A. Insulin units delivered using insulin pen devices as a percentage
`of total insulin use. B. Insulin units delivered using disposable pens as a percentage of total use of insulin pens .
`ROW: Rest of world.
`Data from [1 I.
`
`166
`
`Expert Opin. Drug De/iv. (2007) 4(2)
`
`Sanofi Exhibit 2144.003
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`strength and robustness of the pen, the maximum dose of
`insulin deliverable in one injection, the ease of reading the
`dose display, and the identification of different insulins when
`used in the same type of pen,
`This paper provides an overview of the evolution of pen
`technology, leading to a detailed description of the new
`SoloStar pen, Key tests carried out as part of the sanofi-aventis
`development program are reported, and the relevance of these
`results to patients and healthcare professionals is also discussed,
`
`2. The evolution of insulin pens
`
`The vial and syringe was the predominant route of insulin
`administration for patients with diabetes for over 60 years,
`although in some regions (e.g. the US), the vial and syringe is
`still most commonly used (Figure 1). However, this method of
`administration is associated with numerous disadvantages,
`including fear of injections [3.4], inconvenience, poor dose
`accuracy [5], the lack of social acceptance [6] and inaccuracy
`when self-mixing insulin [7]. These limitations manifest in a
`profound psychological resistance to insulin in both diabetes
`patients and healthcare providers [8.9].
`The advent of insulin pens has gone some way to address
`the unmet needs associated with the vial and syringe method.
`The first pen device, NovoPen, was launched in 1985. It was a
`very simple pen, with a cartridge containing 150 units of
`100 unit/ml short-acting insulin and used a 27-gauge needle.
`The pen delivered 2 units of insulin after a push on the
`button at the top [JO]. Since then, insulin pens have continued
`to evolve , becoming
`increasingly sophisticated devices
`designed to meet more of the needs of the diverse and
`growing diabetes population. The features now offered
`include easy dose dialing and dose correction, large dose
`displays (mechanical and electronic) , low injection force ,
`small, slim and easily portable size, click-in/ click-out cartridge
`change, dose confirmation at the end of injection, higher
`maximum doses, larger cartridge capacity, 1 and ½ unit dial
`increments, and visual and tactile differentiation of pens with
`different insulin.
`In present practice, the Humulin®/Humalog® pen (Eli
`Lilly), hereafter referred to as Lilly Pen, and the FlexPen®
`(Novo Nordisk), are both well accepted and widely used
`disposable
`insulin devices; however, as discussed above,
`devices are continually evolving. The SoloStar pen builds
`upon the strengths of existing devices and combines these
`with additional features , as outlined below. Figure 2 shows a
`photograph of the three pen devices.
`
`3. SoloStar pen
`
`The SoloStar pen is a new medical device for the administration
`of insulin. SoloStar was approved in the EU in 2006. It is a
`disposable insulin pen device, designed for use once or several
`times a day, with a capacity of 300 units (3 ml) of insulin, and is
`available for administration of the basal insulin, insulin glargine
`
`Clarke & Spollett
`
`A
`
`B
`
`C
`
`D
`
`insulin glargine,
`Figure 2. Photographs of SoloStar (A.
`B. insulin glulisine), C. FlexPen and D. Lilly Pen.
`
`(Lantus®, sanofi-aventis) and the prandial insulin, insulin
`glulisine (Apidra®, sanofi-aventis) , for patients with either
`Type 1 or Type 2 diabetes (Figure 3).
`The SoloStar device was effectively developed 'from the
`ground up', taking into consideration human and ergonomic
`factors and limitations, as well as advancements in technology.
`As a result, SoloStar is an intuitive, easy to use device with the
`same common mode of operation as other pens, as well as a
`number of improved features.
`
`Expert Opin. Drug De/iv. (2007) 4(2)
`
`167
`
`Sanofi Exhibit 2144.004
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Dose accuracy and injection force dynamics of a novel disposable insulin pen
`
`A
`
`Pen cap
`
`Pen needle (not included)
`
`Pen body
`
`Protective seal l ~
`~IOut~r u l~~ I u
`
`needle
`cap
`
`Needle
`
`C
`
`B
`
`needle
`cap
`
`Insulin reservoir I
`
`Dosage I I Injection
`selector
`button
`
`Figure 3. The SoloStar pen device showing key components of the pen and needles, and the color schemes used to help
`differentiate between insulin formulations to avoid medication errors.
`
`Human factor input was key in the development of
`SoloStar. Ergonomic tests were carried out to establish what
`features would improve the usability of the device. These tests
`included gathering anthropometric data on the intended user
`populations in order to be able to recommend the most
`suitable basic dimensions of the pen, establishing relevant
`human strength data to identify the maximum operating force
`that is required to push the injection button, and gathering
`information on the optimal dosage display window so that the
`needs of visually impaired users are taken into account.
`These ergonomic findings fed into the development of the
`strength and robustness of SoloStar. In particular, the device
`is strong enough to prevent users from breaking it if they try
`to dial beyond 80 units or selecting more units than that
`which are left in the pen. The findings also influenced the
`desired injection force of SoloStar; due to its highly efficient
`drive mechanism , SoloStar has a significantly lower injection
`force than the FlexPen and the Lilly Pen. Lower injection
`force means that the user can steadily apply pressure to the
`end of the pen, without experiencing hand fatigue or
`diminished grip strength. This is a key feature for users,
`helping them to feel comfortable while delivering their
`injection and confident knowing that it was successfully
`completed. Human factors were also considered when
`developing the dial extension. The dial extension of SoloStar
`has been designed to enable patients to administer even the
`maximum insulin dose with ease. Limited joint mobility of
`the hand, also referred to as cheiroarthropathy, is a significant
`problem for patients with diabetes and may affect daily
`life [l l]. It has been estimated that up to 58% of patients with
`diabetes have limited joint mobility of the hand [12] and
`significantly lower grip strength compared with healthy
`controls [13]. Such impairments are commonly the result of
`connective tissue disorders [14] or diabetic neuropathy [15,16].
`
`To overcome such dexterity problems, a short dial extension
`will
`facilitate easier grip during
`injection and easier
`depression of the injection button.
`Table 1 compares key features of SoloStar, FlexPen and
`Lilly Pen. Lilly Pen has the shortest dial extension for a given
`dose; however, as shown in results in the next section, the
`Lilly pen has a significantly higher injection force. When
`dialing a dose of 60 units , dial extension is 23% lower with
`SoloStar than with FlexPen, and SoloStar requires a lower
`injection force
`than FlexPen. The maximum dose of
`SoloStar is 80 units, which exceeds the maximum dose of
`most other devices, including FlexPen (60 units) and Lilly
`Pen (60 units).
`In order to differentiate the insulin glargine pen from the
`insulin glulisine pen, SoloStar
`is manufactured in two
`different exterior colors: grey for insulin glargine and blue for
`insulin glulisine. This is the first time a disposable insulin pen
`has differentiated the type of insulin contained in the pen
`using a different color pen body. Other disposable devices that
`are used to administer more than one type of insulin have the
`same pen body color, and are differentiated only by the label
`on the pen or by small color details, such as those found on
`the
`injection button. Human
`factors and healthcare
`professional input were taken into account when developing
`the SoloStar. It was suggested that a completely separate color
`would provide additional means of differentiating the two
`insulins and, thus, further minimize any potential to confuse
`the two devices. However, errors in dosing are less likely with
`insulin pens than with the vial and syringe
`[17,101]. In
`addition, the insulin glulisine pen has a differentiating tactile
`feature on the injection button to prevent confusion between
`the pens for patients with visual impairments.
`The injection force and dose accuracy of SoloStar are
`discussed in detail below.
`
`168
`
`Expert Opin. Drug De/iv. (2007) 4(2)
`
`Sanofi Exhibit 2144.005
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Clarke & Spollett
`
`Table 1. The maximum dose, dose increments and dial
`extension (at 60 units) of SoloStar, FlexPen and Lilly Pen.
`
`Maximum dose
`(units)
`
`Dose increments
`(units)
`
`Dial extension at
`60 units (mm)
`
`SoloStar
`
`FlexPen
`
`Lilly Pen
`
`80
`
`60
`
`60
`
`25.5
`
`33
`
`11.2
`
`4. Technical testing of the SoloStar pen
`
`4.1 Applicable design standards
`Like all insulin pens, SoloStar must meet a number of criteria
`specified by the International Organization for Standardization
`(ISO) and, in particular, ISO standards 11608-1, 11608-2 and
`11608-3 for insulin pen devices, needles and cartridge systems,
`respectively. Compliance with these standards is required by the
`relevant medical devices authorities before
`the pen and
`associated accessories can be brought to the market. These
`standards serve to reassure both people with diabetes and
`clinicians that the insulin devices they use are of high quality
`and efficient. For example, when developing an insulin device,
`key features are regulated, including the presence of a scale on
`the cartridge holder and the ability of the device to use standard
`needles. In order to meet the ISO standards, the pens must
`undergo rigorous testing procedures; the dose accuracy test is a
`key ISO test and this is described below.
`
`4.2 Dose accuracy testing
`Dose accuracy is a core aspect of a pen's function. Consistent
`dose accuracy reassures patients that their pen, when used
`properly, will repeatedly deliver the dialed dose, facilitating the
`correct titration of insulin dose without increased risk of hypo(cid:173)
`or hyperglycemia. A more detailed description of the methods
`used for dose accuracy testing is provided elsewhere [18]. In
`brief, SoloStar dose accuracy was tested across a range of
`temperatures (5°C, ambient temperature [18 - 28°C] and
`40°C), after hot and cold storage ( -40°C, + 70°C) and after
`storage in cyclic, atmospheric conditions.
`In accordance with ISO standards, dose accuracy tests were
`performed with SoloStar pens containing insulin glargine at
`doses of 1, 40 and 80 units. A total of 30 pens were used for
`each dose, with two replicates per pen. Pens were also tested
`after a variety of physical events, including dropping from a
`height of 1 m at three different orientations and after
`vibration according to ISO test standards. A different pen
`(always new and unused) was used for each test.
`Table 2 shows results for the dose accuracy of SoloStar pens
`with insulin glargine at 5°C, ambient temperature (18 - 28°C)
`and at 40°C, for dialed doses of 1, 40 and 80 units. These results
`demonstrate that SoloStar is well within the standards for
`accuracy at each dose (1 unit: 0 - 2 units; 40 units; 38 - 42 units;
`
`Table 2. Dose accuracy of the SoloStar pen device
`(insulin glargine) at dialed doses of 1, 40 and 80 units at
`temperatures of 5 °C, ambient temperature (18 - 28 °C)
`and at 40 °C.
`
`Insulin dose (insulin glargine) delivered at
`each dialed dose
`1 unit
`40 units
`
`80 units
`
`Dialed dose
`
`Recommended 0-2
`range according
`to ISO standards
`
`38 - 42
`
`76- 84
`
`Cool
`temperature
`(5 °C)
`
`Ambient
`temperature
`(18 - 28 °C)
`
`1.22 ± 0.78
`
`39.85 ± 0.28 79.75 ± 0.29
`
`1 09 ± 0. 15
`
`39.92 ± 0.34 79.82 ± 0.28
`
`Hot temperature 115 ± 0.11
`(40 °C)
`
`39.87±0.11 79.73±0.14
`
`Results are means ± standard deviation; 30 pens were used for each dose, with
`two replicates per pen.
`ISO: International Organization for Standardization.
`
`80 units; 76 - 84 units). The results of the dose accuracy tests at
`ambient temperature are illustrated in Figure 4.
`results
`the
`All
`tests were
`successfully passed and
`demonstrate that SoloStar pens are very accurate, consistently
`delivering
`the dialed doses of insulin well within the
`specifications of the ISO standard. Therefore, patients using
`this pen to administer insulin glulisine and/or insulin glargine
`can be reassured that the dose dialed is the dose that will be
`administered. Consequently, SoloStar may help to reduce the
`fear of inaccurate delivery as a contributor to hypoglycemia
`that is commonly associated with insulin therapy.
`
`4.3 Injection force testing
`Injection force testing was performed to measure the force
`and force characteristics required to dispense a known volume
`of insulin (40 units) within a fixed time period (4 s). This is
`not part of ISO standards, but was an additional test carried
`out to ensure that the performance of the devices meet the
`needs of the user.
`
`insulin
`
`For this test, the following pens were tested;
`• SoloStar pens containing
`insulin glargine or
`glulisine (20 of each insulin type)
`• FlexPens containing insulin detemir (Levemir®, Novo
`Nordisk), insulin aspart (NovoLog®, Novo Nordisk) or
`Neutral Protamine Hagedorn (NPH) insulin (Insulatard®,
`Novo Nordisk) (20 of each insulin type)
`• Lilly Pens containing NPH insulin (Humulin N®, Eli
`Lilly) or insulin lispro (HumaLog®, Eli Lilly) (20 of each
`insulin type)
`
`For testing, all pens were fitted with Becton Dickinson
`microfine needles (0.25 mm [31 G] x 8 mm). The same needle
`
`Expert Opin. Drug De/iv. (2007) 4(2)
`
`169
`
`Sanofi Exhibit 2144.006
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Dose accuracy and injection force dynamics of a novel disposable insulin pen
`
`Upper limit (84 units) according to DIN EN ISO 11608-1
`84 - - -+ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`82
`
`78
`
`75 -1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`Lower limit (76 units) according to DIN EN ISO 11608-1
`
`0
`
`44
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Upper limit (42 units) according to DIN EN ISO 11608-1
`42 - - -+ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`40 •••• • •• ■ •• •••••••••• ■ ■ ■ ••• ••• •• • ••• ■ ■• ■ ••
`■
`• ■ ••
`■ ■ ■
`••• • ■ •• ■
`••
`•
`
`38 - - -+ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`Lower limit (38 units) according to DIN EN ISO 11608-1
`
`.l!l
`'i:
`2-
`"C
`Q)
`
`-~ cii
`
`"C
`Q)
`1/)
`0
`"C
`.5
`'S
`1/)
`.5
`
`36
`
`0
`
`3
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Upper limit (2 units) according to DIN EN ISO 11608-1
`2 -+ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`............................................................
`
`0 -+-----L-o_w_e_r-li-m-it~O-u-n-it~s-a_c_c_o_rd-in--to_D_IN_E_N_l~S~0-1_1_6_0_8_-1 ______ _
`
`0
`
`10
`
`20
`
`30
`Dose number
`
`40
`
`50
`
`60
`
`Figure 4. The accuracy of the SoloStar pen at ambient conditions (18 - 28 °C) to deliver fixed doses of 1, 40 and 80 units. The
`upper and lower limits, as defined by the Deutsche lnstitut fur Normung, English version of the International Organization for
`Standardization (ISO) standard, 71608-1, are indicated for each dose.
`DIN: Deutsche lnstitut fur Normung; EN: English version.
`
`type was used for all pens to ensure a fair comparison.
`Micro-Fine™ needles are recommended by Becton Dickinson
`for use with SoloStar, FlexPen and Lilly Pens. Studies with the
`FlexPen were repeated using NovoFine® (Novo Nordisk) needles
`(0.25 mm [31 G] x 6 mm). With NovoFine needles,
`the
`injection force was consistently greater than with Becton
`Dickinson needles of the same gauge (31 G) for each insulin type
`(data not shown). Although Novo Nordisk only recommends
`Novofine needles for use with the Flexpen, to avoid such a
`disadvantage for FlexPen, results are reported for all pens using
`Becton Dickinson needles (0.25 mm [31 G] x 8 mm).
`
`force
`into a Zwick Z2.5
`inserted
`Each pen was
`measurement machine with a 250 N load cell, which was
`programmed to drive in the dispense direction at a velocity
`that would cause the pen device to dispense 10 units/s. It is
`common with disposable pens that multiple safety shots are
`required before insulin appears at the end of the needle.
`Thus, to ensure that each pen had been fully primed, each
`new pen was set to deliver a 10-unit priming dose. Each pen
`was then set to deliver three subsequent doses of 40 units
`each. The load cell was reset to zero before commencing
`each test. The force was measured for the duration of each
`
`170
`
`Expert Opin. Drug De/iv. (2007) 4(2)
`
`Sanofi Exhibit 2144.007
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`18
`
`16
`
`14
`
`12
`
`Clarke & Spollett
`
`·-- - - - - - 2
`l+<+•t~ - - 4
`II- U·i H l + -- - 3
`
`--'-'~ - H-- - 5
`
`-
`
`~ 10
`
`GJ
`tJ
`0
`u..
`
`8
`
`6
`
`4
`
`2
`
`0
`
`0
`
`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
`
`7.5
`
`Time (s)
`
`Figure 5. A typical force plot showing the force (N) required for one priming dose (10 units) and one 40-unit dose. The force
`characteristics are represented as horizontal lines. 1. Peak priming force (maximum force measured during the priming dose). 2. Peak
`dose force (maximum force measured during any of the three 40-unit doses). 3. Mean plateau dose force (mean force measured during
`the 2.5 s plateau period of each of the three 40 unit doses). 4. Mean peak plateau dose force (mean of the peak dose force measured
`during the plateau period). 5. Mean dose force for the total dose (mean dose force taken for all three 40 unit doses).
`The grey shaded box shows the 2. 5-s sample that was used for the calculation of the plateau forces for each pen, to eliminate any biasing from the acceleration and/or
`deceleration of the force machine.
`
`force characteristics were calculated as
`the
`dispense;
`demonstrated in Figure 5.
`Table 3 shows a comparison of injection forces for SoloStar,
`FlexPen and Lilly Pen. SoloStar with insulin glulisine has a mean
`total injection force that is > 40% lower than FlexPen with
`insulin aspart, while SoloStar with insulin glargine has a mean
`total injection force that is > 30% lower with FlexPen containing
`insulin detemir. Furthermore, SoloStar with either insulin
`glulisine or insulin glargine has a mean injection force that is less
`than half that of the Lilly Pen containing either insulin lispro or
`NPH insulin.
`Figure 6 shows the force profile for a single dose of 40 units
`delivered in 4 s for SoloStar with insulin glulisine, FlexPen
`with insulin aspart and Lilly Pen with insulin lispro. The force
`profiles shown are representative of each set of results. The
`graph shows that the injection force with SoloStar is the
`lowest of the three pens tested.
`Figure 6 also shows that SoloStar has the smoothest
`injection force profile (the smallest force difference between
`peaks and troughs during the injection), especially when
`compared with FlexPen, which has the highest peak-to-trough
`variation (one peak per unit delivered), with the result that
`
`the injection with SoloStar will feel more soft and gentle, as
`well as easier to use. The smoother injection force with
`SoloStar is primarily due to the smaller force difference
`between the peaks and troughs during injection. Of note is
`the finding that the injection force was low, despite testing
`with a very fine needle gauge; the smaller the pen needle
`gauge, the greater the force needed to complete the injection.
`These results show that SoloStar requires low forces in
`order to inject a dose of insulin. Therefore, patients will find
`it easy to inject insulin with SoloStar.
`
`s. Conclusions
`
`From a patients' perspective , the simplicity of use of a specific
`device is an important factor when deciding on which pen to
`use on a day-to-day basis; SoloStar was designed with this
`factor at the forefront of the design process. From a clinical
`perspective, the accuracy of the dose delivered is a key factor
`when selecting an insulin delivery system. Lack of accuracy
`may increase risk of hypo- or hyperglycemia. The results
`presented here for SoloStar demonstrate that, used correctly,
`SoloStar will accurately administer the dialed dose of insulin,
`
`Expert Opin. Drug De/iv. (2007) 4(2)
`
`171
`
`Sanofi Exhibit 2144.008
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Dose accuracy and injection force dynamics of a novel disposable insulin pen
`
`Table 3. A comparison of injection forces between SoloStar, FlexPen and Lilly Pen.
`
`Pen
`
`Insulin
`
`Mean force for Mean plateau
`total dose (N)
`dose force (N)
`
`Peak dose force Mean peak
`(N)
`plateau dose
`force (N)
`
`Peak priming
`force (N)
`
`SoloStar
`
`FlexPen
`
`Lilly Pen
`
`Insulin glulisine
`
`Insulin glargine
`
`Insulin detemir
`
`Insulin aspart
`
`NPH insulin
`
`NPH insulin
`
`Insulin lispro
`
`70.3
`
`11.3
`
`16.3
`
`17.2
`
`17.7
`
`24.4
`
`25.3
`
`12.0
`
`73.4
`
`18.3
`
`19.2
`
`19.9
`
`28.0
`
`28.8
`
`14.2
`
`15.2
`
`23.9
`
`25.5
`
`25.5
`
`30.7
`
`32.9
`
`12.6
`
`13.9
`
`21 .2
`
`22.7
`
`22.8
`
`28.3
`
`29.2
`
`18.7
`
`17.4
`
`22.6
`
`23.8
`
`21 .7
`
`24.4
`
`26.6
`
`Each pen was set to deliver one 10-unit dose to prime the pen, and then to deliver three subsequent doses of 40 units each. The force characteristics were calculated
`as shown in Figure 5.
`
`allowing reliable dose adjustment and minimizing the risk of
`hypo- or hyperglycemia arising from inaccuracies in dose
`delivery. This may enhance patient adherence to insulin
`therapy and reduce diabetes-related
`treatment costs, as
`demonstrated with other pen devices [2].
`The injection force and profile data presented show that
`SoloStar has significantly improved injection force characteristics
`compared with FlexPen and Lilly Pen. This lower injection force,
`smoother injection profile and shorter dial extension, compared
`with FlexPen, mean that patients can inject their insulin more
`easily. Such mechanical characteristics are of significant clinical
`benefit for the large number of people who have diabetes with
`impaired hand function [13-16], who may otherwise have limited
`ability to inject insulin themselves.
`An ideal pen needs to offer an appropriate combination of
`achievement against multiple features. For example, despite
`the shorter dial extension with the Lilly Pen, the force required
`to inject a dose of insulin is greater. With SoloStar, the
`achievements on injection force and dial extension are coupled
`with many other needed features, including simplicity of
`operation, a higher maximum dose (80 units) and different
`colors for basal and meal time insulin (a first for a disposable
`pen). This combination of design features means that the
`SoloStar pen is suitable for use by most people with Type 1 or
`Type 2 diabetes.
`
`6. Expert opinion
`
`According to the consensus statement from the American
`Diabetes Association and the European Association for the
`Study of Diabetes on management of hyperglycemia in Type
`2 diabetes, a haemoglobin A1c level ~ 7% should serve as a call
`to initiate or change therapy. As diabetes progresses, it
`becomes necessary to introduce insulin therapy to achieve or
`maintain adequate diabetes control.
`As the transition to insulin from oral therapy requires
`intensifying self-care management, it is often a time of stress
`for the patient. Not only does the patient need to consider
`
`how insulin use will affect lifestyle therapies, such as nutrition
`and physical activity, the patient also needs to learn how to
`successfully incorporate a therapy that must be self-injected.
`Pen devices have reduced some of the anxiety associated with
`initiating insulin therapy for many patients, due to their ease
`of use and the fact that they complement the flexibility of
`modern lifestyles by being much more portable than a vial
`and syringe. In most circumstances, patients prefer pen
`devices for the delivery of insulin, and many diabetes patients
`who have been using vial and syringes will request that insulin
`be prescribed
`in pens, citing simplicity, accuracy and
`flexibility as the key reasons for the request. If patients feel
`that the pen is easier to use and more socially acceptable, the
`likelihood of adherence to insulin therapy is increased.
`Patients starting on insulin, such as Type 2 diabetes patients
`who are prescribed oral agents and one injection of basal insulin
`per day,
`find
`that
`the pen device can be more easily
`incorporated into their daily routine. The improvements made
`in the SoloStar device - simplicity of use, reduced injection
`force and high dose capability - make this a desirable device for
`first-time insulin users.
`For patients with Type 1 diabetes or for those with Type 2
`diabetes with significant ~-cell deficit, the present trend is for
`intensive insulin management with a basal insulin, such as insulin
`glargine, plus premeal rapid-acting insulin. This system of
`subcutaneous insulin replacement mimics the body's physiologic
`insulin secretory pattern and results in better glucose control.
`However, in order to successfully adopt this insulin regimen, the
`patient must be willing to give insulin prior to the ingestion of
`any carbohydrate-containing meal or snack. Many patients will
`need to inject insulin 5- to 7-times per day; for these patients,
`insulin pens make intensive therapy
`'liveable'. SoloStar is
`available in two distinct color schemes for patients who use both
`basal and rapid-acting, bolus insulin (Figure 3), to help prevent
`confusing the pens containing the different insulins.
`During the next 5 - 10 years, the use of insulin and pen
`devices for insulin delivery will continue to increase in settings
`outside of the diabetes specialty offices. As the number of patients
`
`172
`
`Expert Opin. Drug De/iv. (2007) 4(2)
`
`Sanofi Exhibit 2144.009
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`35
`
`30
`
`25
`
`GJ
`tJ
`
`~
`0 u..
`
`20
`
`15
`
`10
`
`5
`
`Clarke & Spollett
`
`SoloStar, insulin glulisine
`FlexPen, insulin aspart
`Lilly Pen, insulin lispro
`
`-
`
`0-+-----------------------------------------~
`
`0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0
`Time (s)
`
`Figure 6. The force required to inject 40 units of insulin to be delivered in 4 s for a representative pen of SoloStar with
`insulin glulisine, FlexPen with insulin aspart and Lilly Pen with insulin lispro.
`
`trea